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Sample records for preclinical toxicology studies

  1. Preclinical Studies on the Pharmacokinetics, Safety and Toxicology of Oxfendazole: Toward First in Human Studies

    PubMed Central

    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 two-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 WBC levels, a class effect of benzimidazole anthelminthics, returned to normal during the recovery period. The NOAEL was determined to be >5 but < 25 mg/kg/d and the MTD 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 seven 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

  2. 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

  3. 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

  4. Metabolomics in Toxicology and Preclinical Research

    PubMed Central

    Ramirez, Tzutzuy; Daneshian, Mardas; Kamp, Hennicke; Bois, Frederic Y.; Clench, Malcolm R.; Coen, Muireann; Donley, Beth; Fischer, Steven M.; Ekman, Drew R.; Fabian, Eric; Guillou, Claude; Heuer, Joachim; Hogberg, Helena T.; Jungnickel, Harald; Keun, Hector C.; Krennrich, Gerhard; Krupp, Eckart; Luch, Andreas; Noor, Fozia; Peter, Erik; Riefke, Bjoern; Seymour, Mark; Skinner, Nigel; Smirnova, Lena; Verheij, Elwin; Wagner, Silvia; Hartung, Thomas; van Ravenzwaay, Bennard; Leist, Marcel

    2013-01-01

    Summary Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways. It allows rapid identification of the potential targets of a hazardous compound. It can give information on target organs and often can help to improve our understanding regarding the mode-of-action of a given compound. Such insights aid the discovery of biomarkers that either indicate pathophysiological conditions or help the monitoring of the efficacy of drug therapies. The first toxicological applications of metabolomics were for mechanistic research, but different ways to use the technology in a regulatory context are being explored. Ideally, further progress in that direction will position the metabolomics approach to address the challenges of toxicology of the 21st century. To address these issues, scientists from academia, industry, and regulatory bodies came together in a workshop to discuss the current status of applied metabolomics and its potential in the safety assessment of compounds. We report here on the conclusions of three working groups addressing questions regarding 1) metabolomics for in vitro studies 2) the appropriate use of metabolomics in systems toxicology, and 3) use of metabolomics in a regulatory context. PMID:23665807

  5. Recent developments in preclinical toxicological pathology

    SciTech Connect

    Finch, John M. . E-mail: john.finch@eur.crl

    2005-09-01

    In the late nineteenth century, microscopists developed a quaint method for examining the fine structure of biological specimens: paraffin embedding and staining with hematoxylin and eosin. This ancient technology is here to stay for the foreseeable future, because it can and does reveal the truth about biological processes. However, the role of pathology is developing with ever greater worldwide interaction between pathologists, and better communication and agreeing of international standards. Furthermore, recent techniques including immunohistochemistry, electron microscopy and image analysis complement the traditional tried and tested tools. There is also in toxicologic pathology a willingness to use pathology methods and skills in new contexts, drug discovery in particular. But even in these days of genetic modification, proteomics and high throughput screening, pathologists continue to rely on dyes extracted from a Central American logwood used in Mexico before the Spanish invasion in 1520.

  6. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    SciTech Connect

    Qi, Yanxin; Guo, Huanhuan; Hu, Ningning; He, Dongyun; Zhang, Shi; Chu, Yunjie; Huang, Yubin; Li, Xiao; Sun, LiLi; Jin, Ningyi

    2014-10-15

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10{sup 10} VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10{sup 10} VP/kg) and beagles (2.5 × 10{sup 9} VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10{sup 10} VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10{sup 8} VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad-hTERT-E1a-Apoptin.

  7. Preclinical safety, toxicology, and biodistribution study of adenoviral gene therapy with sVEGFR-2 and sVEGFR-3 combined with chemotherapy for ovarian cancer.

    PubMed

    Tuppurainen, Laura; Sallinen, Hanna; Kokki, Emmi; Koponen, Jonna; Anttila, Maarit; Pulkkinen, Kati; Heikura, Tommi; Toivanen, Pyry; Hmlinen, Kirsi; Kosma, Veli-Matti; Heinonen, Seppo; Alitalo, Kari; Yl-Herttuala, Seppo

    2013-03-01

    Abstract Antiangiogenic and antilymphangiogenic gene therapy with soluble vascular endothelial growth factor receptor-2 (VEGFR-2) and soluble VEGFR-3 in combination with chemotherapy is a potential new treatment for ovarian carcinoma. We evaluated the safety, toxicology, and biodistribution of intravenous AdsVEGFR-2 and AdsVEGFR-3 combined with chemotherapy in healthy rats (n=90) before entering a clinical setting. The study groups were: AdLacZ and AdLacZ with chemotherapy as control groups, low dose AdsVEGFR-2 and AdsVEGFR-3, high dose AdsVEGFR-2 and AdsVEGFR-3, combination of low dose AdsVEGFR-2 and AdsVEGFR-3 with chemotherapy, combination of high dose AdsVEGFR-2 and AdVEGFR-3 with chemotherapy, and chemotherapy only. The follow-up time was 4 weeks. Safety and toxicology were assessed by monitoring the clinical status of the animals and by histological, hematological, and clinical chemistry parameters. For the biodistribution studies, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used. Low dose (210(10) vp) AdsVEGFR-2 and AdsVEGFR-3 gene therapy was well tolerated, even when gene therapy was combined with chemotherapy. Notably, only transient elevation of liver enzymes and mild regenerative changes were seen in liver after the gene transfer in the groups that received high doses (210(11) vp) of AdsVEGFR-2 and AdsVEGFR-3 with or without chemotherapy. No life-threatening adverse effects were noticed in any of the treatment groups. The highest protein concentration of soluble VEGFR-2 (sVEGFR-2) in circulation was seen 1 week after the gene transfer. The combination of chemotherapy to gene therapy seemed to prolong the time of detectable transgene protein at least 1 week in the circulation. The expression of AdsVEGFR-2 and AdsVEGFR-3 transgenes was mainly seen in the liver and spleen as detected by qRT-PCR. According to these results, AdsVEGFR-2 and AdsVEGFR-3 gene therapy combined with chemotherapy is safe and can be brought to clinical testing in ovarian cancer patients. PMID:23692381

  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. Toxicologic studies of SRC materials

    SciTech Connect

    Mahlum, D.D.; Pelroy, R.A.; Drucker, H.; Wilson, B.W.; Massey, M.J.; Schmalzer, D.K.

    1980-02-01

    Investigations on the toxicity of SRC materials are reported. Toxicological studies include: microbial mutageneis (Ames test); in vitro mammalian cell toxicity and transformation assays; epidermal carcinogenesis (skin painting); acute and subchronic oral toxicity; developmental toxicity; dominant lethal assays; inhalation toxicity; and dosimetry and metabolism. The materials tested include: SRC-I process solvent, wash solvent, and light oil; SRC-II heavy distillate, middle distillate, and light distillate; shale oil; crude petroleum; and pure carcinogens. (DC)

  10. Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets

    PubMed Central

    Martin, Pauline L; Bugelski, Peter J

    2012-01-01

    Monoclonal antibodies (mAbs) and fusion proteins directed towards soluble targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 14 currently approved mAbs and fusion proteins targeted to soluble targets. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency Scientific Discussions and United States Food and Drug Administration Pharmacology/Toxicology Reviews and package inserts (United States Prescribing Information). Data on the following approved biopharmaceuticals were included: adalimumab, anakinra, bevacizumab, canakinumab, certolizumab pegol, denosumab, eculizumab, etanercept, golimumab, infliximab, omalizumab, ranibizumab, rilonacept and ustekinumab. Some related biopharmaceuticals in late-stage development were also included for comparison. Good concordance with human pharmacodynamics was found for both non-human primates (NHPs) receiving the human biopharmaceutical and mice receiving rodent homologues (surrogates). In contrast, there was limited concordance for human adverse effects in genetically deficient mice, mice receiving surrogates or NHPs receiving the human pharmaceutical. In summary, the results of this survey show that although both mice and NHPs have good predictive value for human pharmacodynamics, neither species have good predictive value for human adverse effects. No evidence that NHPs have superior predictive value was found. PMID:22168335

  11. Toxicology Studies for Inhaled and Nasal Delivery.

    PubMed

    Wolff, R K

    2015-08-01

    This review examines issues related to the toxicological testing of pharmaceuticals delivered by the inhalation or nasal route. The purpose of the toxicology studies is to conduct studies in animals that will aid the assessment of the safety of these agents delivered to patients. Inhalation toxicology studies present some unique issues because the dosing method differs from more standard administration methods such as oral or injection administration. Also, dose determination issues are more complex, particularly for inhalation administration since it is often difficult to determine the amount of material delivered to the lung both for patients and in animal toxicology studies. PMID:25915006

  12. Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

    PubMed

    Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C

    2015-10-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

  13. 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. PMID:26069576

  14. Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer

    PubMed Central

    Freytag, Svend O; Zhang, Yingshu; Siddiqui, Farzan

    2015-01-01

    The purpose of this study was to examine the toxicity of combining oncolytic adenovirus-mediated cytotoxic and interleukin 12 (IL-12) gene therapy in a preclinical model to support future phase 1 trials. One hundred and twenty C57BL/6 male mice received an intraprostatic injection of saline (n = 24) or an oncolytic adenovirus (Ad5-yCD/mutTKSR39rep-mIL12) expressing two suicide genes and mouse IL-12 (n = 96). The adenovirus was administered at three dose levels (1.3 106, 1.3 107, 1.3 108 vp/kg) followed by 2 weeks of 5-flurocytosine (5-FC) and gancliclovir (GCV) prodrug therapy. There were no premature deaths. Daily observations of animals did not reveal any obvious clinical problems throughout the 78-day in-life phase of the study. Animals in the highest adenovirus dose group exhibited lymphopenia and transaminitis on day 3, both of which resolved by day 17. Except for mild inflammation of the prostate and seminal vesicles, histopathology of major organs was largely unremarkable. IL-12 and interferon-gamma levels in prostate and serum peaked on day 3 and were either undetectable or returned to baseline levels by day 17. No adenoviral DNA was detected in serum in any group at any time point. The results demonstrate that local administration of an oncolytic adenovirus expressing two suicide genes and IL-12 is well tolerated and support moving this investigational approach into human trials. PMID:26767191

  15. Pre-clinical toxicology of nitazoxanide--a new antiparasitic compound.

    PubMed

    Murphy, J R; Friedmann, J C

    1985-04-01

    The acute and subchronic toxicological effects of nitazoxanide were investigated at levels near and in excess of the therapeutic dose in rats, mice, dogs and cats. Single oral gavage doses of 0.625-10 g per kg body weight were administered to rats and mice. Single oral doses of 1-10 g per kg body weight were administered in capsules to dogs and cats. Acute oral LD50 values were greater than 10 g kg-1 in rats, dogs and cats, and 1.4 g kg-1 in mice. Systemic toxicity was evaluated in a repeated dose study in rats at doses of 50, 150 and 450 mg per kg per day for 14 weeks. The highest dose group exhibited intense salivation, increased liver and spleen weight, and decreased thymus weights. Variances between control and treated organ weights were not confirmed by histopathological evaluation. Nitazoxanide was negative when tested in the Ames Salmonella assay using five tester strains with and without metabolic activation at levels from 1 to 100 mg per plate. The drug was also shown to be non-irritating in a test for eye irritation potential. PMID:3889119

  16. Demands on scientific studies in clinical toxicology.

    PubMed

    Maurer, Hans H

    2007-01-17

    Scientific case studies in clinical toxicology on single cases or series of similar cases should document sufficient information on the clinical methodology and observations, the medical laboratory methodology and results, the toxicological analyses methodology and results, the source of used reference values for drug/poison concentrations and kinetics with critical discussion of such values, a description and discussion of the toxicodynamic, the toxicological and the kinetic properties of the detected drugs and/or poisons. The data management, statistical analysis and finally the clinical and/or analytical outcomes must also be described and discussed in correlation to already published data. Statistical methods used for evaluation of clinical as well as for analytical data should be described in detail. When possible, quantitative findings should be presented with appropriate indicators of measurement error or uncertainty. Requirements for such studies are discussed. PMID:16806769

  17. An Indexing Coverage Study of Toxicological Literature

    ERIC Educational Resources Information Center

    Montgomery, Ruth Reinke

    1973-01-01

    The goal of this study was an appraisal of indexing coverage for the interdisciplinary field of toxicology. Information of research significance was limited to primary literature, defined as published documents containing original data from experimental work or case studies. (6 references) (Author/NH)

  18. Oncolysis by paramyxoviruses: preclinical and clinical studies

    PubMed Central

    Matveeva, Olga V; Guo, Zong S; Senin, Vyacheslav M; Senina, Anna V; Shabalina, Svetlana A; Chumakov, Peter M

    2015-01-01

    Preclinical studies demonstrate that a broad spectrum of human malignant cells can be killed by oncolytic paramyxoviruses, which include cells of ecto-, endo-, and mesodermal origin. In clinical trials, significant reduction in size or even complete elimination of primary tumors and established metastases are reported. Different routes of viral administration (intratumoral, intravenous, intradermal, intraperitoneal, or intrapleural), and single- versus multiple-dose administration schemes have been explored. The reported side effects are grade 1 and 2, with the most common among them being mild fever. Some advantages in using para-myxoviruses as oncolytic agents versus representatives of other viral families exist. The cytoplasmic replication results in a lack of host genome integration and recombination, which makes paramyxoviruses safer and more attractive candidates for widely used therapeutic oncolysis in comparison with retroviruses or some DNA viruses. The list of oncolytic paramyxovirus representatives includes attenuated measles virus (MV), mumps virus (MuV), low pathogenic Newcastle disease (NDV), and Sendai (SeV) viruses. Metastatic cancer cells frequently overexpress on their surface some molecules that can serve as receptors for MV, MuV, NDV, and SeV. This promotes specific viral attachment to the malignant cell, which is frequently followed by specific viral replication. The paramyxoviruses are capable of inducing efficient syncytium-mediated lyses of cancer cells and elicit strong immunomodulatory effects that dramatically enforce anticancer immune surveillance. In general, preclinical studies and phase 1–3 clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches. PMID:26640815

  19. Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets

    PubMed Central

    Bugelski, Peter J; Martin, Pauline L

    2012-01-01

    Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency ‘Scientific Discussions’; and the US Food and Drug Administration ‘Pharmacology/Toxicology Reviews’ and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found. PMID:22168282

  20. TOXICOLOGICAL STUDIES OF SMOKE OBSCURANTS

    EPA Science Inventory

    An exposure facility was designed and constructed to support health effect studies of inhaled smoke obscurants generated from light lubricating oils. Concentrations are monitored using gravimetric filter sample analysis and continuous RAM-1 aerosol monitors. Chemical consistency ...

  1. Dissolution DNP for in vivo preclinical studies.

    PubMed

    Comment, Arnaud

    2016-03-01

    The tremendous polarization enhancement afforded by dissolution dynamic nuclear polarization (DNP) can be taken advantage of to perform preclinical in vivo molecular and metabolic imaging. Following the injection of molecules that are hyperpolarized via dissolution DNP, real-time measurements of their biodistribution and metabolic conversion can be recorded. This technology therefore provides a unique and invaluable tool for probing cellular metabolism in vivo in animal models in a noninvasive manner. It gives the opportunity to follow and evaluate disease progression and treatment response without requiring ex vivo destructive tissue assays. Although its considerable potential has now been widely recognized, hyperpolarized magnetic resonance by dissolution DNP remains a challenging method to implement for routine in vivo preclinical measurements. The aim of this article is to provide an overview of the current state-of-the-art technology for preclinical applications and the challenges that need to be addressed to promote it and allow its wider dissemination in the near future. PMID:26920829

  2. Dissolution DNP for in vivo preclinical studies

    NASA Astrophysics Data System (ADS)

    Comment, Arnaud

    2016-03-01

    The tremendous polarization enhancement afforded by dissolution dynamic nuclear polarization (DNP) can be taken advantage of to perform preclinical in vivo molecular and metabolic imaging. Following the injection of molecules that are hyperpolarized via dissolution DNP, real-time measurements of their biodistribution and metabolic conversion can be recorded. This technology therefore provides a unique and invaluable tool for probing cellular metabolism in vivo in animal models in a noninvasive manner. It gives the opportunity to follow and evaluate disease progression and treatment response without requiring ex vivo destructive tissue assays. Although its considerable potential has now been widely recognized, hyperpolarized magnetic resonance by dissolution DNP remains a challenging method to implement for routine in vivo preclinical measurements. The aim of this article is to provide an overview of the current state-of-the-art technology for preclinical applications and the challenges that need to be addressed to promote it and allow its wider dissemination in the near future.

  3. Pharmacognostic and acute toxicological evaluation of Scaptotrigona aff. postica propolis extract in pre-clinical assays.

    PubMed

    Arajo, M J A M; Mattar, N S; Reis, A S; Serra, I C P B; Fialho, E M S; Assuno, A K M; Dutra, R P; Nogueira, A M C; Librio, S A; Guerra, R N M; Lopes, A S; Ribeiro, M N S; Nascimento, F R F

    2011-07-01

    The propolis of Scaptotrigona aff. postica is popularly used in Maranho State, Brazil, for treating wounds and respiratory illnesses. Nevertheless, little is known about the chemical composition of this propolis and the adverse effects of its use. Hence, this study is a pharmacognostic characterisation of the propolis hydroalcoholic extract (PHE) from S. aff. postica. The methodology consisted of an evaluation of the sensory and chemical parameters. Chemical analysis of PHE indicated high concentrations of phenolic and triterpens substances, and the absence of steroids. Additionally, we evaluated the acute toxicity of propolis using 48 Swiss male and female mice. The animals received single doses of PHE (1000, 2000 or 4000 mg kg?) orally and were observed for 14 days. After this period, the mice were sacrificed and the blood was used for biochemical and haematological evaluation. PHE did not induce any death, and the acute treatment significantly reduced serum concentrations of alanine aminotransferase and alkaline phosphatase. The resultant data indicate that PHE from S. aff. postica has low toxicity when used orally, even in high doses. PMID:21500093

  4. The failure to detect drug-induced sensory loss in standard preclinical studies.

    PubMed

    Gauvin, David V; Abernathy, Matthew M; Tapp, Rachel L; Yoder, Joshua D; Dalton, Jill A; Baird, Theodore J

    2015-01-01

    Over the years a number of drugs have been approved for human use with limited signs of toxicity noted during preclinical risk assessment study designs but then show adverse events in compliant patients taking the drugs as prescribed within the first few years on the market. Loss or impairments in sensory systems, such as hearing, vision, taste, and smell have been reported to the FDA or have been described in the literature appearing in peer-reviewed scientific journals within the first five years of widespread use. This review highlights the interactive cross-modal compensation within sensory systems that can occur that reduces the likelihood of identifying these losses in less sentient animals used in standard preclinical toxicology and safety protocols. We provide some historical and experimental evidence to substantiate these sensory effects in and highlight the critical importance of detailed training of technicians on basic ethological, species-specific behaviors of all purpose-bred laboratory animals used in these study designs. We propose that the time, effort and cost of training technicians to be better able to identify and document very subtle changes in behavior will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced sensory loss within current standard regulatory preclinical research protocols. PMID:26045062

  5. Analgesia in Amphibians: Preclinical Studies and Clinical Applications

    PubMed Central

    Stevens, Craig W.

    2010-01-01

    SYNOPSIS Preclinical studies of analgesia in amphibians or recommendations for clinical use of analgesics in amphibian species are extremely limited. This article briefly reviews the issues surrounding the use of analgesics in amphibians starting with common definitions of pain and analgesia when applied to non-human animals. Nociceptive and endogenous opioid systems in amphibians are reviewed and results of preclinical research on opioid and non-opioid analgesics summarized. Recommended opioid and non-opioid analgesics are summarized and practical recommendations made for their clinical use. PMID:21074701

  6. Bridging Translation by Improving Preclinical Study Design in AKI.

    PubMed

    de Caestecker, Mark; Humphreys, Ben D; Liu, Kathleen D; Fissell, William H; Cerda, Jorge; Nolin, Thomas D; Askenazi, David; Mour, Girish; Harrell, Frank E; Pullen, Nick; Okusa, Mark D; Faubel, Sarah

    2015-12-01

    Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development. PMID:26538634

  7. Ushering in the study and treatment of preclinical Alzheimer disease.

    PubMed

    Langbaum, Jessica B; Fleisher, Adam S; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T; Caselli, Richard J; Tariot, Pierre N; Reiman, Eric M

    2013-07-01

    Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

  8. USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

    PubMed Central

    Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

    2014-01-01

    Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

  9. Preclinical in vivo ADME studies in drug development: a critical review.

    TOXLINE Toxicology Bibliographic Information

    Pellegatti M

    2012-02-01

    INTRODUCTION: The last two decades have brought many fundamental changes to the drug development process. One such change is the importance of preclinical pharmacokinetics, which has become an essential part of early drug discovery. Furthermore, bioanalytical methods have become more sensitive and the identification and quantitation of metabolites can now be carried out on limited amount of biological material. There has also been a change in regulatory expectations, which are now particularly focused on the safety of human metabolites.AREAS COVERED: The focus of this paper is on some 'traditional' in vivo ADME studies: excretion balance, metabolic profile and WBA in the toxicological species. These studies, performed with radiolabeled material, have a long history: and are a regular presence in submission dossiers. This paper reviews their value in the perspective of the contemporary drug development process.EXPERT OPINION: These experiments may sometimes still be relevant to explain toxicological findings or for other special purposes but should not be considered required pieces of the registration dossiers. An appropriate investigation of samples coming from safety evaluation and human Phase I studies and the knowledge generated during the lead optimization phase provide, in most instances, all the DMPK information needed to take decisions in the drug development process.

  10. Genetically Engineered Humanized Mouse Models for Preclinical Antibody Studies

    PubMed Central

    Proetzel, Gabriele; Wiles, Michael V.; Roopenian, Derry C.

    2015-01-01

    The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies. PMID:24150980

  11. 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

  12. Toxicity of L-DOPA coated iron oxide nanoparticles in intraperitoneal delivery setting - preliminary preclinical study.

    PubMed

    Com?nescu, Maria Victoria; Mocanu, Mihaela Andreea; Anghelache, Lauren?iu; Marinescu, Bogdan; Dumitrache, Florian; B?doi, Anca Daniela; Manda, Gina

    2015-01-01

    Iron oxide nanoparticles are promising candidates for theranostics in cancer, that aims to achieve in one-step precise tumor imaging by magnetic resonance, and targeted therapy through surface attached anti-cancer drugs. The aim of this study was to investigate in preclinical setting the biocompatibility of new iron oxide-based nanoparticles that were coated with L-DOPA for improved dispersion in biological media. These nanostructures (NPs) were designed for biomedical applications as contrast agents and/or drug carriers. We investigated the effect exerted in vitro by NPs and L-DOPA on the viability and proliferation of normal mouse L929 fibroblasts. NPs exhibited good biocompatibility against these cells. Moreover, L-DOPA contained in NPs sustained fibroblasts proliferation and/or limited anti-proliferative effects of naked nanoparticles. In the animal study, C57BL/6 mice were injected intraperitoneally with a single dose of NPs (approximately 125 mg/kg body weight). We followed up hematological and histological parameters for one, three and seven days after NPs administration. Results indicated that NPs possibly induced local inflammation and consequent recruitment of peripheral lymphocytes, whilst the decrease of platelet counts may reflect tissue lesions caused by NPs. The histopathological study showed mild to moderate alterations in the hepatocytes, splenic and renal cells, while the brain parenchyma only presented nonspecific congestive changes. Taken altogether, the preclinical study indicated that the new iron oxide nanoparticles coated with L-DOPA were biocompatible against fibroblasts and had a convenient toxicological profile when administered intraperitoneally in a single dose to C57BL/6 mice. Accordingly, the proposed nanostructure is a promising candidate for imaging and treating dispersed peritoneal tumors. PMID:26429160

  13. Experimental design and efficient parameter estimation in preclinical pharmacokinetic studies.

    PubMed

    Ette, E I; Howie, C A; Kelman, A W; Whiting, B

    1995-05-01

    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 pharmacokinetic study with a fixed sample size as is usually the case in such studies. The efficiency of parameter estimation obtained with sampling strategies based on the three and four time point designs were evaluated in terms of the percent prediction error, design number, individual and joint confidence intervals coverage for parameter estimates approaches, and correlation analysis. The data sets contained random terms for both inter- and residual intra-animal variability. The results showed that the typical population parameter estimates for clearance and volume were efficiently (accurately and precisely) estimated for both designs, while interanimal variability (the only random effect parameter that could be estimated) was inefficiently (inaccurately and imprecisely) estimated with most sampling schedules of the two designs. The exact location of the third and fourth time point for the three and four time point designs, respectively, was not critical to the efficiency of overall estimation of all population parameters of the model. However, some individual population pharmacokinetic parameters were sensitive to the location of these times. PMID:7479560

  14. A simple method for the formalin fixation of lungs in toxicological pathology studies.

    PubMed

    Qu, Wen-Sheng; Yin, Ji-Ye; Wang, He-Mei; Dong, Yan-Sheng; Ding, Ri-Gao

    2015-10-01

    Optimized lung preparation for detailed structural evaluation is required to improve consistency in preclinical safety evaluation, differences of opinion exist among regulatory agency personnel regarding the optimal methods for routine formalin fixation of lungs from rodent toxicology studies. The simple tracheal ligation fixation method emphasizes tracheal ligation before opening the thorax instead of attempting to re-inflate after lung collapse when opening the thorax. Photomicrographs of this method demonstrated an unprecedented ability to maintain the natural lung architecture, in contrast to the unavoidable changes in the alveolar environment by the intratracheal instillation and vascular perfusion methods. In addition, a comparison of fixation methods on lung morphology in a rodent model of LPS-induced acute lung injury demonstrated that the tracheal ligation fixation method may provide a standard approach for morphometry. Additionally, a TUNEL assay was used to determine the degree of autolysis, which revealed that the autolysis was insignificant in the central areas of each lobe of the lung compared to the lung periphery by tracheal ligation fixation. In conclusion, our novel modified method, which avoids the disadvantages of generating artifacts, fulfills the requirement of preserving the clear, natural morphology of the lung making it suitable and worthy of recommendation for toxicological studies in a good laboratory practice (GLP) lab. PMID:26388042

  15. Resveratrol: A review of preclinical studies for human cancer prevention

    SciTech Connect

    Athar, Mohammad; Back, Jung Ho; Tang Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.

    2007-11-01

    The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.

  16. Preclinical Rodent Toxicity Studies for Long Term Use of Ceftriaxone

    PubMed Central

    Ratti, Elena; Berry, James D.; Greenblatt, David J.; Loci, Lorena; Ellrodt, Amy Swartz; Shefner, Jeremy M.; Cudkowicz, Merit E.

    2015-01-01

    A 6-month rodent toxicology and pharmacokinetic (PK) study was performed to provide supportive safety data for long-term use of intravenous ceftriaxone in a clinical trial in patients with amyotrophic lateral sclerosis (ALS). Ceftriaxone was administered by subcutaneous injection at up to 2 g/kg/day to Sprague-Dawley Crl:CD (SD) rats. Ceftriaxone was found to be safe and well tolerated. Specifically, no significant differences in body weight and food consumption were observed between the treatment and control groups. With the exception of in red cell parameters decrease, there were no ceftriaxone-related changes in hematology, coagulation, clinical chemistry and urinalysis parameters. Injection site trauma and associated reversible anemia, likely due to chronic blood loss at the injection site, were all attributable to subcutaneous route of administration. Cecum dilatation and some skin changes were reversible after recovery period, while bile duct dilatation, observed only in a few animals, persisted. Changes in the non-glandular stomach do not have a human correlate. The no-observed-adverse-effect dose level (NOAEL) was 0.5 g/kg/day ceftriaxone in both sexes. Ceftriaxone showed rapid absorption with half-life values ranging between 1 and 1.5 hours. Additionally, there was no evidence of accumulation and a virtually complete elimination by 16 hours after the last dose. Overall there were no toxicologically meaningful drug-related animal findings associated with the long-term administration (6 months) of ceftriaxone. These results support safety of long-term use of ceftriaxone in human clinical trials. PMID:26705515

  17. 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.

  18. Preliminary toxicological study of ferric acetyl acetonate

    SciTech Connect

    London, J.E.; Smith, D.M.

    1983-01-01

    The calculated acute oral LD/sub 50//sup 30/ (lethal does for 50% of the animals occuring with 30 days after compound administration) values for ferric acetyl acetonate were 584 mg/kg in mice and 995 mg/kg in rats. According to classical guidelines, this compound would be considered slightly toxic in both species. Skin application studies in the rabbit demonstrated the compound to be irritating. The eye irritation study disclosed the compound to be a severe irritant causing permanent damage to the cornea (inflammation and scarring resulting in blindness). The sensitization study in the guinea pig did not show ferric acetyl acetonate to be deleterious in this regard.

  19. Pharmacology and toxicology of sensitizers: mechanism studies

    SciTech Connect

    Rauth, A.M.

    1984-08-01

    Nitroimidazoles are being studied extensively as hypoxic cell radiosensitizers. Besides their ability to selectively sensitize hypoxic cells to radiation, which depends on the parent compound, nitroimidazoles have a variety of other effects in vitro, in vivo and clinically which appear to require reductive metabolism. As a first step to suggesting possible mechanisms for these other biological effects, a summary has been made of the known oxidative and reductive products of the two most widely studied radiosensitizers, metronidazole and misonidazole. As a second step to suggesting possible mechanisms for these biological effects, it is important to view the problem in terms of the in vivo situation where distribution and sites of metabolism of the drug and its reduction products will be important factors. Combining basic information about the reduction chemistry of nitroimidazoles with knowledge about the pharmacology of drugs and their reduced products should allow a better assessment of mechanism of action as well as a better implementation of these drugs clinically.

  20. Comparing potency estimators in aquatic toxicology studies

    SciTech Connect

    Bailer, A.J.; Shumate, B.J.; Oris, J.T.

    1995-12-31

    Potency estimators for concentrations associated with specified levels of reproductive toxicity in Ceriodaphnia dubia are presented and compared. The first estimator, the IC{sub p} or inhibition concentration approach is based upon a ``nonparametric`` estimation routine that assumes responses monotonically decline with increasing concentrations. This estimator also assumes that linear interpolation between mean responses associated with consecutive concentration groups is reasonable. The second estimator, the Rlp or reproductive inhibition concentration approach (Bailer and Oris, Env. Tox. and Chem. 12, 787--791, 1993) is based upon a parametric concentration-response model. This model assumes that the number of young is a Poisson distributed random variable and that the mean number of young can be modeled using an exponential term involving a polynomial in the test concentrations. Given these assumptions, a modeling procedure for reproductive outcomes is developed and is used to derive an estimate of potency of the chemical under test. Confidence intervals for both of these estimators are obtained using a bootstrap resampling procedure. The properties of these estimators, namely bias, mean squared error and coverage probabilities, are compared in a Monte Carlo simulation study. The results from this study suggest that the ``nonparametric`` estimator is more biased and more variable than the ``parametric`` estimator. Further, the confidence intervals associated with the ``nonparametric`` estimator fail to maintain nominal coverage probabilities while the confidence intervals associated with the ``parametric`` estimator perform as nominally stated.

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

    PubMed

    Zamora-Perez, Ana; Gmez-Meda, Belinda C; Ramos-Ibarra, Maria L; Batista-Gonzlez, Cecilia M; Luna-Aguirre, Jaime; Gonzlez-Rodrguez, Andrs; Rodrguez-Avila, Jos L; Ziga-Gonzlez, 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

  2. Pre-clinical and Clinical Safety Studies of CMX-2043: a cytoprotective lipoic acid analogue for ischaemia-reperfusion injury.

    PubMed

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

    2014-11-01

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

  3. Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for IschaemiaReperfusion Injury

    PubMed Central

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

    2014-01-01

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

  4. Novel technology to prepare oral formulations for preclinical safety studies.

    PubMed

    Niwa, Toshiyuki; Hashimoto, Naofumi

    2008-02-28

    A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension. PMID:17942253

  5. Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics*

    PubMed Central

    Harding, John; Mirochnitchenko, Oleg

    2014-01-01

    Induced pluripotent stem cells (iPSCs) and their differentiated derivatives can potentially be applied to cell-based therapy for human diseases. The properties of iPSCs are being studied intensively both to understand the basic biology of pluripotency and cellular differentiation and to solve problems associated with therapeutic applications. Examples of specific preclinical applications summarized briefly in this minireview include the use of iPSCs to treat diseases of the liver, nervous system, eye, and heart and metabolic conditions such as diabetes. Early stage studies illustrate the potential of iPSC-derived cells and have identified several challenges that must be addressed before moving to clinical trials. These include rigorous quality control and efficient production of required cell populations, improvement of cell survival and engraftment, and development of technologies to monitor transplanted cell behavior for extended periods of time. Problems related to immune rejection, genetic instability, and tumorigenicity must be solved. Testing the efficacy of iPSC-based therapies requires further improvement of animal models precisely recapitulating human disease conditions. PMID:24362021

  6. Antidepressant mechanism of ketamine: perspective from preclinical studies

    PubMed Central

    Scheuing, Lisa; Chiu, Chi-Tso; Liao, Hsiao-Mei; Chuang, De-Maw

    2015-01-01

    A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action. Recent preclinical studies indicate that ketamine's antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3?) inactivation. Adjunct GSK-3? inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue. PMID:26257598

  7. Advancing novel molecular imaging agents from preclinical studies to first-in-humans phase I clinical trials in academia--a roadmap for overcoming perceived barriers.

    PubMed

    Reilly, Raymond M; Lam, Karen; Chan, Conrad; Levine, Mark

    2015-04-15

    There is a critical need to advance promising novel molecular imaging (MI) agents for cancer from preclinical studies to first-in-humans Phase I clinical trials in order to realize their full potential for cancer detection and for predicting or monitoring response to targeted ("personalized") cancer therapies. Steps to clinical translation include radiopharmaceutical formulation, preclinical pharmacology and toxicology studies, clinical trial design and human ethics approval, and regulatory agency submission. In this Topical Review, we provide a "roadmap" to advancing one class of novel MI agents to Phase I trials in academia and illustrate the processes that we have successfully applied for (111)In-labeled pertuzumab, a MI probe for monitoring response of HER2-positive breast cancer to treatment with trastuzumab (Herceptin). We hope that our experience will encourage other academic radiopharmaceutical scientists to embrace this challenge. PMID:25781873

  8. Decellularized myocardial matrix hydrogels: In basic research and preclinical studies.

    PubMed

    Wang, Raymond M; Christman, Karen L

    2016-01-15

    A variety of decellularized materials have been developed that have demonstrated potential for treating cardiovascular diseases and improving our understanding of cardiac development. Of these biomaterials, decellularized myocardial matrix hydrogels have shown great promise for creating cellular microenvironments representative of the native cardiac tissue and treating the heart after a myocardial infarction. Decellularized myocardial matrix hydrogels derived from porcine cardiac tissue form a nanofibrous hydrogel once thermally induced at physiological temperatures. Use of isolated cardiac extracellular matrix in 2D and 3D in vitro platforms has demonstrated the capability to provide tissue specific cues for cardiac cell growth and differentiation. Testing of the myocardial matrix hydrogel as a therapy after myocardial infarction in both small and large animal models has demonstrated improved left ventricular function, increased cardiac muscle, and cellular recruitment into the treated infarct. Based on these results, steps are currently being taken to translate these hydrogels into a clinically used injectable biomaterial therapy. In this review, we will focus on the basic science and preclinical studies that have accelerated the development of decellularized myocardial matrix hydrogels into an emerging novel therapy for treating the heart after a myocardial infarction. PMID:26056717

  9. Preclinical experimental stress studies: protocols, assessment and comparison.

    PubMed

    Bali, Anjana; Jaggi, Amteshwar Singh

    2015-01-01

    Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. PMID:25446911

  10. Preclinical safety studies on autologous cultured human skin fibroblast transplantation.

    PubMed

    Zeng, Wei; Zhang, Shuying; Liu, Dai; Chai, Mi; Wang, Jiaqi; Zhao, Yuming

    2014-01-01

    Recently, FDA approved the clinical use of autologous fibroblasts (LAVIV) for the improvement of nasolabial fold wrinkles in adults. The use of autologous fibroblasts for the augmentation of dermal and subcutaneous defects represents a potentially exciting natural alternative to the use of other filler materials for its long-term corrective ability and absence of allergic adverse effects proved by clinical application. However, compared to the clinical evidence, preclinical studies are far from enough. In this study, human skin-derived fibroblasts were cultured and expanded for both in vitro and in vivo observations. In vitro, the subcultured fibroblasts were divided into two groups. One set of cells underwent cell cycle and karyotype analysis at passages 5 and 10. The second group of cells was cocultured in medium with different concentrations of human skin extract D for the measurement of collagen concentration and cell count. In vivo, the subcultured fibroblasts were injected into nude mice subcutaneously. Biopsies were taken for morphology observation and specific collagen staining at 1, 2, and 3 months after injection. The results in vitro showed no significant differences in cell cycle distribution between passages 5 and 10. Cell proliferation and secretion were inhibited as the concentration of extract D increased. In vivo, the fibroblasts were remarkably denser on the experimental side with no dysplastic cells. Mitotic cells were easily observed at the end of the first month but were rare at the end of the third month. Type III collagen was detected at the end of the first month, while collagen type I was positive at the end of the second month. The content of both collagens increased as time passed. The above results indicated that the use of the autologous fibroblasts was safe, providing a basic support for clinical use of fibroblasts. PMID:23211390

  11. Sequential whole bladder photodynamic therapy treatments: A preclinical study.

    PubMed

    Nseyo, U O; Kim, H; Debord, J; Tate, K; Dehaven, J

    1997-01-01

    We postulated that sequential whole bladder photodynamic therapy (WBPDT) treatments with a low WBPDT dose would result in improved safety profile and good local tumor control. However, the drawback with such a proposal is the potential cumulative effect of sequential WBPDT treatments on bladder function. We designed this preclinical study to determine the safety of sequential WBPDT treatments. Six female dogs underwent a single WBPDT treatment comprising 1.5 mg/kg of Photofrin and 15 J/cm(2) of light. Four dogs received a second treatment; and three dogs received three treatments. Pre- and post-WBPDT evaluations included cystoscopy and saline cystometry at baseline, 1 week, and 12 weeks. Gross and histopathologic analysis of cystectomy specimens occurred at 1 and 12 weeks. A single photodynamic therapy (PDT) treatment induced average bladder capacity losses of 11% (0-33) and 0% at post-WBPDT weeks 1 and 12, respectively. A second sequential WBPDT treatment caused average bladder capacity losses of 36% (0-57%) and 17% (2-24%) at weeks 1 and 12, respectively. Three sequential WBPDT treatments induced average bladder capacity losses of 22% (0-42) and 0% at weeks 1 and 12, respectively. Full recovery in bladder capacity occurred in all cases except after the second sequential treatment, which induced a persistent bladder capacity loss of 17% at 12 weeks. Histopathologic analysis of cystectomy specimens revealed a focal discernible injury to the superficial muscle in only one of the dogs that received three treatments. We conclude that sequential WBPDT treatments using low dose PDT Photofrin (1.5 mg/kg and light ?15 J/cm(2)) is safe, and we recommend using this low WBPDT dose in clinical investigation. PMID:21227049

  12. Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: Challenges, considerations and strategy.

    PubMed

    Dobrovolskaia, Marina A

    2015-12-28

    Assorted challenges in physicochemical characterization, sterilization, depyrogenation, and in the assessment of pharmacology, safety, and efficacy profiles accompany pre-clinical development of nanotechnology-formulated drugs. Some of these challenges are not unique to nanotechnology and are common in the development of other pharmaceutical products. However, nanoparticle-formulated drugs are biochemically sophisticated, which causes their translation into the clinic to be particularly complex. An understanding of both the immune compatibility of nanoformulations and their effects on hematological parameters is now recognized as an important step in the (pre)clinical development of nanomedicines. An evaluation of nanoparticle immunotoxicity is usually performed as a part of a traditional toxicological assessment; however, it often requires additional in vitro and in vivo specialized immuno- and hematotoxicity tests. Herein, I review literature examples and share the experience with the NCI Nanotechnology Characterization Laboratory assay cascade used in the early (discovery-level) phase of pre-clinical development to summarize common challenges in the immunotoxicological assessment of nanomaterials, highlight considerations and discuss solutions to overcome problems that commonly slow or halt the translation of nanoparticle-formulated drugs toward clinical trials. Special attention will be paid to the grand-challenge related to detection, quantification and removal of endotoxin from nanoformulations, and practical considerations related to this challenge. PMID:26348388

  13. Nonclinical toxicology study of recombinant-plasmid DNA anti-rabies vaccines.

    PubMed

    Kumar, P Uday; Kumar, B Dinesh; Annapurna, V V; Krishna, T Prasanna; Kalyanasundaram, S; Suresh, P; Harishankar, N; Jagadeesan, V; Hariharan, S; Naidu, A Nadamuni; Krishnaswamy, Kamala; Rangarajan, P N; Srinivasan, V A; Reddy, G S; Sesikeran, B

    2006-04-01

    The absence of standard guidelines from National and International regulatory agencies for the safety evaluation of biotechnology products challenges the ingenuity of toxicologists. At present, the development of standard pre-clinical toxicology protocols for such products is on an individual case basis. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed DNA based anti-rabies vaccine in India. The test compounds were DNA rabies vaccine [DRV (100 microg)] and combination rabies vaccine (CRV (100 microg DRV and 1/50 dose of cell culture vaccine)), intended for clinical use by intramuscular route on 1, 7, 14 and 28 day. As per the regular mandatory requirements, the study has been designed to undertake acute (single dose--10 days), sub-chronic (repeat dose--28 days) and chronic (intended clinical dose--120 days) toxicity tests using three dose levels viz. therapeutic, average (2 x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in Swiss Albino mice. The selection of the rodent model viz. Swiss Albino mice is based on affinity and rapid higher antibody response during the efficacy studies. Apart from physical, physiological, clinical, hematological and histopathology profiles of all target organs, the tier-I immunotoxicity parameters have also been monitored. There were no observational adverse effects even at levels of 10x therapeutic dose administration of DRV and CRV. The procedure also emphasizes on the designing of protocols for the products developed by recombinant technique. PMID:16448727

  14. Mouse Model for the Preclinical Study of Metastatic Disease

    Cancer.gov

    The successful development of new cancer therapeutics requires reliable preclinical data that are obtained from mouse models for cancer. Human tumor xenografts, which require transplantation of human tumor cells into an immune compromised mouse, represent the current standard mouse model for cancer. Since the immune system plays an important role in tumor growth, progression and metastasis, the current standard mouse model is not ideal for accurate prediction of therapeutic effectiveness in patients.

  15. 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...

  16. Stem cell models for drug discovery and toxicology studies.

    PubMed

    Liu, Wenwei; Deng, Yaguang; Liu, Ying; Gong, Wenrong; Deng, Wenbin

    2013-01-01

    Human stem cells and their derivatives could provide virtually unlimited sources of tissue for a wide range of toxicity models that could complement conventional animal models with more relevant, humanized versions. Human embryonic stem cells (hESCs) have already been proven valuable for drug/toxicity screens and mechanistic studies including analysis of disease pathway and developmental toxicity. Human-induced pluripotent stem cells (iPSCs), which are generated by reprogramming somatic cells back to become hESC-like cells, allow assays to be designed where the contribution of an individual's genetic background or environmental exposure history to toxicity response can be determined. Comprehensive profiling of hESC/iPSCs via genomics, proteomics, transcriptomics, and metabolomics could be used to elucidate pathway perturbations that underlie toxicity and disease, enabling the development of predictive assays for toxicity. While technological hurdles still exist for widespread use and implementation, incorporation of human stem cell based assays into drug discovery and toxicity testing offers the potential for safer, more customized medicines and more accurate risk assessment for environmental toxicants, as well as reduced costs and decreased use of animal models. We examine limitations and deficiencies of current toxicology approaches and how human stem cell based in vitro assays may overcome them. We describe how human stem cells are used for predictive toxicology. We also identify technological limitations that prevent stem cells from being integrated into standard practice, as well as new tools and technologies that may overcome them. We discuss research priorities that are most useful for transforming cell-based toxicology models into reality, and research areas in which stem cell technology could make substantial contributions to the development and implementation of stem cell based models for toxicity testing. Increased use of human in vitro models of toxicity could reduce the use of animals in safety and risk assessment studies and offers the potential to dramatically enhance our understanding of the molecular basis of toxicity, leading to improved human models and assays for predicting biological response to drugs and environmental hazards. PMID:23293059

  17. Review of Preclinical Studies on Treatment of Mucositis and Associated Pain

    PubMed Central

    Viet, C.T.; Corby, P.M.; Akinwande, A.; Schmidt, B.L.

    2014-01-01

    Oral mucositis is a significant problem in cancer patients treated with radiation or chemotherapy, often hindering definitive cancer treatment. For patients with oral mucositis, pain is the most distressing symptom, leading to loss of orofacial function and poor quality of life. While oral mucositis has been well-described, its pathophysiology is poorly understood. Oral health professionals treating patients with mucositis have almost no effective therapies to treat or prevent oral mucositis. The purpose of this review is to (1) describe the current preclinical models of oral mucositis and their contribution to the understanding of mucositis pathophysiology, (2) explore preclinical studies on therapies targeting mucositis and discuss the clinical trials that have resulted from these preclinical studies, and (3) describe the proposed pathophysiology of oral mucositis pain and preclinical modeling of oral mucositis pain. PMID:24943201

  18. THE USE OF STEM CELLS FOR TOXICOLOGY STUDIES AND RISK ASSESSMENTS

    EPA Science Inventory

    In general terms, toxicology studies are used in support of risk assessments of adverse health outcomes as a result of exposures to chemical and physical agents. In particular, toxicological data are used to provide information that aids in the assessment of disease outcomes at e...

  19. Systematic approaches to toxicology in the zebrafish.

    PubMed

    Peterson, Randall T; Macrae, Calum A

    2012-01-01

    As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology. PMID:22017682

  20. ORAL TOXICOLOGY STUDIES WITH XYLENE ISOMERS AND MIXED XYLENES

    EPA Science Inventory

    Xylene isomers and mixed xylenes were administered to male and female Sprague-Dawley rats to evaluate their effects on standard toxicological parameters rnhich included body and organ weights, hematology, serum chemistries, urinalysis and histopathological examination. n the init...

  1. Intravital microscopy as a tool to study drug delivery in preclinical studies

    PubMed Central

    Amornphimoltham, Panomwat; Masedunskas, Andrius; Weigert, Roberto

    2010-01-01

    The technical developments in the field of non-linear microscopy have made intravital microscopy one of the most successful techniques for studying physiological and pathological processes in live animals. Intravital microscopy has been utilized to address many biological questions in basic research and is now a fundamental tool for preclinical studies, with an enormous potential for clinical applications. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have empowered investigators to use this discipline to study the mechanisms of action of therapeutic agents and assess the efficacy on their targets in vivo. The goal of this review is to provide a general overview of the recent advances in intravital microscopy and to discuss some of its applications in preclinical studies. PMID:20933026

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

    PubMed

    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 (SD(50)) in the CAM were measured and calculated for these drugs. The resultant ideal LD(50) 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 (r(2)=0.42 - 0.68, P<0.005-0.05) between the ideal LD(50) values obtained using the CAM model with LD(50) 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

  3. 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

  4. Environmental Toxicology

    NASA Astrophysics Data System (ADS)

    Wright, David A.; Welbourn, Pamela

    2002-03-01

    Environmental Toxicology is a comprehensive introductory textbook dealing with most aspects of the subject, from the molecular to the ecosystem level. Early chapters deal with basic to advanced concepts, methods and approaches. The next discusses the environmental toxicology of individual or groups of substances. The third part addresses complex issues, in which many of the concepts, approaches and substances covered in earlier parts are incorporated. The fourth part includes chapters on risk assessment, rehabilitation and regulatory toxicology. The book concludes with a summary of present and future areas of emphasis. Each chapter contains a comprehensive list of references and further reading, case studies from different jurisdictions, and student exercises.

  5. The effect of learning styles and study behavior on success of preclinical students in pharmacology

    PubMed Central

    Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F. Nihan; Cicek, Ekrem

    2016-01-01

    Objectives: To evaluate the effect of learning styles and study behaviors on preclinical medical students’ pharmacology exam scores in a non-Western setting. Materials and Methods: Grasha–Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Results: Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Conclusions: Preclinical medical students’ study behaviors are independent predictive factors for short-term pharmacology success. PMID:26997716

  6. Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys.

    PubMed

    Burel, Sebastien A; Han, So-Ri; Lee, Hong-Soo; Norris, Daniel A; Lee, Byoung-Seok; Machemer, Todd; Park, Shin-Young; Zhou, Tianyuan; He, Guobin; Kim, Youngsoo; MacLeod, A Robert; Monia, Brett P; Lio, Shirley; Kim, Tae-Won; Henry, Scott P

    2013-06-01

    ISIS 481464 is a constrained ethyl (cEt) modified phosphorothioate antisense oligonucleotide (ASO) targeting signal transducer and activator of transcription 3 (STAT3) studied in mice and monkey to support oncology clinical trials. Six-week toxicology studies were performed in mice and cynomolgus monkey (up to 70 and 30 mg/kg/week respectively). Reduction in STAT3 protein up to 90% of control was observed in monkey. Cynomolgus monkey was considered the most relevant species to human with respect to pharmacokinetic properties, but mice are useful in their relative sensitivity to the potential proinflammatory and hepatic effects of oligonucleotides. In monkeys, there was no impact on organ function at doses up to 30 mg/kg/week for 6 weeks. Minimal to slight proximal tubular epithelial cell degeneration and regeneration within the kidney was observed, which had no impact on renal function and showed reversibility at the end of the treatment-free period. Additionally, mild and transient activated partial thromboplastin time elevations and mild increases in complement Bb were observed at the higher doses by intravenous dosing only. In mice, the alterations at 70 mg/kg/week included spleen weight increase up to 1.4-fold relative to control, increases in alanine aminotransferase and aspartate aminotransferase up to 1.8-fold over control, interleukin-10 increases up to 3.7-fold, and monocyte chemoattractant protein-1 increase up to 1.9-fold over control. No significant clinical pathology or histopathology changes were seen in mice at 20 mg/kg/week or less. The toxicity profile of ISIS 481464 is consistent with effects observed with phosphorothioate ASOs containing 2'-O-methoxyethylribose modifications instead of cEt. PMID:23692080

  7. Developmental Toxicology##

    EPA Science Inventory

    Developmental toxicology encompasses the study of developmental exposures, pharmacokinetics, mechanisms, pathogenesis, and outcomes potentially leading to adverse health effects. Manifestations of developmental toxicity include structural malformations, growth retardation, functi...

  8. Preclinical studies of noncharged oxime reactivators for organophosphate exposure.

    PubMed

    Okolotowicz, Karl J; Dwyer, Mary; Smith, Emily; Cashman, John R

    2014-01-01

    A countermeasure that protects the brain from organophosphate toxicity is an unmet need. Few small molecule reactivators that can cross the blood brain barrier and reactivate brain acetyl cholinesterases have been reported. Herein, we describe preclinical investigations of a new class of amidine-oxime reactivator of cholinesterases with improved potency and blood brain barrier permeability. (Z)-N-((E)-1-(Dimethylamino)-2-(hydroxyimino)ethylidene)butan-1-aminium chloride, 1, is zwitterionic at physiological pH but possesses increased oxime nucleophilicity because of the adjacent amidine functionality. The amidine-oximes reported herein were observed to be nontoxic (up to 200 mg/kg in vivo) and are chemically and metabolically stable. The results presented herein show that uncharged amidine-oxime reactivators such as 1 can penetrate the blood brain barrier in animals and protect from the toxicity of nerve agent model compounds. PMID:23943350

  9. Toxicology study of the high-energy plasticizer FEFO

    SciTech Connect

    Swearengen, P.M.; Johnson, J.S.

    1989-03-01

    This document contains information on the high energy plasticizer FEFO (1,1'-(methylenebis(oxy))bis(2-fluoro-2,2-dinitroethanel)). It includes interview comments from thirteen known users of the chemical through December, 1987. Included as appendices are other reference documents on FEFO. The first of these, Appendix A, is a survey on worker experiences with FEFO, Appendix B is a toxicology screening study of FEFO. Appendix C is a material safety data sheet on FEFO. Appendix D is an internal memorandum on personnel hazards associated with FEFO. Appendix E is a series of excerpted pages from a formerly classified document at the China Lake Naval Weapons Laboratory. Appendix F is a file on medical treatment associated with FEFO exposure. The interview comments and the appendices of related information on FEFO were provided to the LLNL Health Services Department along with Industrial Hygiene recommendations from the Safety Science Group. The response of the Health Services Director is included in this document as a preface. Taken together, the document and the medical observations provide a summary of information and recommended guidance for the safe handling of the high energy plasticizer FEFO. The material is believed to be quite biologically active by all observers. It is also believed that by correct use of strict industrial hygiene controls it can be used in large amounts with relative safety.

  10. Magnetic Fluid Hyperthermia for Bladder Cancer: A Preclinical Dosimetry Study

    PubMed Central

    Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea D.; Etienne, Wiguins; Ashcraft, Kathleen A.; McNerny, Katie L.; Mashal, Alireza; Nouls, John; Maccarini, Paolo F.; Beyer, Wayne F.; Inman, Brant; Dewhirst, Mark W.

    2014-01-01

    Purpose This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with Magnetic Fluid Hyperthermia (MFH), performed by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Materials and Methods The bladders of twenty-five female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42°C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fiberoptic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterization method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. Results Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ≥1°C/min to a steady-state of 42°C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. Conclusion These data demonstrate that our MFH system with magnetite-based nanoparticles provide well-localized heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues. PMID:24050253

  11. Preclinical gene therapy studies for hemophilia using adenoviral vectors.

    PubMed

    Thorrez, Lieven; VandenDriessche, Thierry; Collen, Dsir; Chuah, Marinee K

    2004-04-01

    Hemophilia A and B are hereditary coagulation defects resulting from a deficiency of factor VIII (FVIII) and factor IX (FIX), respectively. Introducing a functional FVIII or FIX gene could potentially provide a cure for these bleeding disorders. Adenoviral vectors have been used as tools to introduce potentially therapeutic genes into mammalian cells and are by far the most efficient vectors for hepatic gene delivery. Long-term expression of both FVIII and FIX has been achieved in preclinical (hemophilic) mouse models using adenoviral vectors. Therapeutic levels of FVIII and FIX also have been achieved in hemophilic dogs using adenoviral vectors and in some cases expression was long-term. The performance of earlier generation adenoviral vectors, which retained residual viral genes, was compromised by potent acute and chronic inflammatory responses that contributed to significant toxicity and morbidity and short-term expression of FVIII and FIX. The development of improved adenoviral vectors devoid of viral genes (gutless or high-capacity adenoviral vectors) was therefore warranted, which led to a significant reduction in acute and chronic toxicity and more prolonged expression of FVIII and FIX. Strategies aimed at making these vectors safer and less immunogenic and their implications for hemophilia gene therapy are discussed in this review. PMID:15118929

  12. Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study

    PubMed Central

    Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

    Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2′-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours. PMID:24851905

  13. Manpower Development in Toxicology. EURO Reports and Studies, No. 9.

    ERIC Educational Resources Information Center

    World Health Organization, Copenhagen (Denmark). Regional Office for Europe.

    This report addresses the widely held view that currently available literature in toxicology is inadequate in that there is a need to identify manpower deficiencies in this field and to suggest means to correct these deficiencies. It contains a list of specific recommendations including the organization of a working group, sponsored by the World…

  14. Manpower Development in Toxicology. EURO Reports and Studies, No. 9.

    ERIC Educational Resources Information Center

    World Health Organization, Copenhagen (Denmark). Regional Office for Europe.

    This report addresses the widely held view that currently available literature in toxicology is inadequate in that there is a need to identify manpower deficiencies in this field and to suggest means to correct these deficiencies. It contains a list of specific recommendations including the organization of a working group, sponsored by the World

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

    SciTech Connect

    Kienhuis, Anne S.; Bessems, Jos G.M.; Pennings, Jeroen L.A.; Driessen, Marja; Delft, Joost H.M. van

    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.

  16. 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.…

  17. Preclinical studied of general toxic properties of preparations containing ultralow doses of antibodies to endogenous regulators.

    PubMed

    Karpova, G V; Fomina, T I; Vetoshkina, T V; Dubskaya, T Yu; Voronova, O L; Timina, E A; Abramova, E V; Ermolaeva, L A; Perova, A V

    2009-09-01

    Preclinical study of the safety of 6 preparations containing ultralow doses of antibodies to endogenous regulators showed that they are relatively safe, are well tolerated by animals in doses more than 1000-fold surpassing the therapeutic dose for humans, and produce no general toxic effect on the organism of laboratory animals. PMID:20396736

  18. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke.

    PubMed

    Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J; Allan, Stuart M

    2016-03-01

    Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

  19. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

    PubMed Central

    Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J

    2015-01-01

    Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

  20. 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.

  1. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

    PubMed Central

    Vu, Quynh; Xie, Kate; Eckert, Mark; Zhao, Weian

    2014-01-01

    Objectives: To evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that correlate with differences in MSC effects. Methods: A literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints. Results: Of 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral > intra-arterial > IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate > rat > mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs ≥24 hours poststroke; results were overall very similar. Conclusions: In preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans. PMID:24610327

  2. SOCIETY OF TOXICOLOGIC PATHOLOGY POSITION PAPER: BEST PRACTICES FOR REPORTING PATHOLOGY INTERPRETATIONS WITHIN GLP TOXICOLOGY STUDIES.

    EPA Science Inventory

    The study pathologist provides specialized expertise to the interpretation of the toxicity and safety of pharmaceuticals, biological agents, human and animal food additives, environmental and industrial chemicals, and medical devices in animal studies. The study pathologist's fin...

  3. Assessing the scientific research productivity of a leading toxicology journal: A case study of Human & Experimental Toxicology from 2003 to 2012

    PubMed Central

    Zyoud, Saed H; Al-Jabi, Samah W; Sweileh, Waleed M; Awang, Rahmat

    2014-01-01

    Background: Bibliometric studies are increasingly being used for research assessments. Bibliometric indicators involve the application of statistical methods to scientific publications to obtain the bibliographics for each journal. The main objective of this study was to conduct a bibliometric evaluation of Human & Experimental Toxicology retrieved from the Scopus database. Methods: This study obtained data from Scopus published from 1 January 2003 till 31 December 2012. The keywords entered in Scopus to accomplish the objective of this study were Human, Experimental and Toxicology as Source Title. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analysing (a) total and trends in Human & Experimental Toxicology contributions in research between 2003 and 2012; (b) Human & Experimental Toxicology authorship patterns and productivity; (c) collaboration patterns; and (d) the citations received by the publications. Results: There were 1229 research articles published in Human & Experimental Toxicology. Of the articles included, 947 (77.1%) were original articles and 104 (8.5%) were review articles. The Hirsch-index of the retrieved documents was 35. The largest number of publications in Human & Experimental Toxicology was from the United States (19.6%), followed by India (12.8%) and Turkey (10.9%). The total number of citations was 9119, with a median (interquartile range) of 3 (19) in 6797 documents. The highest median (interquartile range) number of citations was 8 (2.712.7) for France, followed by 7.5 (222.5) for Iran and 6 (313.5) for the United Kingdom. The country most often citing articles that were published in Human & Experimental Toxicology was the United States, which made citations in 1508 documents, followed by India with citations in 792 documents. Conclusion: The documents in Human & Experimental Toxicology focus principally on original data, with very few review articles. Review articles tend to have higher citation rates than original articles, and hence, the editors and authors of Human & Experimental Toxicology might usefully promote the submission of reviews in the future to improve the impact of the journal. PMID:26770709

  4. 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.

  5. Oral delivery of highly lipophilic poorly water-soluble drugs: spray-dried dispersions to improve oral absorption and enable high-dose toxicology studies of a P2Y1 antagonist.

    PubMed

    Chen, Xue-Qing; Stefanski, Kevin; Shen, Hong; Huang, Christine; Caporuscio, Christian; Yang, Wu; Lam, Patrick; Su, Ching; Gudmundsson, Olafur; Hageman, Michael

    2014-12-01

    BMS-B is a highly lipophilic compound (clog P 7.72) with poor aqueous solubility (<10 ng/mL at pH 1 and 6.5). The compound exhibits low bioavailability in preclinical species when dosed as cosolvent solution formulations, with reduced exposure upon dose escalation. The purpose of this study was to evaluate spray-dried dispersions (SDDs) for enhancing oral exposure and enabling toxicology studies of BMS-B. SDD solids of BMS-B were prepared with 10%-25% drug in hydroxypropyl methylcellulose acetate succinate and showed an enhanced dissolution profile relative to the neat form of the compound. When dosed in rats and monkeys at 5 mg/kg, the SDD exhibited comparable exposure relative to the solution formulation. The SDD was also dosed in rats at 200 and 400 mg/kg and showed dose-proportional exposure compared to the solution formulation. Based on in vitro and in vivo data, the SDD formulation was selected for the toxicology study of BMS-B in rats. In summary, although the SDD approach could be quite challenging for highly lipophilic compounds because of the limitation on wetting and dissolution, the present study demonstrated that SDD can be applied in drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic poorly water-soluble compounds. PMID:25308627

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

    SciTech Connect

    Medin, Paul M.; Boike, Thomas P.

    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.

  7. Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies.

    PubMed

    Girard, Philippe; Chauvin, Marcel; Verleye, Marc

    2016-01-01

    Nefopam is a non-opioid, non-steroidal, centrally acting analgesic drug used to prevent postoperative pain, primarily in the context of multimodal analgesia. This paper reviews preclinical and clinical studies in which nefopam has been combined with opioids, non-steroidal anti-inflammatory compounds, and paracetamol. This report focuses on the literature during the last decade and discusses the translational efforts between animal and clinical studies in the context of multimodal or balanced analgesia. In preclinical rodent models of acute and inflammatory pain, nefopam combinations including opioids revealed a synergistic interaction or enhanced morphine analgesia in six out of seven studies. Nefopam combinations including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, ketoprofen or nimesulide) or paracetamol likewise showed enhanced analgesic effects for the associated compound in all instances. Clinical studies have been performed in various types of surgeries involving different pain intensities. Nefopam combinations including opioids resulted in a reduction in morphine consumption in 8 out of 10 studies of severe or moderate pain. Nefopam combinations including NSAIDs (ketoprofen or tenoxicam) or paracetamol also demonstrated a synergic interaction or an enhancement of the analgesic effect of the associated compound. In conclusion, this review of nefopam combinations including various analgesic drugs (opioids, NSAIDs and paracetamol) reveals that enhanced analgesia was demonstrated in most preclinical and clinical studies, suggesting a role for nefopam in multimodal analgesia based on its distinct characteristics as an analgesic. Further clinical studies are needed to evaluate the analgesic effects of nefopam combinations including NSAIDs or paracetamol. PMID:26475417

  8. From Bench to Bedside: Lessons Learned in Translating Preclinical Studies in Cancer Drug Development

    PubMed Central

    2013-01-01

    The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited. PMID:24052618

  9. Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen

    PubMed Central

    2014-01-01

    Background Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34+) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics. Methods Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence. Results The results reported in this work demonstrate that BK0023 is comparable in terms of biological activity, efficacy and safety to Neupogen. Conclusions BK0023 has the same pharmacokinetic profile, efficacy and safety as the reference commercial filgrastim Neupogen and therefore could be further developed to become a convenient option to treat neutropenia in oncological patients. Trial registration Trial registration number (TRN): NCT01933971. Date of registration: Sept 6th 2013. PMID:24555723

  10. 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 β-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

  11. 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

  12. Technetium-99m galactosyl-neoglycoalbumin: preparation and preclinical studies

    SciTech Connect

    Vera, D.R.; Stadalnik, R.C.; Krohn, K.A.

    1985-10-01

    Technetium-99m galactosyl-neoglycoalbumin ((Tc) NGA), a labeled analog ligand to the hepatocyte-specific receptor, hepatic binding protein (HBP), was prepared and tested for labeling yield, stability, biodistribution, toxicity, and dosimetry. The ligand was synthesized by the covalent coupling of a carbohydrate bifunctional reagent, 2-imino-2-ethyloxymethyl-1-thiogalactose, to human serum albumin. Testing in mice and rabbits revealed the product to be nontoxic and apyrogenic. Biodistribution studies in rabbits demonstrated the liver as the single focus of tracer uptake. Dosimetry was based on kinetic studies in three baboons. Absorbed doses to liver, small intestine, urinary bladder wall, and uterus were 0.089, 0.28, 0.56, and 0.88 rad/mCi, respectively. Total body, lens of the eye, red marrow, ovaries, and testes were less than 0.06 rad/mCi. High liver specificity imparted by receptor binding combined with high labeling yield, stability, acceptable dosimetry, and safety provide (Tc)NGA with the attributes required for routine clinical assessment of hepatocyte function.

  13. Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies

    PubMed Central

    Kobayashi, Yvonne M.; Rader, Erik P.; Crawford, Robert W.; Campbell, Kevin P.

    2011-01-01

    Loss of mobility influences the quality of life for patients with neuromuscular diseases. Common measures of mobility and chronic muscle damage are the six-minute walk test and serum creatine kinase. Despite extensive pre-clinical studies of therapeutic approaches, characterization of these measures is incomplete. To address this, a six-minute ambulation assay, serum creatine kinase, and myoglobinuria were investigated for the mdx mouse, a dystrophinopathy mouse model commonly used in pre-clinical studies. Mdx mice ambulated shorter distances than normal controls, a disparity accentuated after mild exercise. An asymmetric pathophysiology in mdx mice was unmasked with exercise, and peak measurements of serum creatine kinase and myoglobinuria were identified. Our data highlights the necessity to consider asymmetric pathology and timing of biomarkers when testing potential therapies for muscular dystrophy. PMID:22154712

  14. Potential antianxiety activity of Fumaria indica: A preclinical study

    PubMed Central

    Singh, Gireesh K.; Chauhan, Sudhir K.; Rai, Geeta; Chatterjee, Shyam S.; Kumar, Vikas

    2013-01-01

    Background: In the view of diverse CNS modulating properties of Fumaria indica, present study was planned to evaluate its putative anxiolytic activity in behavioural models of rats, followed by elucidation of mechanism of observed activity through biochemical estimations. Materials and Methods: Effects of seven daily 100, 200 and 400 mg/kg oral doses of a Fumaria indica extract (FI) was compared with those of an acute oral dose (5 mg/kg) of lorazepam in a battery of rat models consisting of open-field, elevated plus and zero maze, social interaction, and novelty induced feeding tests. Results: Dose dependant antianxiety effects of FI observed in all tests were qualitatively similar to those of the reference anxiolytic drug. Although FI treatments did not alter the concentrations of noradrenaline and serotonin in hippocampus and hypothalamus, concentrations of both these monoamines were dose dependently elevated in prefrontal cortex of FI treated animals. Flunitrazepam binding in brain frontal cortex was also elevated by the extract. Moreover, higher levels of brain expressions of the cytokines TNF-?, IL-1?, and IL-10 observed in animals with prior experience on elevated plus maze were almost completely reversed by the lowest dose of FI tested in the behavioral models. Conclusion: Taken together, these observations strongly suggest that FI is a functionally novel type of antianxiety agent, and that inhibition of cytokine expressions in the brain could be involved in its mode of action. PMID:23661988

  15. Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.

    PubMed

    Morfouace, Marie; Nimmervoll, Birgit; Boulos, Nidal; Patel, Yogesh T; Shelat, Anang; Freeman, Burgess B; Robinson, Giles W; Wright, Karen; Gajjar, Amar; Stewart, Clinton F; Gilbertson, Richard J; Roussel, Martine F

    2016-01-01

    Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials. PMID:26518542

  16. 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

  17. Essentials for starting a pediatric clinical study (4): Clinical pediatric safety planning based on preclinical toxicity studies and pediatric pharmacovigilance guidance.

    PubMed

    Sheth, Neha

    2009-01-01

    Juvenile toxicology studies in animals provide useful information to guide monitoring of potential adverse effects in children especially on growth and development. In order to continue to gain knowledge and build upon these preclinical studies, recent experience has suggested that additional approaches for monitoring of safety concerns in the pediatric population may be required. Recently, pediatric guidance has become available from the health authorities which provide pharmacovigilance concepts as they specifically relate to drugs being developed for pediatric indications. Clinical trials are typically not robust enough to detect rare or delayed safety effects as the pediatric trials are relatively short-term. Furthermore, such long term or rare effects may not be detected via standard voluntary postmarketing surveillance. Safety monitoring of children with Juvenile Inflammatory Arthritis (JIA) taking nonsteroid anti-inflammatory drug (NSAID)s will be used as an example to describe a post-marketing risk management and pharmacovigilance program that serves to better evaluate safety data from various sources. The intent of this program is to identify adverse events (AE), including events with longer latency, which may be associated with NSAID use in a pediatric population. In this presentation, the 4 major components of the program are to be addressed. Such a program may serve as a model to proactively generate and monitor safety data in order to identify AEs that may be associated with new therapeutics for a pediatric population. PMID:19571487

  18. SIMPLE, INEXPENSIVE HEART RATE MONITOR AND ARRHYTHMIA DETECTOR FOR USE IN TOXICOLOGICAL STUDIES

    EPA Science Inventory

    Many toxic agents have been reported to produce acute, adverse effects on cardiac function. Often these data are neglected in toxicological studies because of the difficulty and expense of monitoring cardiac parameters. We have developed a simple, inexpensive heart rate monitor (...

  19. 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.

  20. A retrospective evaluation of species-specific sensitivity for neurological signs in toxicological studies: Is the dog more sensitive than the non-human primate?

    PubMed

    Backes, Kathrin; Lorenz, Helga; Laplanche, Loic; Hudzik, Thomas J; Potschka, Heidrun; Hempel, Katja

    2016-01-22

    Selection of the appropriate non-rodent species in preclinical programs is crucial for good translatability and human safety. There is no data available in the literature which provides exact comparison of dog and non-human primate (NHP) sensitivity regarding neurological signs in toxicological studies. We performed a retrospective analysis of 174 toxicity studies with 15 neuroscience substances. Neurological signs in dogs and NHPs were evaluated in correlation to exposure data. Overall incidence of substance induced convulsions was similar in both species and no gender differences were observed. The reported liability of beagles to spontaneous convulsions was not confirmed in our studies. The symptom tremor showed the best inter-species translatability. The current toxicological study design does not include exposure assessment at the time-point of neurological signs, therefore, we propose to include additional toxicokinetic samples. Our analysis revealed factors including housing, handling, and behavior, which prevents direct species comparison. In addition only one non-rodent species is routinely tested in development programs, therefore data for both species is rare. We however, had sufficient data which enabled comparison for one compound. In the spirit of 3Rs further examples should be evaluated. PMID:26732424

  1. 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

  2. Nonclinical pharmacologic and toxicologic considerations for evaluating biologic products.

    PubMed

    Weissinger, J

    1989-12-01

    Prior to a Phase 1 clinical study, products are studied preclinically to establish evidence of pharmacologic activity, gain an understanding of the mechanism of action, evaluate the potential human risk, and establish a clinical study dose range. Although it is possible to follow this generic itinerary for the development of biologic products, it is difficult to develop generic protocols that will suffice for addressing these preclinical concerns for every biological product. Peptide hormones, cytokines, growth factors, vaccines, allergenics, plasma proteins, enzymes, toxins, monoclonal antibodies, and other heterologous antisera are unique in their physiological interactions, and therefore the toxicologic concerns and suggested studies are tailored to the uniqueness of the compound. This paper represents an attempt to share the thought processes that have been used at the Food and Drug Administration (FDA) to address the nonclinical pharmacology and toxicology study concerns. This presentation of considerations is based on an analysis of what has been done in recent years as a basis for initiating Phase 1 studies (first administration of drugs to humans) and progressing to Phase 2/3 studies (evaluation of optimal dose, effectiveness, and safety in humans), while I was Assistant Director (Pharmacology/Toxicology) of the Office of Biologics and since, as Assistant Director (Pharmacology/Toxicology) of the Office of Drug Evaluation II and a consultant to the Center for Biologics Evaluation and Research. PMID:2602582

  3. 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 5years 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

  4. Chemical constituents and toxicological studies of leaves from Mimosa caesalpiniifolia Benth., a Brazilian honey plant

    PubMed Central

    Monção, Nayana Bruna Nery; Costa, Luciana Muratori; Arcanjo, Daniel Dias Rufino; Araújo, Bruno Quirino; Lustosa, Maria do Carmo Gomes; Rodrigues, Klinger Antônio da França; Carvalho, Fernando Aécio de Amorim; Costa, Amilton Paulo Raposo; Lopes Citó, Antônia Maria das Graças

    2014-01-01

    Background: Mimosa caesalpiniifolia Benth. (Leguminosae) is widely found in the Brazilian Northeast region and markedly contributes to production of pollen and honey, being considered an important honey plant in this region. Objective: To investigate the chemical composition of the ethanol extract of leaves from M. caesalpiniifolia by GC-MS after derivatization (silylation), as well as to evaluate the in vitro and in vivo toxicological effects and androgenic activity in rats. Materials and Methods: The ethanol extract of leaves from Mimosa caesalpiniifolia was submitted to derivatization by silylation and analyzed by gas chromatography-mass spectrometry (GC-MS) to identification of chemical constituents. In vitro toxicological evaluation was performed by MTT assay in murine macrophages and by Artemia salina lethality assay, and the in vivo acute oral toxicity and androgenic evaluation in rats. Results: Totally, 32 components were detected: Phytol-TMS (11.66%), lactic acid-2TMS (9.16%), α-tocopherol-TMS (7.34%) and β-sitosterol-TMS (6.80%) were the major constituents. At the concentrations analyzed, the ethanol extract showed low cytotoxicity against brine shrimp (Artemia salina) and murine macrophages. In addition, the extract did not exhibit any toxicological effect or androgenic activity in rats. Conclusions: The derivatization by silylation allowed a rapid identification of chemical compounds from the M. caesalpiniifolia leaves extract. Besides, this species presents a good safety profile as observed in toxicological studies, and possess a great potential in the production of herbal medicines or as for food consumption. PMID:25298660

  5. Preparation and, in vitro, preclinical and clinical studies of aceclofenac spherical agglomerates.

    PubMed

    Usha, Achutha Nayak; Mutalik, Srinivas; Reddy, Meka Sreenivasa; Ranjith, Averineni Kumar; Kushtagi, Pralhad; Udupa, Nayanabhirama

    2008-10-01

    Aceclofenac agglomerates were prepared by spherical crystallization technique using a three solvent system comprising acetone: dichloromethane (DCM): water (bridging liquid, good solvent and bad solvent, respectively). Hydroxypropyl methylcellulose-50cps (HPMC) in different concentrations was used as hydrophilic polymer. The effect of speed of rotation and amount of bridging liquid on spherical agglomeration were studied. The agglomerates were subjected to various physicochemical evaluations such as practical yield, drug content, particle size, loss on drying, porosity, IR spectroscopy, differential scanning calorimetry, X-ray diffraction studies, relative crystallinity, scanning electron microscopy, micromeritic properties, solubility and dissolution studies. The agglomerates showed improved micromeritic properties as well as dissolution behaviour in comparison to conventional drug crystals. The optimized agglomerates (F-9) showed good sphericity as well as high drug release, and hence they were compressed into tablets by direct compression. The tablets were found within the limits with respect to various physicochemical parameters. The dissolution rate of prepared tablets was better than that of marketed tablet and pure drug. The optimized agglomerates and tablet formulations were found to be stable for 6 months under accelerated conditions. The in vivo studies (preclinical pharmacokinetics, pharmacodynamics and toxicity studies, and clinical pharmacokinetics) of optimized agglomerates were carried out. The results of preclinical studies revealed that the agglomerates provided improved pharmacodynamic and pharmacokinetic profiles of drug besides being nontoxic. The results of pharmacokinetic studies of optimized tablet in human subjects indicated improved pharmacokinetic parameters of drug in comparison with that of marketed tablet. PMID:18606224

  6. Preclinical electrogastrography in experimental pigs

    PubMed Central

    Kv?tina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kune, Martin; Bure, Jan; Tachec, Ilja; Rejchrt, Stanislav; Kop?ov, Marcela

    2010-01-01

    Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

  7. 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

  8. 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

  9. 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

  10. A preclinical study on the combination therapy of everolimus and transarterial chemoembolization in hepatocellular carcinoma.

    PubMed

    Chow, Ariel Km; Yau, Thomas Cc; Ng, Lui; Chu, Andrew Cy; Law, Wai-Lun; Poon, Ronnie Tp; Pang, Roberta Wc

    2015-01-01

    Transarterial chemoembolization (TACE) is commonly used for the treatment of locally advanced hepatocellular carcinoma (HCC) by its dual effects of chemotherapy and ischemic hypoxia. However, one of the side effects of TACE is the introduction of hypoxic condition, which in turn activates hypoxia-induced survival pathways and enhances VEGF-induced neovascularization by stabilizing HIF-1? expression. Herein, the preclinical therapeutic efficacy of the combined treatment of everolimus, a novel mTOR inhibitor and TACE for the treatment of HCC was investigated. The MHCC-97L cells were used for the study of the effect of combined treatment on cell proliferation and cellular apoptosis. HUVEC cells were used for the study on tube formation under different treatments. Inhibitions on the Akt/mTOR pathways were also studied. Finally, the effect on tumor growth was further study using an in vivo orthotopic model. The results demonstrated that everolimus enhanced the therapeutic efficacy of TACE in inhibiting cell proliferation, promoting apoptosis and inhibiting tube formation of endothelial cells by blocking the Akt/mTOR signaling pathway in vitro and inhibiting tumor growth and neoangiogenesis in vivo. Based on this preclinical study, the potential of combining everolimus with TACE was guaranteed which suggested the use of the combination therapy in the clinical treatment of advanced HCC patients. PMID:26396913

  11. A preclinical study on the combination therapy of everolimus and transarterial chemoembolization in hepatocellular carcinoma

    PubMed Central

    Chow, Ariel KM; Yau, Thomas CC; Ng, Lui; Chu, Andrew CY; Law, Wai-Lun; Poon, Ronnie TP; Pang, Roberta WC

    2015-01-01

    Transarterial chemoembolization (TACE) is commonly used for the treatment of locally advanced hepatocellular carcinoma (HCC) by its dual effects of chemotherapy and ischemic hypoxia. However, one of the side effects of TACE is the introduction of hypoxic condition, which in turn activates hypoxia-induced survival pathways and enhances VEGF-induced neovascularization by stabilizing HIF-1? expression. Herein, the preclinical therapeutic efficacy of the combined treatment of everolimus, a novel mTOR inhibitor and TACE for the treatment of HCC was investigated. The MHCC-97L cells were used for the study of the effect of combined treatment on cell proliferation and cellular apoptosis. HUVEC cells were used for the study on tube formation under different treatments. Inhibitions on the Akt/mTOR pathways were also studied. Finally, the effect on tumor growth was further study using an in vivo orthotopic model. The results demonstrated that everolimus enhanced the therapeutic efficacy of TACE in inhibiting cell proliferation, promoting apoptosis and inhibiting tube formation of endothelial cells by blocking the Akt/mTOR signaling pathway in vitro and inhibiting tumor growth and neoangiogenesis in vivo. Based on this preclinical study, the potential of combining everolimus with TACE was guaranteed which suggested the use of the combination therapy in the clinical treatment of advanced HCC patients. PMID:26396913

  12. Issues in pharmaceutical development of thymosin alpha1 from preclinical studies through marketing.

    PubMed

    Tuthill, Cynthia

    2007-09-01

    SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin alpha1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin alpha1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries. The recent development of the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use" (ICH) guidelines allows for a clearer definition of the required battery of toxicology studies, although some countries still have not adopted these guidelines, and the local regulations have had to be understood and followed. Other hurdles include the complications that manufacturing requirements can differ between countries, and certain countries require local clinical experience trials in addition to SciClone's cumulative clinical data. A further obstacle was the pleiotropic nature of the mechanism of action of thymosin alpha1, with the resulting difficulty in the unraveling of its pharmacologic effects. With close attention to these regulatory details, SciClone has obtained approvals in more than 30 countries and has successfully begun commercial sales. PMID:17947591

  13. Genetic toxicology: web resources.

    PubMed

    Young, Robert R

    2002-04-25

    Genetic toxicology is the scientific discipline dealing with the effects of chemical, physical and biological agents on the heredity of living organisms. The Internet offers a wide range of online digital resources for the field of Genetic Toxicology. The history of genetic toxicology and electronic data collections are reviewed. Web-based resources at US National Library of Medicine (NLM), including MEDLINE, PUBMED, Gateway, Entrez, and TOXNET, are discussed. Search strategies and Medical Subject Headings (MeSH) are reviewed in the context of genetic toxicology. The TOXNET group of databases are discussed with emphasis on those databases with genetic toxicology content including GENE-TOX, TOXLINE, Hazardous Substances Data Bank, Integrated Risk Information System, and Chemical Carcinogenesis Research Information System. Location of chemical information including chemical structure and linkage to health and regulatory information using CHEMIDPLUS at NLM and other databases is reviewed. Various government agencies have active genetic toxicology research programs or use genetic toxicology data to assist fulfilling the agency's mission. Online resources at the US Food and Drug Administration (FDA), the US Environmental Protection Agency (EPA), the National Institutes of Environmental Health Sciences, and the National Toxicology Program (NTP) are outlined. Much of the genetic toxicology for pharmaceuticals, industrial chemicals and pesticides that is performed in the world is regulatory-driven. Regulatory web resources are presented for the laws mandating testing, guidelines on study design, Good Laboratory Practice (GLP) regulations, and requirements for electronic data collection and reporting. The Internet provides a range of other supporting resources to the field of genetic toxicology. The web links for key professional societies and journals in genetic toxicology are listed. Distance education, educational media resources, and job placement services are also available online in the field of genetic toxicology. As molecular biology and computational tools improve, new areas within genetic toxicology such as structural activity relationship analysis, mutational spectra databases and toxicogenomics, now have resources online as well. PMID:11955688

  14. Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity.

    PubMed

    Healing, Guy; Sulemann, Tabassum; Cotton, Peter; Harris, Jayne; Hargreaves, Adam; Finney, Rowena; Kirk, Sarah; Schramm, Carolin; Garner, Clare; Pivette, Perrine; Burdett, Lisa

    2016-01-01

    Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation. PMID:25959454

  15. 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...

  16. 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, ...

  17. Onco-retroviral and lentiviral vector-based gene therapy for hemophilia: preclinical studies.

    PubMed

    Van Damme, An; Chuah, Marinee K L; Collen, Dsir; VandenDriessche, Thierry

    2004-04-01

    Hemophilia A and B gene therapy requires long-term and stable expression of coagulation factor VIII (FVIII) or factor IX (FIX), respectively, and would need to compare favorably with protein replacement therapy. Onco-retroviral and lentiviral vectors are attractive vectors for gene therapy of hemophilia. These vectors have the potential for long-term expression because they integrate stably in the target cell genome. Whereas onco-retroviral vectors can only transduce dividing cells, lentiviral vectors can transduce a broad variety of cell types irrespective of cell division. Several preclinical and clinical studies have explored the use of onco-retroviral and, more recently, lentiviral vectors for gene therapy of hemophilia A or B. Both ex vivo and in vivo gene therapy approaches have been evaluated, resulting in therapeutic FVIII or FIX levels in preclinical animal models. Whereas in vivo gene therapy using onco-retroviral or lentiviral vectors often led to long-term FVIII or FIX expression from transduced hepatocytes, ex vivo approaches were generally hampered by either low or transient expression of FVIII or FIX levels in vivo and/or inefficient engraftment. Furthermore, immune responses against the transgene product remain a major issue that must be resolved before the full potential of these vectors eventually can be exploited clinically. Nevertheless, the continued progress in vector design combined with a better understanding of vector biology may ultimately yield more effective gene therapy approaches using these integrating vectors. PMID:15118930

  18. Development and characterization of a Versatile Engineered Nanomaterial Generation System (VENGES) suitable for toxicological studies

    PubMed Central

    Demokritou, Philip; Büchel, Robert; Molina, Ramon M.; Deloid, Glen M.; Brain, Joseph D.; Pratsinis, Sotiris E.

    2015-01-01

    A novel system for generation of engineered nanomaterials suitable for in situ toxicological characterization within biological matrices was developed. This Versatile Engineered Nanomaterial Generation System (VENGES) is based on industry-relevant, flame spray pyrolysis (FSP) aerosol reactors that can scaleably produce engineered nanomaterials (ENMs) with controlled primary and aggregate particle size, crystallinity and morphology. ENMs are produced continuously in the gas phase, allowing their continuous transfer to inhalation chambers, without altering their state of agglomeration. Freshly generated ENMs are also collected on Teflon filters for subsequent physico-chemical and morphological characterization and for in vitro toxicological studies. The ability of the VENGES system to generate families of ENMs of pure and selected mixtures of iron oxide, silica and nanosilver with controlled physico-chemical properties was demonstrated using a range of state-of-the-art-techniques. Specific surface area was measured by nitrogen adsorption using the Brunauer-Emmett-Teller (BET) method, and crystallinity was characterized by X-ray diffraction (XRD). Particle morphology and size were evaluated by scanning and transmission electron microscopy (STEM/TEM). The suitability of the VENGES system for toxicological studies was also shown in both in vivo and in vitro studies involving Sprague-Dawley rats and human alveolar-like monocyte derived macrophages, respectively. We demonstrated linkage between physico-chemical ENM properties and potential toxicity. PMID:20701428

  19. Developmental toxicology: new directions workshop: refining testing strategies and study designs.

    PubMed

    Brannen, Kimberly C; Fenton, Suzanne E; Hansen, Deborah K; Harrouk, Wafa; Kim, James H; Shuey, Dana

    2011-10-01

    In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled "Developmental Toxicology-New Directions." The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non-animal-based testing paradigms, including how to define a "signal" or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource-intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session's presentations and discussion and describes some key areas that warrant further consideration. PMID:22006510

  20. Heparin in malignant glioma: review of preclinical studies and clinical results.

    PubMed

    Schnoor, Rosalie; Maas, Sybren L N; Broekman, Marike L D

    2015-09-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumor that is invariably lethal. Novel treatments are desperately needed. In various cancers, heparin and its low molecular weight derivatives (LMWHs), commonly used for the prevention and treatment of thrombosis, have shown therapeutic potential. Here we systematically review preclinical and clinical studies of heparin and LMWHs as anti-tumor agents in GBM. Even though the number of studies is limited, there is suggestive evidence that heparin may have various effects on GBM. These effects include the inhibition of tumor growth and angiogenesis in vitro and in vivo, and the blocking of uptake of extracellular vesicles. However, heparin can also block the uptake of (potential) anti-tumor agents. Clinical studies suggest a non-significant trend of prolonged survival of LMWH treated GBM patients, with some evidence of increased major bleedings. Heparin mimetics lacking anticoagulant effect are therefore a potential alternative to heparin/LMWH and are discussed as well. PMID:26123362

  1. Educational Challenges in Toxicology.

    ERIC Educational Resources Information Center

    Dixon, Robert L.

    1984-01-01

    Issues and topics related to educational challenges in toxicology at all levels are discussed. They include public awareness and understanding, general approach to toxicology, quality structure-activity relationships, epidemiological studies, quantification of risk, and the types of toxicants studied. (JN)

  2. Pig models of neurodegenerative disorders: Utilization in cell replacement-based preclinical safety and efficacy studies.

    PubMed

    Dolezalova, Dasa; Hruska-Plochan, Marian; Bjarkam, Carsten R; Srensen, Jens Christian H; Cunningham, Miles; Weingarten, David; Ciacci, Joseph D; Juhas, Stefan; Juhasova, Jana; Motlik, Jan; Hefferan, Michael P; Hazel, Tom; Johe, Karl; Carromeu, Cassiano; Muotri, Alysson; Bui, Jack; Strnadel, Jan; Marsala, Martin

    2014-08-15

    An important component for successful translation of cell replacement-based therapies into clinical practice is the utilization of large animal models to conduct efficacy and/or safety cell dosing studies. Over the past few decades, several large animal models (dog, cat, nonhuman primate) were developed and employed in cell replacement studies; however, none of these models appears to provide a readily available platform to conduct effective and large-scale preclinical studies. In recent years, numerous pig models of neurodegenerative disorders were developed using both a transgenic approach as well as invasive surgical techniques. The pig model (nave noninjured animals) was recently used successfully to define the safety and optimal dosing of human spinal stem cells after grafting into the central nervous system (CNS) in immunosuppressed animals. The data from these studies were used in the design of a human clinical protocol used in amyotrophic lateral sclerosis (ALS) patients in a Phase I clinical trial. In addition, a highly inbred (complete major histocompatibility complex [MHC] match) strain of miniature pigs is available which permits the design of comparable MHC combinations between the donor cells and the graft recipient as used in human patients. Jointly, these studies show that the pig model can represent an effective large animal model to be used in preclinical cell replacement modeling. This review summarizes the available pig models of neurodegenerative disorders and the use of some of these models in cell replacement studies. The challenges and potential future directions in more effective use of the pig neurodegenerative models are also discussed. PMID:24610493

  3. Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study.

    PubMed

    Patel, Yogesh T; Jacus, Megan O; Boulos, Nidal; Dapper, Jason D; Davis, Abigail D; Vuppala, Pradeep K; Freeman, Burgess B; Mohankumar, Kumarasamypet M; Throm, Stacy L; Gilbertson, Richard J; Stewart, Clinton F

    2015-05-01

    Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.120.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued. PMID:25724157

  4. Alcohols toxicology

    SciTech Connect

    Wimer, W.W.; Russell, J.A.; Kaplan, H.L.

    1984-01-01

    A comprehensive reference volume which summarizes literature reports of the known consequences of human and animal contact with alcohols and alcohol-derived substances is presented. Following a discussion of alcohol nomenclature and a brief history of alcohols, the authors have provided detailed chapters on the toxicology of methanol, ethanol, normal and isopropanol, and the butanols. Properties of these alcohols are compared; industrial hygiene and exposure limits are discussed. Additional sections are included covering processing and production technology and exhaust emissions studies. Of particular interest are the section containing abstracts and synopses of principal works and the extensive bibliography of studies dating from the 1800s. 331 references, 26 figures, 56 tables

  5. Systematic reviews and meta-analysis of preclinical studies: why perform them and how to appraise them critically

    PubMed Central

    Sena, Emily S; Currie, Gillian L; McCann, Sarah K; Macleod, Malcolm R; Howells, David W

    2014-01-01

    The use of systematic review and meta-analysis of preclinical studies has become more common, including those of studies describing the modeling of cerebrovascular diseases. Empirical evidence suggests that too many preclinical experiments lack methodological rigor, and this leads to inflated treatment effects. The aim of this review is to describe the concepts of systematic review and meta-analysis and consider how these tools may be used to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research akin to their use in improving the conduct and reporting of randomized controlled trials in clinical research. As with other research domains, systematic reviews are subject to bias. Therefore, we have also suggested guidance for their conduct, reporting, and critical appraisal. PMID:24549183

  6. 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...

  7. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., emergence, plant vigor, reproduction and yields. (ii) More than 50 percent of aquatic plants show adverse... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of a pesticide to terrestrial or aquatic wildlife or plants if, relative to all previously submitted...

  8. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., emergence, plant vigor, reproduction and yields. (ii) More than 50 percent of aquatic plants show adverse... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of a pesticide to terrestrial or aquatic wildlife or plants if, relative to all previously submitted...

  9. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., emergence, plant vigor, reproduction and yields. (ii) More than 50 percent of aquatic plants show adverse... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of a pesticide to terrestrial or aquatic wildlife or plants if, relative to all previously submitted...

  10. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., emergence, plant vigor, reproduction and yields. (ii) More than 50 percent of aquatic plants show adverse... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of a pesticide to terrestrial or aquatic wildlife or plants if, relative to all previously submitted...

  11. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., emergence, plant vigor, reproduction and yields. (ii) More than 50 percent of aquatic plants show adverse... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of a pesticide to terrestrial or aquatic wildlife or plants if, relative to all previously submitted...

  12. Behavioral toxicology

    SciTech Connect

    Needleman, H.L.

    1995-09-01

    The new fields of behavioral toxicology and behavioral teratology investigate the outcome of specific toxic exposures in humans and animals on learning, memory, and behavioral characteristics. Three important classes of behavioral neurotoxicants are metals, solvents, and pesticides. The clearest data on the deleterious effects of prenatal exposure to toxicants comes from the study of two metals, lead and mercury, and form epidemiological investigations of the effects of alcohol taken during pregnancy. Less complete data are available for two other groups of agents, solvents, and pesticides. What we do know about their effects on the fetal brain is convincing enough to make us demand caution in their distribution. 15 refs.

  13. 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...

  14. Exploring Polymeric Micelles for Improved Delivery of Anticancer Agents: Recent Developments in Preclinical Studies

    PubMed Central

    Tan, Chalet; Wang, Yingzhe; Fan, Wei

    2013-01-01

    As versatile drug delivery systems, polymeric micelles have demonstrated particular strength in solubilizing hydrophobic anticancer drugs while eliminating the use of toxic organic solvents and surfactants. However, the true promise of polymeric micelles as drug carriers for cancer therapy resides in their potential ability to preferentially elevate drug exposure in the tumor and achieve enhanced anticancer efficacy, which still remains to be fully exploited. Here, we review various micellar constructs that exhibit the enhanced permeation and retention effect in the tumor, the targeting ligands that potentiate the anticancer efficacy of micellar drugs, and the polyplex micelle systems suitable for the delivery of plasmid DNA and small interference RNA. Together, these preclinical studies in animal models help us further explore polymeric micelles as emerging drug carriers for targeted cancer therapy. PMID:24300405

  15. Resveratrol: A Review of Pre-clinical Studies for Human Cancer Prevention

    PubMed Central

    Athar, Mohammad; Back, Jung Ho; Tang, Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.

    2007-01-01

    The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3, 4′, 5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and anti-oxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol’s anti-cancer effects to support its potential as an anticancer agent in human populations. PMID:17306316

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

    PubMed Central

    Ahluwalia, Manmeet; de Groot, John; Liu, Wei (Michael)

    2011-01-01

    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, eg, 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. Word count =99/100 PMID:20947248

  17. Contribution of large pig for renal ischemia-reperfusion and transplantation studies: the preclinical model.

    PubMed

    Giraud, S; Favreau, F; Chatauret, N; Thuillier, R; Maiga, S; Hauet, T

    2011-01-01

    Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions. PMID:21403881

  18. Preclinical animal acute toxicity studies of new developed MRI contrast agent based on gadolinium

    NASA Astrophysics Data System (ADS)

    Nam, I. F.; Zhuk, V. V.

    2015-04-01

    Acute toxicity test of new developed MRI contrast agent based on disodium salt of gadopentetic acid complex were carried out on Mus musculus and Sprague Dawley rats according to guidelines of preclinical studies [1]. Groups of six animals each were selected for experiment. Death and clinical symptoms of animals were recorded during 14 days. As a result the maximum tolerated dose (MTD) for female mice is 2.8 mM/kg of body weight, male mice - 1.4 mM/kg, female rats - 2.8 mM/kg, male rats - 5.6 mM/kg of body weight. No Observed Adverse Effect Dose (NOAEL) for female mice is 1.4 mM/kg, male mice - 0.7 mM/kg, male and female rats - 0.7 mM/kg. According to experimental data new developed MRI contrast agent based on Gd-DTPA complex is low-toxic.

  19. Delivery of small molecules for bone regenerative engineering: preclinical studies and potential clinical applications

    PubMed Central

    Laurencin, Cato T.; Ashe, Keshia M.; Henry, Nicole; Kan, Ho Man; Lo, Kevin W-H.

    2014-01-01

    Stimulation of bone regeneration using growth factors is a promising approach for musculoskeletal regenerative engineering. Common limitations with protein growth factors are high manufacturing costs, protein instability, contamination issues, and unwanted immunogenic responses of the host. New strategies for bone regeneration that obviate these problems can have a significant impact on the treatment of skeletal injury and diseases. Over the past decade, a large number of small molecules with the potential of regenerating skeletal tissue have been reported in the literature. Here, we review this literature, paying specific attention to the prospects for small molecule-based bone-regenerative engineering. We also review the preclinical study of small molecules associated with bone regeneration. PMID:24508820

  20. Toxicological study of ''Aralhex Brush'' and its two components

    SciTech Connect

    London, J.E.; Smith, D.M.

    1985-09-01

    The acute oral LD/sub 50/ values for the adhesive ''Aralhex Brush'' for mice and rats are greater than 5g/kg. According to classified guidelines, the mixture would be considered only slightly toxic or practically nontoxic in both species. Skin application studies in the rabbit with the adhesive demonstrated that it was cutaneously mildly irritating; however, based on the primary irritation index, the adhesive's two precursor components were nonirritating. The adhesive and components I were mildly irritating in the rabbit eye application studies and component II was non-irritating. The sensitization study in the guinea pig did not show ''Aralhex Brush'' or its two components to be sensitizers. 5 refs., 3 tabs.

  1. 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...

  2. Recent trends in preclinical drug-drug interaction studies of flavonoids?-?Review of case studies, issues and perspectives.

    PubMed

    Srinivas, Nuggehally R

    2015-11-01

    Because of health benefits that are manifested across various disease areas, the consumption of herbal products and/or health supplements containing different kinds of flavonoids has been on the rise. While the drug-drug interaction potential between flavonoids and co-ingested drugs still remain an issue, opportunities exist for the combination of flavonoids with suitable anti-cancer drugs to enhance the bioavailability of anti-cancer drugs and thereby reduce the dose size of the anti-cancer drugs and improve its therapeutic index. In recent years, scores of flavonoids have undergone preclinical investigation with variety of drugs encompassing therapeutic areas such as oncology (etoposide, doxorubicin, paclitaxel, tamoxifen etc.), immunosuppression (cyclosporine) and hypertension (losartan, felodipine, nitrendipine etc.). The review provides examples of the recent trends in the preclinical investigation of 14 flavonoids (morin, quercetin, silibinin, kaempferol etc.) with various co-administered drugs. The relevance of combination of flavonoids with anti-cancer drugs and a framework to help design the in vitro and in vivo preclinical studies to gain better mechanistic insights are discussed. Also, concise discussions on the various physiological factors that contribute for the reduced bioavailability of flavonoids along with the significant challenges in the data interpretation are provided. Copyright 2015 John Wiley & Sons, Ltd. PMID:26343418

  3. 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

  4. Toxicological studies on safety of rare earths used in agriculture.

    PubMed

    Ji, Y J; Cui, M Z

    1988-10-01

    Studies on the toxicity and safety of a mixture of rare earth metal nitrates (Ce, La, Nd, Pr, and Sm) used in agricultural operations are reported. In mice, rats, and guinea pigs, the oral LD50 ranged from 1397 to 1876 mg/kg; absorption in the gastrointestinal tract was low. The accumulation coefficient was greater than 5. In rabbits, a topical application of a suspension of 500 mg/ml produced mild irritation of the skin and eye mucosa. Subchronic and chronic toxicity studies were done at different dose levels in monkeys (100 mg/kg) and rats (200 and 1800 mg/kg); biochemical and histopathological examination of tissues showed no abnormal or specific pathological changes. In chronic feeding studies with rats, the incidence of tumors and malignant tumors in test groups was lower than that in the control. Rat fetuses did not show any teratogenicity when the dams were orally fed up to 330 mg/kg of this nitrate mixture. Ames mutagenicity tests were negative at a 50 mg/kg level. The results indicate that an oral dose of 60 mg/kg should be considered as a no-effect level with an ADI of 0.6 mg/kg and that the level of rare earth nitrates used in Chinese agriculture is within acceptable risk or safety limits. PMID:2855920

  5. Environmental fate and aquatic toxicology studies on phthalate esters.

    PubMed Central

    Group, E F

    1986-01-01

    A comprehensive environmental fate and effects testing program, sponsored by the Chemical Manufacturers Association (CMA) Phthalate Esters Program Panel, has been completed. Based on the results, a preliminary safety assessment has shown that all of the 14 commercially important phthalates tested have sufficiently high safety factors to demonstrate low potential for adverse environmental effects. This program comprised acute toxicity studies on nine representative species of aquatic life, chronic reproduction studies on Daphnia magna, biodegradation (fate) testing, and physicochemical property (mobility) determinations on 14 phthalate esters. The objectives of this program were to determine for each test compound: The concentration at which effects on aquatic life might occur, the potential for bioconcentration in aquatic life, and the relative persistence in the environment. These data would provide the basis for an environmental safety assessment and would identify potential effects that might require further investigation. A total of 195 individual studies were carried out. Tests on a wide variety of aquatic organisms representing different food chain levels in both fresh and salt water environments showed that no single test species was unusually sensitive to the test materials. The higher molecular weight (longer side-chain) phthalates exhibited no toxic effects up to their limits of water solubility in the test systems. Even though the lower molecular weight, more water-soluble phthalates produced toxic effects below their limits of water solubility, no product exhibited unusually severe effects of concern.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3709460

  6. Proteomics for systems toxicology

    PubMed Central

    Titz, Bjoern; Elamin, Ashraf; Martin, Florian; Schneider, Thomas; Dijon, Sophie; Ivanov, Nikolai V.; Hoeng, Julia; Peitsch, Manuel C.

    2014-01-01

    Current toxicology studies frequently lack measurements at molecular resolution to enable a more mechanism-based and predictive toxicological assessment. Recently, a systems toxicology assessment framework has been proposed, which combines conventional toxicological assessment strategies with system-wide measurement methods and computational analysis approaches from the field of systems biology. Proteomic measurements are an integral component of this integrative strategy because protein alterations closely mirror biological effects, such as biological stress responses or global tissue alterations. Here, we provide an overview of the technical foundations and highlight select applications of proteomics for systems toxicology studies. With a focus on mass spectrometry-based proteomics, we summarize the experimental methods for quantitative proteomics and describe the computational approaches used to derive biological/mechanistic insights from these datasets. To illustrate how proteomics has been successfully employed to address mechanistic questions in toxicology, we summarized several case studies. Overall, we provide the technical and conceptual foundation for the integration of proteomic measurements in a more comprehensive systems toxicology assessment framework. We conclude that, owing to the critical importance of protein-level measurements and recent technological advances, proteomics will be an integral part of integrative systems toxicology approaches in the future. PMID:25379146

  7. Proteomics for systems toxicology.

    PubMed

    Titz, Bjoern; Elamin, Ashraf; Martin, Florian; Schneider, Thomas; Dijon, Sophie; Ivanov, Nikolai V; Hoeng, Julia; Peitsch, Manuel C

    2014-08-01

    Current toxicology studies frequently lack measurements at molecular resolution to enable a more mechanism-based and predictive toxicological assessment. Recently, a systems toxicology assessment framework has been proposed, which combines conventional toxicological assessment strategies with system-wide measurement methods and computational analysis approaches from the field of systems biology. Proteomic measurements are an integral component of this integrative strategy because protein alterations closely mirror biological effects, such as biological stress responses or global tissue alterations. Here, we provide an overview of the technical foundations and highlight select applications of proteomics for systems toxicology studies. With a focus on mass spectrometry-based proteomics, we summarize the experimental methods for quantitative proteomics and describe the computational approaches used to derive biological/mechanistic insights from these datasets. To illustrate how proteomics has been successfully employed to address mechanistic questions in toxicology, we summarized several case studies. Overall, we provide the technical and conceptual foundation for the integration of proteomic measurements in a more comprehensive systems toxicology assessment framework. We conclude that, owing to the critical importance of protein-level measurements and recent technological advances, proteomics will be an integral part of integrative systems toxicology approaches in the future. PMID:25379146

  8. Toxicological, Pathological, and Teratological Studies in Animals with Cephradine

    PubMed Central

    Hassert, G. L.; DeBaecke, P. J.; Kulesza, J. S.; Traina, V. M.; Sinha, D. P.; Bernal, E.

    1973-01-01

    Cephradine, a semisynthetic cephalosporin antibiotic, has a low order of oral and parenteral toxicity in animals. The oral LD50 in mice and rats ranged from 5 to >8 g/kg, and the intraperitoneal LD50 values in mice and rats were 0.7 to 1.5 g/kg and 4.0 g/kg, respectively. The intravenous LD50 in mice ranged from 3.0 to 3.8 g/kg. In anesthetized dogs, intravenous doses of cephradine (40 and 120 mg/kg, given 45 min apart) had no effect on either the renal or cardiovascular systems. Single intramuscular injections (0.25 ml or 0.5 ml of a solution containing 125 to 235 mg of cephradine/ml) elicited no signs of either pain or local irritation in dogs, and only transient signs of slight-to-moderate irritation were observed in rabbits. In subacute toxicity studies, cephradine was administered for 4 weeks to rats (daily intraperitoneal doses of 160, 480, or 1,600 mg/kg) and dogs (daily intravenous doses of 80, 240, or 800 mg/kg); in addition, over a 2-week period, monkeys were given daily intravenous doses of 60, 180, or 600 mg/kg. No clinical, biochemical, gross, or micropathological changes due to cephradine were observed in these animals; especially notable was the absence of any signs of nephrotoxicity. In chronic toxicity studies, daily doses of cephradine were administered orally to rats (100 to 1,000 mg/kg), dogs (50 to 500 mg/kg), and monkeys (50 to 500 mg/kg) for 26, 26, and 13 weeks, respectively. Significant responses were observed only in rats, in which grossly enlarged, but histologically normal, ceca developed, a common finding in rodents dosed with antibiotics; in addition, there were increases in the relative and absolute weights of the adrenal glands. None of these effects was observed in rats that were necropsied 3 weeks after termination of dosage. In reproduction studies in mice and rats given either daily oral doses (100 or 300 mg/kg) or daily intraperitoneal doses (rats only; 80 or 320 mg/kg) of cephradine, no drug-related teratogenic changes in the offspring were observed. PMID:4790617

  9. Antimicrobial and toxicological studies of Ochthochloa compressa plant.

    PubMed

    Ahmad, Saeed; Bashir, Muhammad Tayyab; Khaliq, Farhan Hameed; Mannan, Abdul; Mukhtar, Muhammad Fahad

    2014-09-01

    The present study demonstrates the biological activity of Ochthochloa compressa, since extensive literature survey has shown no documented biological activity of this plant. Ethanolic extract of whole plant was prepared and evaporated under reduced pressure by rota vapor. The crude extract was further fractionated into n-hexane, dichloromethane, ethyl acetate and n-butanol soluble fractions. These fractions were screened for antifungal, phytotoxic, cytotoxic and antibacterial activities. Dichloromethane soluble fraction showed significant phytotoxicity whereas n-hexane, ethyl acetate, and n-butanol soluble fractions showed non-significant phytotoxicity. Similarly, ethyl acetate soluble fraction was the only fraction, which showed significant cytotoxic activity. There was no antibacterial but moderate antifungal activity was shown by these fractions against selected strains of bacteria and fungi. This is the first report on the biological activity of O. compressa. PMID:25176377

  10. Inhalation developmental toxicology studies: Gallium arsenide in mice and rats

    SciTech Connect

    Mast, T.J.; Greenspan, B.J.; Dill, J.A.; Stoney, K.H.; Evanoff, J.J.; Rommereim, R.L.

    1990-12-01

    Gallium arsenide is a crystalline compound used extensively in the semiconductor industry. Workers preparing solar cells and gallium arsenide ingots and wafers are potentially at risk from the inhalation of gallium arsenide dust. The potential for gallium arsenide to cause developmental toxicity was assessed in Sprague- Dawley rats and CD-1 (Swiss) mice exposed to 0, 10, 37, or 75 mg/m{sup 3} gallium arsenide, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and {approx}30 positively mated rats or {approx}24 positively mated mice. Mice were exposed on 4--17 days of gestation (dg), and rats on 4--19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. Gallium and arsenic concentrations were determined in the maternal blood and uterine contents of the rats (3/group) at 7, 14, and 20 dg. 37 refs., 11 figs., 30 tabs.

  11. 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

  12. Ethical implications of using the minipig in regulatory toxicology studies.

    PubMed

    Webster, John; Bollen, Peter; Grimm, Herwig; Jennings, Maggy

    2010-01-01

    Two key questions are addressed in this article. What are the potential harms to minipigs relative to the harms for dogs and non-human primates and can these harms be reduced more easily in minipigs than in other species? Are there potential benefits resulting from the use of minipigs relative to dogs and non-human primates? In considering the answers to these questions, we present an ethical framework which was developed taking into account the viewpoint of all concerned parties. This ethical matrix provides a framework upon which to identify and explore issues raised by the moral imperative to seek a fair compromise between the differing needs of different interest groups, which includes both the moral agents and the moral patients. The moral agents are the different groups of human stakeholders including society at large, regulatory bodies, industrialists and animal care staff. The moral patients are the laboratory animals, both breeding stock held by the animal supplier, and experimental animals in laboratories. In considering these animals it cannot be assumed that dogs, monkeys and minipigs differ with regard to the pain and suffering that they may experience and undergo when treated in studies designed for safety assessment. On this basis we rejected the argument that minipigs are more acceptable experimental animals than dogs or monkeys despite the fact that their use may prove less offensive to some groups within society at large. Species selection must be made on a case-by-case basis where the benefits are assessed by weighing the scientific evidence relating to the predictivity of the animal model, against the harm that may accrue to the animals both from the test procedures and their lifetime experience within the laboratory environment. PMID:20566379

  13. The Elizabeth River Story: A Case Study in Evolutionary Toxicology.

    PubMed

    Di Giulio, Richard T; Clark, Bryan W

    2015-01-01

    The Elizabeth River system is an estuary in southeastern Virginia, surrounded by the towns of Chesapeake, Norfolk, Portsmouth, and Virginia Beach. The river has played important roles in U.S. history and has been the location of various military and industrial activities. These activities have been the source of chemical contamination in this aquatic system. Important industries, until the 1990s, included wood treatment plants that used creosote, an oil-derived product that is rich in polycyclic aromatic hydrocarbons (PAH). These plants left a legacy of PAH pollution in the river, and in particular Atlantic Wood Industries is a designated Superfund site now undergoing remediation. Numerous studies examined the distribution of PAH in the river and impacts on resident fauna. This review focuses on how a small estuarine fish with a limited home range, Fundulus heteroclitus (Atlantic killifish or mummichog), has responded to this pollution. While in certain areas of the river this species has clearly been impacted, as evidenced by elevated rates of liver cancer, some subpopulations, notably the one associated with the Atlantic Wood Industries site, displayed a remarkable ability to resist the marked effects PAH have on the embryonic development of fish. This review provides evidence of how pollutants have acted as evolutionary agents, causing changes in ecosystems potentially lasting longer than the pollutants themselves. Mechanisms underlying this evolved resistance, as well as mechanisms underlying the effects of PAH on embryonic development, are also described. The review concludes with a description of ongoing and promising efforts to restore this historic American river. PMID:26505693

  14. The Elizabeth River Story: A Case Study in Evolutionary Toxicology

    PubMed Central

    Di Giulio, Richard T.; Clark, Bryan W.

    2015-01-01

    The Elizabeth River system is an estuary in southeastern Virginia, surrounded by the towns of Chesapeake, Norfolk, Portsmouth, and Virginia Beach. The river has played important roles in U.S. history and has been the location of various military and industrial activities. These activities have been the source of chemical contamination in this aquatic system. Important industries, until the 1990s, included wood treatment plants that used creosote, an oil-derived product that is rich in polycyclic aromatic hydrocarbons (PAH). These plants left a legacy of PAH pollution in the river, and in particular Atlantic Wood Industries is a designated Superfund site now undergoing remediation. Numerous studies examined the distribution of PAH in the river and impacts on resident fauna. This review focuses on how a small estuarine fish with a limited home range, Fundulus heteroclitus (Atlantic killifish or mummichog), has responded to this pollution. While in certain areas of the river this species has clearly been impacted, as evidenced by elevated rates of liver cancer, some subpopulations, notably the one associated with the Atlantic Wood Industries site, displayed a remarkable ability to resist the marked effects PAH have on the embryonic development of fish. This review provides evidence of how pollutants have acted as evolutionary agents, causing changes in ecosystems potentially lasting longer than the pollutants themselves. Mechanisms underlying this evolved resistance, as well as mechanisms underlying the effects of PAH on embryonic development, are also described. The review concludes with a description of ongoing and promising efforts to restore this historic American river. PMID:26505693

  15. Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies.

    PubMed Central

    Rossman, Toby G; Uddin, Ahmed N; Burns, Fredric J; Bosland, Maarten C

    2002-01-01

    Although epidemiologic evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung, and bladder cancers, no animal model for arsenic carcinogenesis has been successful. This lack has hindered mechanistic studies of arsenic carcinogenesis. Previously, we and others found that low concentrations (< or =5 microm) of arsenite (the likely environmental carcinogen), which are not mutagenic, can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR) and alkylating agents. This enhancing effect appears to result from inhibition of DNA repair by arsenite, but not via inhibition of DNA repair enzymes. Rather, low concentrations of arsenite disrupt p53 function and upregulate cyclin D1. Failure to find an animal model for arsenic carcinogenesis might be because arsenite is not a carcinogen per se but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice were given 10 mg/L sodium arsenite in drinking water (or not) and irradiated with 1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no tumors appeared in any organs in control mice or in mice given arsenite alone. After 26 weeks irradiated mice given arsenite had a 2.4-fold increase in skin tumor yield compared with mice given UVR alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite were much larger and more invasive. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling. Skin cancers in populations drinking water containing arsenic may be caused by the enhancement by arsenic compounds of carcinogenesis induced by UVR (or other environmental agents). It is possible that lung and bladder cancers associated with arsenic in drinking water may also require a carcinogenic partner. PMID:12426125

  16. Evaluation of nutritional and sub-acute toxicological study of plant based supplement of Achyranthes aspera.

    PubMed

    Fatima, Nudrat; Dar, Nabeela G; Imran, Hina; Sohail, Tehmina; Asghar, Uzma; Yaqeen, Zahra; Syed, Shazia; Jamil, Khalid

    2014-09-01

    The present study was conducted for the nutritional, microbiological and toxicological evaluation of test compound having main ingredient Achyranthes aspera. Nutritional value assessment, microbiological analysis and toxicological studies were conducted according to the standard reported methods which exhibited that A. aspera contains moisture 4.05%, proteins 20.54%, fats 0.903%, ash 20.25%, carbohydrates 54,26% and energy 294 Kcal. Vitamin profile was found to be B(1) 0.27mg/100g, B(2) 0.28mg/100g, B(3) 0.58mg/100g, B(6) 0.27mg/100g and B(9) 39μg/100g. The content of sodium, calcium, magnesium, potassium, chloride and phosphorus was found to be 1119.67, 5385.23, 5446.08, 1343.6, 675880.73 and 1447.5mg/kg respectively and trace metals i.e. iron, copper, zinc, manganese and aluminum were detected as 283.05, 8.062, 48.37, 16.12 and 9.853 mg/kg respectively. The microbiological result indicated that the compound qualifies the international standards of microbial limit and was found free from Salmonella species. The toxicological study was conducted to find safe use of Achyranthes aspera compound in human as a nutritive supplement in blood disorders. The toxicity studies exhibited that the test compound has a good effect on general health as an increase in body weights of animals of test group was noticed as compared to that of control group. Blood parameters before and after the study were monitored which confirms our hypothesis by showing an increase in hemoglobin from 9.133 to 10.96, RBC count from 3.11 to 3.6, WBC count from 5.68 to 5.73 and platelets from 245 to 319. PMID:25176360

  17. Inhalation developmental toxicology studies: Teratology study of tetrahydrofuran in mice and rats: Final report

    SciTech Connect

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

    1988-08-01

    Tetrahydrofuran (THF), a four-carbon cyclic ether, is widely used as an industrial solvent. Although it has been used in large quantities for many years, few long-term toxicology studies, and no reproductive or developmental studies, have been conducted on THF. This study addresses the potential for THF to cause developmental toxicity in rodents by exposing Sprague-Dawley rats and Swiss (CD-1) mice to 0, 600, 1800, or 5000 ppm tetrahydrofuran (THF) vapors, 6 h/day, 7 dy/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.33 positively mated rats or mice. Positively mated mice were exposed on days 6--17 of gestation (dg), and rats on 6--19 dg. The day of plug or sperm detection was designated as O dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 27 refs., 6 figs., 23 tabs.

  18. 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

  19. Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies.

    PubMed

    Britton, Gabrielle B

    2012-02-01

    There is evidence from animal studies that repeated exposure to methylphenidate (MPH), a widely used psychostimulant for the treatment of attention deficit hyperactivity disorder (ADHD), produces behavioural, structural and neurochemical changes that persist long after drug administration has ended. However, the translational utility of much of this work is compromised by the use of drug doses and routes of administration that produce plasma and brain MPH levels that fall outside the clinical range, i.e. experimental parameters more relevant to drug abuse than ADHD. We used PubMed to identify pre-clinical studies that employed repeated MPH administration at low doses in young rodents and examined long-term effects on cognition, emotion, and brain structure and function. A review of this work suggests that repeated MPH treatment during early development can modify a number of cognitive, behavioural and brain processes, but these are reduced when low therapeutic doses are employed. Moreover, MPH sites of action extend beyond those implicated in ADHD. Studies that combined neurobiological and behavioural approaches provide important insights into the mechanisms underlying MPH-produced effects on cognitive and behavioural processes, which may be relevant to MPH therapeutic efficacy. There is an emerging consensus that pharmacological treatment of childhood psychiatric disorders produces persistent neuroadaptations, highlighting the need for studies that assess long-term effects of early developmental pharmacotherapy. In this regard, studies that mimic clinical therapy with rodents are useful experimental approaches for defining the behavioural and neural plasticity associated with stimulant therapy in paediatric populations. PMID:21439107

  20. Hypotensive, hypoglycaemic and toxicological studies on the flavonol C-glycoside shamimin from Bombax ceiba.

    PubMed

    Saleem, R; Ahmad, M; Hussain, S A; Qazi, A M; Ahmad, S I; Qazi, M H; Ali, M; Faizi, S; Akhtar, S; Husnain, S N

    1999-05-01

    Shamimin, a C-flavonol glucoside from Bombax ceiba leaves showed significant potency as a hypotensive agent at the doses of 15 mg/kg, 3 mg/kg, 1 mg/kg and significant hypoglycaemic activity at 500 mg/kg in Sprague-Dawley rats. Further studies revealed that it did not cause any mortality in mice at the dose of 1 g/kg but in rats 500 mg/kg is a lethal dose. Aqueous and methanolic extracts of Bombax ceiba leaves and one of its fractions were also subjected to pharmacological and toxicological screening. PMID:10364838

  1. 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.

  2. 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

  3. TOXICOLOGY OF PESTICIDES

    EPA Science Inventory

    This report includes the results of five toxicological studies of pesticide compounds conducted by the Institute for Medical Research and Occupational Health, Zagreb, Yugoslavia. In the first study, the reactions of two groups of esterases (cholinesterases and arylesterases) with...

  4. HDL and Atherosclerosis Regression: Evidence from Pre-clinical and Clinical Studies

    PubMed Central

    Feig, Jonathan E.; Hewing, Bernd; Smith, Jonathan D.; Hazen, Stanley L.; Fisher, Edward A.

    2014-01-01

    High density lipoprotein particles (HDL) transport, among other molecules, cholesterol (HDL-C). In epidemiologic studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease (CVD). It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, a number of recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased CVD risk, giving rise to a controversy over whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. On balance, the evidence from pre-clinical and (limited) clinical studies show that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. While more research will be needed on basic mechanisms and to establish that these changes translate clinically to reduced CVD events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent, but emphasizes the important distinction between HDL function and plasma levels of HDL-C. PMID:24385513

  5. Preclinical and clinical studies of recombinant poxvirus vaccines for carcinoma therapy.

    PubMed

    Arlen, Philip M; Gulley, James L; Madan, Ravi A; Hodge, James W; Schlom, Jeffrey

    2007-01-01

    Tumor-associated antigens (TAAs) are by definition either weakly immunogenic or functionally nonimmunogenic. Vaccine strategies have been designed to present TAAs to the immune system that may result in far greater activation of T cells than that occurring naturally in the host. These strategies include (1) placing the gene coding for the tumor antigen into poxvirus vectors as a transgene; (2) using diversified prime-and-boost vaccine strategies employing two different types of poxvirus vectors; (3) using T-cell costimulation; and (4) using cytokines, including GM-CSF, as biologic adjuvants. Preclinical studies have been performed comparing the effects on induction of antigen-specific CD8 and CD4 T-cell responses using recombinant poxvirus vectors containing transgenes for a TAA and costimulatory molecules B7-1, ICAM-1, and LFA-3 (designated TRICOM). Antigen-specific T-cell responses were greatest in the group receiving the CEA-TRICOM vaccines and were shown to correlate with survival. We have now completed the first clinical trials with poxvirus vectors containing TRICOM, using the TAAs PSA, CEA, and MUC-1. In addition, clinical studies combining vaccines with radiation therapy, chemotherapy, and second-line hormone therapy have provided preliminary evidence of prolongation of time to disease progression and antigen cascade postvaccination. PMID:18197807

  6. Videotaped Feedback Method to Enhance Learning in Preclinical Operative Dentistry: An Experimental Study.

    PubMed

    Shah, Dipali Yogesh; Dadpe, Ashwini Manish; Kalra, Dheeraj Deepak; Garcha, Vikram P

    2015-12-01

    The aim of this study was to investigate if a videotaped feedback method enhanced teaching and learning outcomes in a preclinical operative laboratory setting for novice learners. In 2013, 60 dental students at a dental school in India were randomly assigned to two groups: control (n=30) and experimental (n=30). The control group prepared a Class II tooth preparation for amalgam after receiving a video demonstration of the exercise. The experimental group received the same video demonstration as the control group, but they also participated in a discussion and analysis of the control groups' videotaped performance and then performed the same exercise. The self-evaluation scores (SS) and examiner evaluation scores (ES) of the two groups were compared using the unpaired t-test. The experimental group also used a five-point Likert scale to rate each item on the feedback form. The means of SS (13.652.43) and ES (14.751.97) of the experimental group were statistically higher than the means of SS (11.552.09) and ES (11.601.82) of the control group. Most students in the experimental group perceived that this technique enhanced their learning experience. Within the limits of this study, the videotaped feedback using both ideal and non-ideal examples enhanced the students' performance. PMID:26632301

  7. Ularitide for the treatment of acute decompensated heart failure: from preclinical to clinical studies

    PubMed Central

    Anker, Stefan D.; Ponikowski, Piotr; Mitrovic, Veselin; Peacock, W. Frank; Filippatos, Gerasimos

    2015-01-01

    The short- and long-term morbidity and mortality in acute heart failure is still unacceptably high. There is an unmet need for new therapy options with new drugs with a new mode of action. One of the drugs currently in clinical testing in Phase III is ularitide, which is the chemically synthesized form of the human natriuretic peptide urodilatin. Urodilatin is produced in humans by differential processing of pro-atrial natriuretic peptide in distal renal tubule cells. Physiologically, urodilatin appears to be the natriuretic peptide involved in sodium homeostasis. Ularitide exerts its pharmacological actions such as vasodilation, diuresis, and natriuresis through the natriuretic peptide receptor/particulate guanylate cyclase/cyclic guanosine monophosphate pathway. In animal models of heart failure as well as Phase I and II clinical studies in heart failure patients, ularitide demonstrated beneficial effects such as symptom relief and vasodilation, while still preserving renal function. Subsequently, the pivotal acute decompensated heart failure (ADHF) Phase III study, called TRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients with ADHF compared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF. PMID:25670819

  8. Ularitide for the treatment of acute decompensated heart failure: from preclinical to clinical studies.

    PubMed

    Anker, Stefan D; Ponikowski, Piotr; Mitrovic, Veselin; Peacock, W Frank; Filippatos, Gerasimos

    2015-03-21

    The short- and long-term morbidity and mortality in acute heart failure is still unacceptably high. There is an unmet need for new therapy options with new drugs with a new mode of action. One of the drugs currently in clinical testing in Phase III is ularitide, which is the chemically synthesized form of the human natriuretic peptide urodilatin. Urodilatin is produced in humans by differential processing of pro-atrial natriuretic peptide in distal renal tubule cells. Physiologically, urodilatin appears to be the natriuretic peptide involved in sodium homeostasis. Ularitide exerts its pharmacological actions such as vasodilation, diuresis, and natriuresis through the natriuretic peptide receptor/particulate guanylate cyclase/cyclic guanosine monophosphate pathway. In animal models of heart failure as well as Phase I and II clinical studies in heart failure patients, ularitide demonstrated beneficial effects such as symptom relief and vasodilation, while still preserving renal function. Subsequently, the pivotal acute decompensated heart failure (ADHF) Phase III study, called TRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients with ADHF compared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF. PMID:25670819

  9. Impact of platinum group metals on the environment: a toxicological, genotoxic and analytical chemistry study.

    PubMed

    Gagnon, Zofia E; Newkirk, Catherine; Hicks, Steven

    2006-01-01

    Recent studies show particles of Platinum Group Metals (PGMs); primarily platinum, palladium and rhodium; released from automobile catalytic converters are being deposited alongside roadways. This deposition is leading to increasing concentrations of PGMs in the environment, raising concerns about the environmental impact and toxicity of these elements in living organisms. The objective of this study was to determine how PGMs alter the patterns of growth, development, and physiology by studying the toxicological and genotoxic effects of these metals. Two vastly different species were used as models: plant-a wild wetland common Sphagnum moss, and animal-6-week old rats Sprague-Dawley. Both species were exposed, in controlled environments, to different concentrations of the PGMs. Toxicological and genotoxic effects were determined by assessment of plant growth, animal survival and pathology, and influence on DNA in both models. Our results on the uptake of PGMs by Sphagnum showed significant decreases in plant length and biomass as PGM concentration increased. Histological and pathological analysis of the animal model revealed vacuolization, eosinophil inclusion bodies in adrenal glands, shrinkage of glomeruli in the kidney, and enlargement of white pulp in the spleen. In both models, DNA damage was detected. Chemical analysis using ICP-AES atomic absorption demonstrated accumulation of PGMs in plant tissues at all PGM levels, proportional to concentration. PMID:16484072

  10. Advanced Clinical Imaging and Tissue-based Biomarkers of the Eye for Toxicology Studies in Minipigs.

    PubMed

    Atzpodien, Elke-Astrid; Jacobsen, Bjoern; Funk, Juergen; Altmann, Bernd; Silva Munoz, Manuel A; Singer, Thomas; Gyger, Cyrill; Hasler, Pascal; Maloca, Peter

    2016-04-01

    There is increased interest to use minipigs in ocular toxicology studies due to their anatomical similarities with human eyes and as a substitute for nonhuman primates. This requires adaptation of enhanced optical coherence tomography (OCT) techniques and of ocular relevant immunohistochemistry (IHC) or in situ hybridization (ISH) markers to porcine eyes. In this study, OCT and OCT angiography (AngioOCT) were performed on adult Göttingen minipigs. To increase structural information on retinal and choroidal vasculature, OCT data were speckle denoized and choroidal blood vessels were segmented with threshold filtering. In addition, we established a set of IHC and ISH markers on Davidson's fixed paraffin-embedded minipig eyes: neurofilament-160, neuronal nuclei, calretinin, protein kinase C-α, vimentin, glial fibrillary acidic protein, glutamine synthetase, ionized calcium-binding adaptor molecule-1, rhodopsin, synaptophysin, postsynaptic density protein-95, retinal pigment epithelium (RPE)-specific protein-65, von Willebrand factor, α-smooth muscle actin, desmin, and Ki-67, thus enabling visualization of retinal neuronal and glial cells, photoreceptors, synapses, RPE, blood vessels, myocytes, macrophages, or cell proliferation. Using ISH, transcripts of vascular endothelial growth factor A, angiopoietin-2, and endothelial tyrosine kinase were visualized. This article describes for the first time in minipig eyes speckle noise-free OCT, AngioOCT, and a set of IHC/ISH markers on Davidson's fixed paraffin-embedded tissues and helps to establish the minipig for ocular toxicology and pharmacology studies. PMID:26680760

  11. Green toxicology.

    PubMed

    Maertens, Alexandra; Anastas, Nicholas; Spencer, Pamela J; Stephens, Martin; Goldberg, Alan; Hartung, Thomas

    2014-01-01

    Historically, early identification and characterization of adverse effects of industrial chemicals was difficult because conventional toxicological test methods did not meet R&D needs for rapid, relatively inexpensive methods amenable to small amounts of test material. The pharmaceutical industry now front-loads toxicity testing, using in silico, in vitro, and less demanding animal tests at earlier stages of product development to identify and anticipate undesirable toxicological effects and optimize product development. The Green Chemistry movement embraces similar ideas for development of less toxic products, safer processes, and less waste and exposure. Further, the concept of benign design suggests ways to consider possible toxicities before the actual synthesis and to apply some structure/activity rules (SAR) and in silico methods. This requires not only scientific development but also a change in corporate culture in which synthetic chemists work with toxicologists. An emerging discipline called Green Toxicology (Anastas, 2012) provides a framework for integrating the principles of toxicology into the enterprise of designing safer chemicals, thereby minimizing potential toxicity as early in production as possible. Green Toxicology`s novel utility lies in driving innovation by moving safety considerations to the earliest stage in a chemical`s lifecycle, i.e., to molecular design. In principle, this field is no different than other subdisciplines of toxicology that endeavor to focus on a specific area - for example, clinical, environmental or forensic toxicology. We use the same principles and tools to evaluate an existing substance or to design a new one. The unique emphasis is in using 21st century toxicology tools as a preventative strategy to "design out" undesired human health and environmental effects, thereby increasing the likelihood of launching a successful, sustainable product. Starting with the formation of a steering group and a series of workshops, the Green Toxicology concept is currently spreading internationally and is being refined via an iterative process. PMID:25061898

  12. Preclinical endodontic teaching

    PubMed Central

    Narayanaraopeta, Udaya; AlShwaimi, Emad

    2015-01-01

    Objectives: To provide an overview of the general curricula in preclinical endodontic training from 6 established dental schools in Saudi Arabia. Methods: This study was conducted in January 2014 including only schools that had more than 2 groups of student graduates prior to the study. We included 2 dental schools from the Central region, one from Qassim region, one from the Makkah region (west), one from Abha region (south west), and one from the eastern region. An internet-based questionnaire was sent to the course directors of preclinical endodontics department of the 6 schools. The survey comprised 20 questions that examined various aspects of preclinical endodontics. Results: It was demonstrated that a significant number of faculty members had Doctor of Philosophy (PhD) degrees (n=21), Masters degrees (n=15), and Saudi board certifications (n=8). We determined that the faculty to student ratio varied from 2:1 to 8: 1 among the colleges. The participating dental schools were found to teach the Step Back, as well as the Step Down techniques for root canal preparation. Five of the 6 schools implemented the use of nickel titanium rotary instruments. All dental schools predominantly used radiographs as the means of the working length determination. Conclusion: The curriculum for preclinical endodontics in Saudi Arabia is comparable to that followed in most European countries. A more comprehensive survey is needed that would involve more schools to formulate generalized guidelines for preclinical endodontic training in Saudi Arabia. PMID:25630011

  13. A New Mini-External Fixator for Treating Hallux Valgus: A Preclinical, Biomechanical Study.

    PubMed

    Erdil, Mehmet; Ceylan, Hasan Huseyin; Polat, Gokhan; Kara, Deniz; Bozdag, Ergun; Sunbuloglu, Emin

    2016-01-01

    Proximal metatarsal osteotomy is the most effective technique for correcting hallux valgus deformities, especially in metatarsus primus varus. However, these surgeries are technically demanding and prone to complications, such as nonunion, implant failure, and unexpected extension of the osteotomy to the tarsometatarsal joint. In a preclinical study, we evaluated the biomechanical properties of the fixator and compared it with compression screws for treating hallux valgus with a proximal metatarsal osteotomy. Of 18 metatarsal composite bone models proximally osteotomized, 9 were fixed with a headless compression screw and 9 with the mini-external fixator. A dorsal angulation of 10 and displacement of 10mm were defined as the failure threshold values. Construct stiffness and the amount of interfragmentary angulation were calculated at various load cycles. All screw models failed before completing 1000 load cycles. In the fixator group, only 2 of 9 models (22.2%) failed before 1000 cycles, both between the 600th and 700th load cycles. The stability of fixation differed significantly between the groups (p<.001). The stability provided by the mini-external fixator was superior to that of compression screw fixation. Additional testing of the fixator is indicated. PMID:26190777

  14. Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study

    PubMed Central

    Ferrari, Cristina; Niccoli Asabella, Artor; Villano, Carlo; Giacobbi, Beatrice; Coccetti, Daniela; Panichelli, Paola; Rubini, Giuseppe

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic) of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy. PMID:26649294

  15. Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain: preclinical and clinical studies.

    PubMed

    Smith, Maree T; Anand, Praveen; Rice, Andrew S C

    2016-02-01

    Neuropathic pain affects up to 10% of the general population, but drug treatments recommended for the treatment of neuropathic pain are associated with modest efficacy and/or produce dose-limiting side effects. Hence, neuropathic pain is an unmet medical need. In the past 2 decades, research on the pathobiology of neuropathic pain has revealed many novel pain targets for use in analgesic drug discovery programs. However, these efforts have been largely unsuccessful as molecules that showed promising pain relief in rodent models of neuropathic pain generally failed to produce analgesia in early phase clinical trials in patients with neuropathic pain. One notable exception is the angiotensin II type 2 (AT2) receptor that has clinical validity on the basis of a successful double-blind, randomized, placebo-controlled, clinical trial of EMA401, a highly selective, orally active, peripherally restricted AT2 receptor antagonist in patients with postherpetic neuralgia. In this study, we review research to date on target validation, efficacy, and mode of action of small molecule AT2 receptor antagonists in rodent models of peripheral neuropathic pain and in cultured human sensory neurons, the preclinical pharmacokinetics of these compounds, and the outcome of the above clinical trial. PMID:26785154

  16. 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. PMID:26175713

  17. A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

    PubMed Central

    Hooper, Jody E.; Cantor, Emma L.; Ehlen, Macgregor S.; Banerjee, Avirup; Malempati, Suman; Stenzel, Peter; Woltjer, Randy L.; Gandour-Edwards, Regina; Goodwin, Neal C.; Yang, Yan; Kaur, Pali; Bult, Carol J.; Airhart, Susan D.; Keller, Charles

    2015-01-01

    Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study. PMID:26696773

  18. Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies.

    PubMed

    Finocchiaro, Gaetano; Pellegatta, Serena

    2016-01-01

    Different approaches have been explored to raise effective antitumor responses against glioblastoma (GBM), the deadliest of primary brain tumors. In many clinical studies, cancer vaccines have been based on dendritic cells (DCs) loaded with peptides, representing one or more specific tumor antigens or whole lysates as a source of multiple antigens. Randomized clinical trials using DCs are ongoing, and results of efficacy are not yet available. Such strategies are feasible and safe; however, immune-suppressive microenvironment, absence of appropriate specific epitopes to target, and cancer immunoediting can limit their efficacy. The aim of this review is to describe how the definition of novel and more specific targets may increase considerably the possibility of successful DC immunotherapy. By proposing to target glioblastoma stem-like cells (GSCs), the immune response will be pointed to eradicating factors and pathways highly relevant to GBM biology. Preclinical observations on efficacy, and preliminary results of immunotherapy trials, encourage exploring the clinical efficacy of DC immunotherapy in GBM patients using high-purity, GSC-loaded DC vaccines. PMID:26377689

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

    PubMed

    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. PMID:26175713

  20. Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) in Preclinical Studies of Antivascular Treatments

    PubMed Central

    Nielsen, Thomas; Wittenborn, Thomas; Horsman, Michael R.

    2012-01-01

    Antivascular treatments can either be antiangiogenic or targeting established tumour vasculature. These treatments affect the tumour microvasculature and microenvironment but may not change clinical measures like tumour volume and growth. In research on antivascular treatments, information on the tumour vasculature is therefore essential. Preclinical research is often used for optimization of antivascular drugs alone or in combined treatments. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an in vivo imaging method providing vascular information, which has become an important tool in both preclinical and clinical research. This review discusses common DCE-MRI imaging protocols and analysis methods and provides an overview of preclinical research on antivascular treatments utilizing DCE-MRI. PMID:24300371

  1. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study

    PubMed Central

    Vos, Stephanie J.B.; Xiong, Chengjie; Visser, Pieter Jelle; Jasielec, Mateusz S.; Hassenstab, Jason; Grant, Elizabeth A.; Cairns, Nigel J.; Morris, John C.; Holtzman, David M.; Fagan, Anne M.

    2013-01-01

    Background New research criteria for preclinical Alzheimer’s disease (AD)have been proposed by the National Institute on Aging and Alzheimer’s Association. They include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and injury markers (stage 2) and abnormal amyloid and injury markers and subtle cognitive changes (stage 3). We investigated the occurrence and long-term outcome of these stages. Methods Cerebrospinal fluidamyloid-β1–42 and tau levels and a memory composite score were used to classify 311 cognitively normal(Clinical Dementia Rating [CDR]=0) research participants ≥65 years as normal (both markers normal), preclinical AD stage 1–3, or Suspected Non-Alzheimer Pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). Outcome measures were progression to CDR≥0·5 symptomatic AD and mortality up to 15 years after baseline (average=4 years). Findings 129 (41·5%) of participants were normal, 47 (15%)were in stage 1, 36 (12%) in stage 2, 13 (4%)in stage 3, 72 (23%) had SNAP, and 14 (4·5%) remained unclassified. The proportion of preclinical AD (stage 1–3) in our cohort was higher in individuals older than 72 years and in APOE-ε4 carriers. The 5-year progression rate to CDR≥0·5 symptomatic AD was 2% for normal participants, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with normal individuals, participants with preclinical AD had an increased risk of death (HR=6·2, p=0·0396). Interpretation Preclinical AD is common in cognitively normal elderly and strongly associated with future cognitive decline and mortality. Preclinical AD thus should be an important target for therapeutic interventions. PMID:24012374

  2. National Toxicology Program

    MedlinePLUS

    ... Searches, & Other Resources Reports & Publications Pathology Tables for Peer Review Summaries & Associations of Study Results Tox21 Nanotechnology Safety Initiative Public Health Public Health Impact Report on Carcinogens Evaluation of Alternative Toxicological Methods Health Assessment and Translation ...

  3. Fluorescence detection of tumors: studies on the early diagnosis of microscopic lesions in preclinical and clinical studies

    NASA Astrophysics Data System (ADS)

    Mang, Thomas S.; McGinnis, Carolyn; Crean, David H.; Khan, S.; Liebow, Charles

    1991-06-01

    The growth of microscopic tumor lesions at or beyond treatment field lesions poses major problems in the diagnosis and curative treatment of numerous cancers. Early detection techniques which clearly define the extent of condemned or field spread of disease may improve the primary treatment of the disease. In vivo fluorescence photometry is a non-imaging technique which digitally displays relative fluorescence values in volts. The sensitivity of the instrument has allowed the detection of micrometastases in both pre-clinical and clinical studies using drug doses that are 80-90 lower than those used therapeutically. This technique is now being applied in preliminary experiments to the hamster cheek pouch models to (1) discern varying grades of dysplasia; (2) levels of uptake of the drug in normal growing and quiescent tumors. Results will be shown in two models in which this technique has shown to be efficacious preclinically in the Pollard rat adenocarcinoma model in which micrometastases in the lymph node have been detected, and preliminary studies involving the hamster cheek pouch model in which the pouch is painted with 9, 10 dimethyl-1, 2-benzanthracene (DMBA) for initiation and promotion of tumors. Clinically results will be shown in which fluorescence detection, confirmed by biopsy and histopathological examination, was capable of detecting the existence of micrometastatic involvement of less than 100 cells.

  4. An integrated study on Gammarus elvirae (Crustacea, Amphipoda): perspectives for toxicology of arsenic-contaminated freshwater.

    PubMed

    Davolos, Domenico; Chimenti, Claudio; Ronci, Lucilla; Setini, Andrea; Iannilli, Valentina; Pietrangeli, Biancamaria; De Matthaeis, Elvira

    2015-10-01

    The Italian region Latium is characterized by extensive quaternary volcanic systems that contribute greatly to arsenic (As) contamination of freshwater, including drinking water supplies. However, knowledge of the possible toxic effects in these aquatic environments is, despite being highly relevant to public health, still limited. In this paper, we approach this issue using Gammarus elvirae, an amphipod species that inhabits rivers and streams in central Italy, including Latium. We explored the possibility of using G. elvirae in the toxicology of freshwater by addressing the most relevant issues. First, we tested the usefulness of hemocytes from G. elvirae in determining non-specific DNA damage by means of the Comet assay after exposure (24 h and 7 days) to different river water samples in Latium; second, we provided an interpretative overview of the usefulness of hepatopancreatic epithelial cells of G. elvirae as a means of assessing toxicity after long-term exposure to As and other pollutants; third, the LC (50-240 h) value for G. elvirae was estimated for arsenate, which is usually the dominant arsenic species in surface waters. Our study sheds light on G. elvirae at different levels, providing a background for future toxicological research of freshwater. PMID:26013740

  5. Forensic toxicology.

    PubMed

    Davis, Gregory G

    2012-01-01

    Toxicologic analysis is an integral part of death investigation, and the use or abuse of an unsuspected substance belongs in the differential diagnosis of patients who have a sudden, unexpected change in their condition. History and physical findings may alter suspicion that intoxication played a role in a patient's decline or death, but suspicions cannot be confirmed and is performed, analysis unless toxicologic no toxicologic analysis is possible unless someone collects the proper specimens necessary for analysis. In a hospital autopsy the only specimens that can rightfully be collected are those within the restrictions stated in the autopsy permit. Autopsies performed by the medical examiner do not have these restrictions. Sometimes the importance of toxicologic testing in a case is not evident until days or weeks after the change in the patient's status, thus retaining the appropriate specimens until investigation of that case has ended is important. Proper interpretation of toxicologic findings requires integrating the clinical setting and findings with the toxicologic results in a way that makes medical sense. If called upon to testify concerning findings, answer the questions truthfully, politely, and in a way that is understandable to someone who has no special training in toxicology. PMID:22693783

  6. A comparative toxicological study of Rasamanikya prepared with three different methods.

    PubMed

    Sud, Sushant; Reddy, P Sekhar; Sujatha, K; Honwad, Sudheendra

    2013-07-01

    Rasamanikya a familiar drug, frequently used by Ayurvedic physicians. It also has a high demand in current pharmaceutical industry. Rasamanikya possesses different pharmaceutical methods with many a proved clinical studies. But it is of utmost importance to understand the safety profile of drug based on assurance which could be done by carrying out animal experimentation. In the present study, Rasamanikya was prepared with three methods. The toxicological study was carried out on acute and sub-acute toxicity of the drug. The three samples when compared together showed that Rasamanikya prepared out of classical Abhraka Patra method and modified Sharava Samputa method showed minimal histopathological changes proving its non-toxicity, whereas Rasamanikya prepared out of electric bulb method showed mild toxicity, but with chances of recovery. Acute toxicity study showed no immediate and evident toxic signs and mortality in histopathology reports and liver function test. However, sub-acute toxicity study showed mild to moderate fatty changes in liver. PMID:24501530

  7. A comparative toxicological study of Rasamanikya prepared with three different methods

    PubMed Central

    Sud, Sushant; Reddy, P. Sekhar; Sujatha, K.; Honwad, Sudheendra

    2013-01-01

    Rasamanikya a familiar drug, frequently used by Ayurvedic physicians. It also has a high demand in current pharmaceutical industry. Rasamanikya possesses different pharmaceutical methods with many a proved clinical studies. But it is of utmost importance to understand the safety profile of drug based on assurance which could be done by carrying out animal experimentation. In the present study, Rasamanikya was prepared with three methods. The toxicological study was carried out on acute and sub-acute toxicity of the drug. The three samples when compared together showed that Rasamanikya prepared out of classical Abhraka Patra method and modified Sharava Samputa method showed minimal histopathological changes proving its non-toxicity, whereas Rasamanikya prepared out of electric bulb method showed mild toxicity, but with chances of recovery. Acute toxicity study showed no immediate and evident toxic signs and mortality in histopathology reports and liver function test. However, sub-acute toxicity study showed mild to moderate fatty changes in liver. PMID:24501530

  8. Designing More Efficient Preclinical Experiments: A Simulation Study in Chemotherapy-Induced Myelosupression

    PubMed Central

    Martin, Emma C.; Aarons, Leon; Yates, James W. T.

    2016-01-01

    A new more efficient preclinical study design (referred to as a compact design) is proposed that removes the need for satellite animals for the collection of toxicokinetic (TK) data by sampling from the main study animals, taking no more than one sample in 24 h to build up a full profile over the course of the study. The compact design’s performance was tested with a simulation study, using an example of chemotherapy-induced myelosupression in rats. Data sets were simulated from a model based on available data, following both the compact design and a traditional design using satellite animals, with 100 studies being simulated for each. The effect of the compact design on parameter and variance estimates for the TK and neutrophil models were investigated, as well as the potential effect of interoccasion variability (IOV). The compact design performed equally as well as the traditional design, and had little impact on parameter or variation estimates, indicating that it would be a suitable alternative to traditional satellite designs while reducing the number of animals required. When IOV was present but not accounted for during the TK analysis some parameter estimates were biased and interindividual variation and residual errors inflated; this was reduced by allowing for IOV in the analysis. Using the compact design removes the need for a satellite group, reducing the number of animals required, without affecting the ability to model the data. If large IOV is suspected, caution should be exercised to avoid parameter estimation bias, and inflation of variability and residual error. PMID:26678701

  9. Designing More Efficient Preclinical Experiments: A Simulation Study in Chemotherapy-Induced Myelosupression.

    PubMed

    Martin, Emma C; Aarons, Leon; Yates, James W T

    2016-03-01

    A new more efficient preclinical study design (referred to as a compact design) is proposed that removes the need for satellite animals for the collection of toxicokinetic (TK) data by sampling from the main study animals, taking no more than one sample in 24?h to build up a full profile over the course of the study. The compact design's performance was tested with a simulation study, using an example of chemotherapy-induced myelosupression in rats. Data sets were simulated from a model based on available data, following both the compact design and a traditional design using satellite animals, with 100 studies being simulated for each. The effect of the compact design on parameter and variance estimates for the TK and neutrophil models were investigated, as well as the potential effect of interoccasion variability (IOV). The compact design performed equally as well as the traditional design, and had little impact on parameter or variation estimates, indicating that it would be a suitable alternative to traditional satellite designs while reducing the number of animals required. When IOV was present but not accounted for during the TK analysis some parameter estimates were biased and interindividual variation and residual errors inflated; this was reduced by allowing for IOV in the analysis. Using the compact design removes the need for a satellite group, reducing the number of animals required, without affecting the ability to model the data. If large IOV is suspected, caution should be exercised to avoid parameter estimation bias, and inflation of variability and residual error. PMID:26678701

  10. Toxicology of antisense therapeutics.

    PubMed

    Jason, Tracey L H; Koropatnick, James; Berg, Randal W

    2004-11-15

    Targeting unique mRNA molecules using antisense approaches, based on sequence specificity of double-stranded nucleic acid interactions should, in theory, allow for design of drugs with high specificity for intended targets. Antisense-induced degradation or inhibition of translation of a target mRNA is potentially capable of inhibiting the expression of any target protein. In fact, a large number of proteins of widely varied character have been successfully downregulated using an assortment of antisense-based approaches. The most prevalent approach has been to use antisense oligonucleotides (ASOs), which have progressed through the preclinical development stages including pharmacokinetics and toxicological studies. A small number of ASOs are currently in human clinical trials. These trials have highlighted several toxicities that are attributable to the chemical structure of the ASOs, and not to the particular ASO or target mRNA sequence. These include mild thrombocytopenia and hyperglycemia, activation of the complement and coagulation cascades, and hypotension. Dose-limiting toxicities have been related to hepatocellular degeneration leading to decreased levels of albumin and cholesterol. Despite these toxicities, which are generally mild and readily treatable with available standard medications, the clinical trials have clearly shown that ASOs can be safely administered to patients. Alternative chemistries of ASOs are also being pursued by many investigators to improve specificity and antisense efficacy and to reduce toxicity. In the design of ASOs for anticancer therapeutics in particular, the goal is often to enhance the cytotoxicity of traditional drugs toward cancer cells or to reduce the toxicity to normal cells to improve the therapeutic index of existing clinically relevant cancer chemotherapy drugs. We predict that use of antisense ASOs in combination with small molecule therapeutics against the target protein encoded by the antisense-targeted mRNA, or an alternate target in the same or a connected biological pathway, will likely be the most beneficial application of this emerging class of therapeutic agent. PMID:15519609

  11. Uses of available record systems in epidemiologic studies of reproductive toxicology

    SciTech Connect

    Polednak, A.P.; Janerich, D.T.

    1983-01-01

    The uses of available record systems in epidemiologic studies of reproductive toxicology are described with reference to New York State. The available record systems (and relevant reproductive end points) described include: a newborn screening program for metabolic diseases and hemoglobinopathies (relevant to point mutations); chromosome registries and prenatal cytogenetics (for chromosome anomalies); live birth certificates (for birth defects, birthweight, sex ratio, etc); fetal death certificates (for spontaneous fetal deaths); and a statewide cancer registry (for childhood cancers and transplacental carcinogenesis). The uses and limitations of these record systems are discussed, along with examples of their use in descriptive and analytic epidemiologic studies. Descriptive studies outlined include investigations of temporal and geographic trends in birth defects, birth weight, and fetal deaths, with reference to environmental questions (eg, Love Canal, nuclear power plants). Analytic studies described concern parental occupation in relation to specific birth defects (neural tube defects and Down syndrome) and maternal use of contraceptive drugs.

  12. Antimicrobial and toxicological studies on fruit pulp of Citrullus colocynthis L.

    PubMed

    Shaikh, Jahanzeb; Shaikh, Dilnawaz; Rahman, Asif Bin; Shafi, Sumaira

    2016-01-01

    The methanolic extract of dried fruit pulp of Citrulluscolocyn this (Cucurbitaceae) has been studied with respect to antimicrobial and toxicological properties. The antimicrobial profile was investigated against thirty bacterial isolates (10 Gram +ve and 20 Gram-ve) and five fungal species. None of the bacterial or fungal culture used in the study showed sensitivity against the extract. Acute toxicity studies carried out in Albino mice NMRI indicated the highly toxic nature of the colocynth. A very significant decrease in body weight of test animals was noted at P<0.05. The LD50 was calculated as 1000mg/kg body weight. Within four days of experimentation mortality was 100%. Histopathological studies confirmed the toxic nature of extract. Gross changes in histology of Heart, Liver and Kidneys were noted. Section of spleen did not exhibit any abnormality. PMID:26826821

  13. Pharmacological Intervention Studies Using Mouse Models of the Inflammatory Bowel Diseases: Translating Preclinical Data into New Drug Therapies

    PubMed Central

    Koboziev, Iurii; Karlsson, Fridrik; Zhang, Songlin; Grisham, Matthew B.

    2010-01-01

    Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in well-controlled clinical trials is to identify the most relevant mouse models IBD and pharmacologic strategies that most closely mimic the clinical situation. To begin this process, we present a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies. PMID:21312318

  14. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

    PubMed Central

    Eissa, Maha M.; El-Moslemany, Riham M.; Ramadan, Alyaa A.; Amer, Eglal I.; El-Azzouni, Mervat Z.; El-Khordagui, Labiba K.

    2015-01-01

    Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting via the oral route. From a clinical point of view, data suggest MFS-LNCs as a potential single dose oral nanomedicine for enhanced therapy of schistosomiasis mansoni and possibly other diseases. PMID:26574746

  15. COMPARATIVE EFFECTIVENESS AND SAFETY OF IMAGE GUIDANCE SYSTEMS IN NEUROSURGERY: A PRECLINICAL RANDOMIZED STUDY

    PubMed Central

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

    2015-01-01

    Object Over the last decade image guidance systems have been widely adopted in neurosurgery. Nonetheless, the evidence supporting the use of these systems in surgery remains limited. The aim of this study was to compare simultaneously the effectiveness and safety of various image guidance systems against standard surgery. Methods In this preclinical randomized study 50 novice surgeons were allocated to: (1) no image guidance, (2) triplanar display, (3) always-on solid overlay, (4) always-on wire mesh overlay, and (5) on-demand inverse realism overlay. Each participant was asked to identify a basilar tip aneurysm in a validated model head. The primary outcomes were time to task completion (seconds), and tool path length (millimeters). The secondary outcomes were recognition of an unexpected finding (a surgical clip), and subjective depth perception using a Likert scale. Results The time to task completion and tool path length were significantly lower when utilizing any form of image guidance compared to no image guidance (p < 0·001 and p = 0·003, respectively). The tool path distance was also lower in groups utilizing augmented reality compared to triplanar display (p = 0·010). Always-on solid overlay resulted in the greatest inattentional blindness (20% recognition of unexpected finding). Wire mesh and on-demand overlays mitigated but did not negate inattentional blindness, and were comparable to triplanar display (40% recognition of unexpected finding in all groups). Wire mesh and inverse realism overlays also resulted in better subjective depth perception than always-on solid overlay (p = 0·031 and p = 0·008, respectively). Conclusions New augmented reality platforms may improve performance in less experienced surgeons. However, all image display modalities, including existing triplanar display, carry a risk of inattentional blindness. PMID:25909567

  16. Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

    PubMed Central

    Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

    2012-01-01

    The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

  17. Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma.

    PubMed

    Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

    2012-05-01

    The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

  18. 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, ...

  19. Executive Function Changes before Memory in Preclinical Alzheimer’s Pathology: A Prospective, Cross-Sectional, Case Control Study

    PubMed Central

    Harrington, Michael G.; Chiang, Jiarong; Pogoda, Janice M.; Gomez, Megan; Thomas, Kris; Marion, Sarah DeBoard; Miller, Karen J.; Siddarth, Prabha; Yi, Xinyao; Zhou, Feimeng; Lee, Sherri; Arakaki, Xianghong; Cowan, Robert P.; Tran, Thao; Charleswell, Cherise; Ross, Brian D.; Fonteh, Alfred N.

    2013-01-01

    Background Early treatment of Alzheimer’s disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer’s disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology. Methods and Findings We recruited adults with probable Alzheimer’s disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer’s disease. We separated the asymptomatic group into those with (n = 34; preclinical Alzheimer’s disease) and without (n = 36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-ε genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR = 0.13, 95% CI = 0.04–0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study. Conclusions Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer’s disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach. PMID:24260210

  20. Implications of the stability behavior of zinc oxide nanoparticles for toxicological studies

    NASA Astrophysics Data System (ADS)

    Meißner, Tobias; Oelschlägel, Kathrin; Potthoff, Annegret

    2014-08-01

    The increasing use of zinc oxide (ZnO) nanoparticles in sunscreens and other cosmetic products demands a risk assessment that has to be done in toxicological studies. Such investigations require profound knowledge of the behavior of ZnO in cell culture media. The current study was performed to get well-dispersed suspensions of a hydrophilic (ZnO-hydro) and a lipophilic coated (ZnO-lipo) ZnO nanomaterial for use in in vitro tests. Therefore, systematic tests were carried out with common dispersants (phosphate, lecithin, proteins) to elucidate chemical and physical changes of ZnO nanoparticles in water and physiological solutions (PBS, DMEM). Non-physiological stock suspensions were prepared using ultrasonication. Time-dependent changes of pH, conductivity, zeta potential, particle size and dissolution were recorded. Secondly, the stock suspensions were added to physiological media with or without albumin (BSA) or serum (FBS), to examine characteristics such as agglomeration and dissolution. Stable stock suspensions were obtained using phosphate as natural and physiological electrostatic stabilizing agent. Lecithin proved to be an effective wetting agent for ZnO-lipo. Although the particle size remained constant, the suspension changed over time. The pH increased as a result of ZnO dissolution and formation of zinc phosphate complexes. The behavior of ZnO in physiological media was found to depend strongly on the additives used. Applying only phosphate as additive, ZnO-hydro agglomerated within minutes. In the presence of lecithin or BSA/serum, agglomeration was inhibited. ZnO dissolution was higher under physiological conditions than in the stock suspension. Serum especially promoted this process. Using body-related dispersants (phosphate, lecithin) non-agglomerating stock suspensions of hydrophilic and lipophilic ZnO were prepared as a prerequisite to perform meaningful toxicological investigation. Both nanomaterials showed a non-negligible dissolution behavior that strongly depended on the surrounding conditions. Agglomeration of ZnO particles in physiological media is a complex function of particle coating, used dispersants and serum proteins if supplemented. The present study gives a clear guideline how to prepare and handle suspensions with ZnO for in vitro testing and allows the correlation between the chemical-physical particles behavior with findings from toxicological tests.

  1. 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.

  2. Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa.

    PubMed

    Conlon, Thomas J; Deng, Wen-Tao; Erger, Kirsten; Cossette, Travis; Pang, Ji-jing; Ryals, Renee; Clment, Nathalie; Cleaver, Brian; McDoom, Issam; Boye, Shannon E; Peden, Marc C; Sherwood, Mark B; Abernathy, Corinne R; Alkuraya, Fowzan S; Boye, Sanford L; Hauswirth, William W

    2013-03-01

    Abstract Proof of concept for MERTK gene replacement therapy has been demonstrated using different viral vectors in the Royal College of Surgeon (RCS) rat, a well characterized model of recessive retinitis pigmentosa that contains a mutation in the Mertk gene. MERTK plays a key role in renewal of photoreceptor outer segments (OS) by phagocytosis of shed OS tips. Mutations in MERTK cause impaired phagocytic activity and accumulation of OS debris in the interphotoreceptor space that ultimately leads to photoreceptor cell death. In the present study, we conducted a series of preclinical potency and GLP-compliant safety evaluations of an adeno-associated virus type 2 (AAV2) vector expressing human MERTK cDNA driven by the retinal pigment epithelium-specific, VMD2 promoter. We demonstrate the potency of the vector in RCS rats by improved electroretinogram (ERG) responses in treated eyes compared with contralateral untreated controls. Toxicology and biodistribution studies were performed in Sprague-Dawley (SD) rats injected with two different doses of AAV vectors and buffer control. Delivery of vector in SD rats did not result in a change in ERG amplitudes of rod and cone responses relative to balanced salt solution control-injected eyes, indicating that administration of AAV vector did not adversely affect normal retinal function. In vivo fundoscopic analysis and postmortem retinal morphology of the vector-injected eyes were normal compared with controls. Evaluation of blood smears showed the lack of transformed cells in the treated eyes. All injected eyes and day 1 blood samples were positive for vector genomes, and all peripheral tissues were negative. Our results demonstrate the potency and safety of the AAV2-VMD2-hMERTK vector in animal models tested. A GMP vector has been manufactured and is presently in clinical trial. PMID:23692380

  3. Correlates of preclinical cardiovascular disease in Indigenous and Non-Indigenous Australians: a case control study

    PubMed Central

    Haluska, Brian A; Chan, Lionel; Jeffriess, Leanne; Shaw, A Andrew; Shaw, Joanne; Marwick, Thomas H

    2008-01-01

    Background The high frequency of premature death from cardiovascular disease in indigenous Australians is often attributed to the high prevalence of risk factors, especially type II diabetes mellitus (DM). We evaluated the relationship of ethnicity to atherosclerotic burden, as evidenced by carotid intima-media thickness (IMT), independent of risk factor status. Methods We studied 227 subjects (147 men; 50 13 y): 119 indigenous subjects with (IDM, n = 54), and without DM (InDM, n = 65), 108 Caucasian subjects with (CDM, n = 52), and without DM (CnDM, n = 56). IMT was measured according to standard methods and compared with clinical data and cardiovascular risk factors. Results In subjects both with and without DM, IMT was significantly greater in indigenous subjects. There were no significant differences in gender, body mass index (BMI), systolic blood pressure (SBP), or diastolic blood pressure (DBP) between any of the groups, and subjects with DM showed no difference in plasma HbA1c. Cardiovascular risk factors were significantly more prevalent in indigenous subjects. Nonetheless, ethnicity (? = -0.34; p < 0.0001), age (? = 0.48; p < 0.0001), and smoking (? = 0.13; p < 0.007) were independent predictors of IMT in multiple linear regression models. Conclusion Ethnicity appears to be an independent correlate of preclinical cardiovascular disease, even after correction for the high prevalence of cardiovascular risk factors in indigenous Australians. Standard approaches to control currently known risk factors are vital to reduce the burden of cardiovascular disease, but in themselves may be insufficient to fully address the high prevalence in this population. PMID:18627637

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

    PubMed Central

    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 Harmonisation. 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. Pharmacological treatment of idiopathic pulmonary fibrosis – preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine

    PubMed Central

    Myllärniemi, Marjukka; Kaarteenaho, Riitta

    2015-01-01

    Three recent clinical trials on the pharmacologic treatment of idiopathic pulmonary fibrosis (IPF) mark a new chapter in the management of patients suffering from this very severe fibrotic lung disease. This review article summarizes the published investigations on the preclinical studies of three novel IPF drugs, namely pirfenidone, nintedanib, and N-acetylcysteine (NAC). In addition, the study protocols, differences, and the main findings in the recent clinical trials of these pharmacological treatments are reviewed. The strategy for drug development and the timeline from the discovery to the clinical use have been very different in these regimens. Pirfenidone was discovered in 1976 but only recently received approval in most countries, and even now its exact mechanism of action is unknown. On the contrary, nintedanib (BIBF1120) was identified in large drug screening tests as a very specific inhibitor of certain tyrosine kinases, but no published data on preclinical tests existed until 2014. NAC, a mucolytic drug with an antioxidant mechanism of action was claimed to possess distinct antifibrotic properties in several experimental models but proved to be ineffective in a recent randomized placebo-controlled trial. At present, no curative treatment is available for IPF. A better understanding of the molecular mechanisms of IPF as well as relevant preclinical tests including animal models and in vitro experiments on human lung cells are needed to promote the development of therapeutic drugs. PMID:26557253

  6. Zebrafish (Danio rerio) neuromast: promising biological endpoint linking developmental and toxicological studies.

    PubMed

    Froehlicher, Mirjam; Liedtke, Anja; Groh, Ksenia J; Neuhauss, Stephan C F; Segner, Helmut; Eggen, Rik I L

    2009-12-13

    Aquatic toxicology is facing the challenge to assess the impact of complex mixtures of compounds on diverse biological endpoints. So far, ecotoxicology focuses mainly on apical endpoints such as growth, lethality and reproduction, but does not consider sublethal toxic effects that may indirectly cause ecological effects. One such sublethal effect is toxicant-induced impairment of neurosensory functions which will affect important behavioural traits of exposed organisms. Here, we critically review the mechanosensory lateral line (LL) system of zebrafish as a model to screen for chemical effects on neurosensory function of fish in particular and vertebrates in general. The LL system consists of so-called neuromasts, composed of centrally located sensory hair cells, and surrounding supporting cells. The function of neuromasts is the detection of water movements that is essential for the fish's ability to detect prey, to escape predator, to socially interact or to show rheotactic behaviour. Recent advances in the study of these organs provided researchers with a broad area of molecular tools for easy and rapid detection of neuromasts dysfunction and/or disturbed development. Further, genes involved in neuromasts differentiation have been identified using auditory/mechanosensory mutants and morphants. A number of environmental toxicants including metals and pharmaceuticals have been shown to affect neuromasts development and/or function. The use of the LL organ for toxicological studies offers the advantage to integrate the available profound knowledge on developmental biology of the neuromasts with the study of chemical toxicity. This combination may provide a powerful tool in environmental risk assessment. PMID:19467721

  7. 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

  8. 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.

  9. Toxicological studies on silver nanoparticles: challenges and opportunities in assessment, monitoring and imaging

    PubMed Central

    Stensberg, Matthew Charles; Wei, Qingshan; McLamore, Eric Scott; Porterfield, David Marshall; Wei, Alexander; Sepúlveda, Marĺa Soledad

    2012-01-01

    Silver nanoparticles (Ag NPs) are becoming increasingly prevalent in consumer products as antibacterial agents. The increased use of Ag NP-enhanced products may lead to an increase in toxic levels of environmental silver, but regulatory control over the use or disposal of such products is lagging due to insufficient assessment on the toxicology of Ag NPs and their rate of release into the environment. In this article we discuss recent research on the transport, activity and fate of Ag NPs at the cellular and organismic level, in conjunction with traditional and recently established methods of nanoparticle characterization. We include several proposed mechanisms of cytotoxicity based on such studies, as well as new opportunities for investigating the uptake and fate of Ag NPs in living systems. PMID:21793678

  10. A primary culture system of adult rat heart cells for the study of toxicologic agents.

    PubMed

    Welder, A A; Grant, R; Bradlaw, J; Acosta, D

    1991-12-01

    Tricyclic antidepressants (TCAs) are currently used in the treatment of mental depression and nocturnal enuresis. Clinically, these drugs are useful; however, cardiotoxicity can occur even with therapeutic dosages. For example, TCAs are known to alter myocardial function, induce arrhythmias, and produce heart block in individuals with a normal cardiovascular history. The present study was undertaken to establish a culture system of spontaneously contracting adult primary myocardial cells for toxicologic testing and to examine their contractility, morphology, and lactate dehydrogenase release (LDH) after treatment with one of the most cardiotoxic TCAs, amitriptyline. Primary myocardial cell cultures were obtained from approximately 60- to 90-day-old Sprague-Dawley rats. After the cells had been grown in culture for 11 days, they were treated with amitriptyline (1 x 10(-3), 1 x 10(-4), and 1 x 10(-5) M) for 2 to 24 h. The highest concentration of amitriptyline (1 x 10(-3) M) completely destroyed the cardiac muscle cells. In addition to moderate and severe vacuole, granule, and pseudopodia formation, all contractile activity was inhibited as early as 2 h after exposure to the intermediate concentration of 1 x 10(-4) M amitriptyline. Significant LDH release did not occur until 8 h after treatment with this intermediate concentration. Even though there was no significant LDH release at all 3 time points tested, there was a 50% decrease in beating activity (154 +/- 9 to 77 +/- 5 beats/min) and initiation of vacuole formation by 2 h with the lowest concentration of amitriptyline (1 x 10(-5) M). This study presents a new apparatus for the isolation of adult cardiac myocytes for the establishment of primary cell cultures for toxicologic testing. Furthermore, these data demonstrate that amitriptyline induces a concentration- and time-dependent cardiotoxic profile in a model of spontaneously contracting adult cardiac muscle cells in culture. PMID:1757397

  11. 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 Αβ (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 Αβ (RRR = 8.3), APOE ε4 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 ε4 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 Αβ) and unique (e.g., APOE ε4 genotype) determinants. PMID:25585532

  12. 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...

  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. OPTIMIZATION OF THE HAMILTON-THORN COMPUTERIZED SPERM MOTILITY ANALYSIS SYSTEM FOR USE WITH RAT SPERMATOZOA IN TOXICOLOGICAL STUDIES

    EPA Science Inventory

    To optimize the Hamilton-Thorn Motility Analyzer (HIM, 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. ideotapes of both fast ...

  15. 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...

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

    SciTech Connect

    Chen Yuhchyau; Pandya, Kishan J.; Hyrien, Ollivier; Keng, Peter C.; Smudzin, Therese; Anderson, Joy; Qazi, Raman; Smith, Brian; Watson, Thomas J.; Feins, Richard H.; Johnstone, David W.

    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.

  17. Microminipigs as a new experimental animal model for toxicological studies: comparative pharmacokinetics of perfluoroalkyl acids.

    PubMed

    Guruge, Keerthi S; Noguchi, Michiko; Yoshioka, Koji; Yamazaki, Eriko; Taniyasu, Sachi; Yoshioka, Miyako; Yamanaka, Noriko; Ikezawa, Mitsutaka; Tanimura, Nobuhiko; Sato, Masumi; Yamashita, Nobuyoshi; Kawaguchi, Hiroaki

    2016-01-01

    In this study, we evaluated the efficacy of a novel minipig strain, the Microminipig (MMPig), as an animal model for studying the pharmacokinetics of a mixture of 10 perfluoroalkyl acids (PFAAs). After a single oral dose was given, we found that the blood depuration of PFAAs (blood t1/2), which we calculated using first-order elimination curves, ranged from 1.6 to 86.6 days. Among the five body compartments analyzed, the liver was the greatest site of accumulation of perfluorooctanesulfonate and longer chain perfluorinated carboxylates such as perfluorodecanoic acid, perfluoroundecanoic acid and perfluorododecanoic acid. We observed an increasing accumulation trend of perfluorinated carboxylates in the organs associated with the fluorinated carbon chain length. The perfluorononanoic acid burden was the highest among the treated compounds 21 days after a single exposure, as 29% of the given perfluorononanoic acid dose was accumulated in the tissues. The persistence of PFAAs in edible pig tissues even after 21 days post-exposure raises concerns about the safety of swine products. This was the first study to use MMPigs to elucidate the pharmacokinetics of a group of environmental pollutants. We found that MMPigs could be excellent experimental animals for toxicological studies due to their easy handling, cost efficacy for target compounds and ease of waste treatment. PMID:25877231

  18. Comparative Toxicological Studies of Amphotericin B Methyl Ester and Amphotericin B in Mice, Rats, and Dogs

    PubMed Central

    Keim, G. R.; Sibley, P. L.; Yoon, Y. H.; Kulesza, J. S.; Zaidi, I. H.; Miller, M. M.; Poutsiaka, J. W.

    1976-01-01

    In acute and subacute toxicological studies, amphotericin B methyl ester was shown to be much less toxic than the parent antibiotic. As a single intravenous dose in mice, the methyl ester was approximately 20 times less toxic than amphotericin B. Also, the acute toxicity of the methyl ester in mice was not enhanced by the presence of chemically induced hepatic or renal damage or by the concurrent administration of amphotericin B or flucytosine. In a 1-month intraperitoneal study in rats, the methyl ester was about one-fourth as nephrotoxic as amphotericin B. In a 1-month intravenous study in dogs, the methyl ester was about one-eighth as nephrotoxic and one-fourth to one-half as hepatotoxic as the parent compound. In addition, the methyl ester, unlike amphotericin B, produced minimal renal effects, which did not increase in severity with increasing dosage. Based on the results of these studies, it is concluded that amphotericin B methyl ester has the potential for an improved therapeutic ratio in the treatment of systemic mycoses. PMID:984803

  19. Toxicological evaluation of Yulangsan polysaccharide in Wistar rats: A 26-week oral gavage study.

    PubMed

    Chen, Chunxia; Nong, Zhihuan; Meng, Mingyu; Wen, Qingwei; Lin, Xing; Qin, Feizhang; Huang, Jianchun; Huang, Renbin

    2016-01-01

    Although numerous studies have proven the medicinal values of Yulangsan polysaccharide (YLSP), the toxicity of this active ingredient is unknown. In the acute toxicity study, a single oral administration of 24g/kg YLSP caused neither toxicological symptoms nor mortality, and the LD50 was estimated >24g/kg. In the chronic toxicity study, we administered doses of 0, 0.6, 1.2 and 2.4g/kg YLSP in rats by oral gavage for 26 weeks followed by a 3-week recovery period. There was no mortality or remarkable clinical signs observed during this 26-week study. Additionally, there were no toxic differences in the following parameters: body weight, food consumption, hematology, clinical biochemistry, organ weight, and macroscopic ?ndings. There were no adverse effects on histopathology observed in males or female rats treated with YLSP. Based on the results, the no-observed-adverse-effect-level of YLSP in rats is greater than 2.4g/kg when administered orally for 26 consecutive weeks. PMID:26645132

  20. Advances in reproductive toxicology

    SciTech Connect

    Scialli, A.R. )

    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.

  1. 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

  2. Aerospace Toxicology and Microbiology

    NASA Technical Reports Server (NTRS)

    James, John T.; Parmet, A. J.; Pierson, Duane L.

    2007-01-01

    Toxicology dates to the very earliest history of humanity with various poisons and venom being recognized as a method of hunting or waging war with the earliest documentation in the Evers papyrus (circa 1500 BCE). The Greeks identified specific poisons such as hemlock, a method of state execution, and the Greek word toxos (arrow) became the root of our modern science. The first scientific approach to the understanding of poisons and toxicology was the work during the late middle ages of Paracelsus. He formulated what were then revolutionary views that a specific toxic agent or "toxicon" caused specific dose-related effects. His principles have established the basis of modern pharmacology and toxicology. In 1700, Bernardo Ramazzini published the book De Morbis Artificum Diatriba (The Diseases of Workers) describing specific illnesses associated with certain labor, particularly metal workers exposed to mercury, lead, arsenic, and rock dust. Modern toxicology dates from development of the modern industrial chemical processes, the earliest involving an analytical method for arsenic by Marsh in 1836. Industrial organic chemicals were synthesized in the late 1800 s along with anesthetics and disinfectants. In 1908, Hamilton began the long study of occupational toxicology issues, and by WW I the scientific use of toxicants saw Haber creating war gases and defining time-dosage relationships that are used even today.

  3. Incorporation of a micronucleus study into a developmental toxicology and pharmacokinetic study of L-selenomethionine in nonhuman primates

    SciTech Connect

    Choy, Wai Nang; Henika, P.R.; Willhite, C.C.; Tarantal, A.F. )

    1993-01-01

    Concomitant to a developmental toxicology study of selenium in long-tailed macaques (Macaca fascicularis), a transplacental bone marrow micronucleus assay was conducted in the fetuses of treated animals. Selenium was administered as L-selenomethionine by nasogastric intubation at 0, 150 or 300 [mu]g/kg-day to pregnant macaques daily throughout organogenesis (gestation days 20-50). Pregnancy was terminated on gestation day 100 [+-] 2 and fetuses were obtained by hysterotomy. Selenium concentrations in maternal blood were monitored throughout pregnancy and selenium concentrations in fetal blood were measured at hysterotomy. Maternal circulating selenium did not exceed 4 ppm in plasma or 3.7 ppm in erthrocytes. Selenium in cord blood was [<=] 0.1 ppm in plasma and [<=] 1.1 ppm in erthrocytes at 300 [mu]g/kg-day. Fetal bone marrow smears were prepared from the humerus and micronucleated polychromatic erythrocytes were scored. No increase of micronucleus frequency was detected in any dose group, although signs of maternal selenosis were obvious. This finding is compared to the previous observation that micronuclei were induced in the bone marrow of adult nonpregnant macaques treated at 600 [mu]g/kg-day, a lethal dose yielding blood selenium levels to 7.3 ppm in plasma and 5.7 ppm in erthyrocytes after 15 days of daily treatment, when death occurred. These data demonstrate that measurement of circulating xenobiotics can be useful for the interpretation of genetic toxicology results. 32 refs., 4 figs., 4 tabs.

  4. Sauropus androgynus (L.) Merr. Induced Bronchiolitis Obliterans: From Botanical Studies to Toxicology

    PubMed Central

    Bunawan, Hamidun; Bunawan, Siti Noraini; Baharum, Syarul Nataqain; Noor, Normah Mohd.

    2015-01-01

    Sauropus androgynus L. Merr. is one of the most popular herbs in South Asia, Southeast Asia, and China where it was known as a slimming agent until two outbreaks of pulmonary dysfunction were reported in Taiwan and Japan in 1995 and 2005, respectively. Several studies described that the excessive consumption of Sauropus androgynus could cause drowsiness, constipation, and bronchiolitis obliterans and may lead to respiratory failure. Interestingly, this herb has been used in Malaysia and Indonesia in cooking and is commonly called the “multigreen” or “multivitamin” plant due to its high nutritive value and inexpensive source of dietary protein. The plant is widely used in traditional medicine for wound healing, inducing lactation, relief of urinary disorders, as an antidiabetic cure and also fever reduction. Besides these medicinal uses, the plant can also be used as colouring agent in food. This review will explore and compile the fragmented knowledge available on the botany, ethnobotany, chemical constitutes, pharmacological properties, and toxicological aspects of this plant. This comprehensive review will give readers the fundamental, comprehensive, and current knowledge regarding Sauropus androgynus L. Merr. PMID:26413127

  5. Mechanisms of aortic aneurysm formation: translating preclinical studies into clinical therapies.

    PubMed

    Davis, Frank M; Rateri, Debra L; Daugherty, Alan

    2014-10-01

    Aneurysms are common in the abdominal and thoracic regions of the aorta. While generally asymptomatic, progression of aneurysms is associated with the devastating consequences of aortic rupture. Current therapeutic options to prevent rupture are restricted to surgical repair, as there remains a lack of validated pharmaceutical approaches. Absence of proven medical therapies may be a consequence of the paucity of knowledge on mechanisms of aneurysmal initiation, progression and rupture. Many potential therapeutic targets have been identified in several widely used animal models of these diseases. A small number of these targets are currently under clinical evaluation, while many more are in preclinical stages of evaluation. The purpose of this review is to: (1) overview current understanding of mechanisms of aneurysmal initiation and progression and (2) summarise medical therapies that have been investigated clinically, as well as highlight future therapeutic targets. PMID:25060754

  6. Therapeutic Vaccination in Chronic Hepatitis B: Preclinical Studies in the Woodchuck

    PubMed Central

    Kosinska, Anna D.; Zhang, Ejuan; Lu, Mengji; Roggendorf, Michael

    2010-01-01

    Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to a satisfactory result. Induction of HBV-specific T cells by therapeutic vaccination or immunotherapies may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients did not result in effective control of HBV infection, suggesting that new formulations of therapeutic vaccines are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing the new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments with nucleos(t)ide analogues, DNA vaccines, and protein vaccines were tested in the woodchuck model. In this paper we summarize the available data concerning therapeutic immunization and gene therapy using recombinant viral vectors approaches in woodchucks, which show encouraging results. In addition, we present potential innovations in immunomodulatory strategies to be evaluated in this animal model. PMID:21188201

  7. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies.

    PubMed

    Magnuson, B A; Burdock, G A; Doull, J; Kroes, R M; Marsh, G M; Pariza, M W; Spencer, P S; Waddell, W J; Walker, R; Williams, G M

    2007-01-01

    Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener. PMID:17828671

  8. The relationship among microsomal enzyme induction, liver weight, and histological change in cynomolgus monkey toxicology studies.

    PubMed

    Amacher, David E; Schomaker, Shelli J; Boldt, Sherri E; Mirsky, Michael

    2006-04-01

    The purpose of this investigation was to examine the relationship among hepatic microsomal enzyme induction, liver weight, histological evidence of hepatic injury, and serum clinical chemistry markers of hepatic origin in the cynomolgus monkey. We report here the results from independent toxicology studies for 10 investigative drug candidates representing four therapeutic classes. Study conditions were selected to elicit target organ toxicity. We found that six of the 10 compounds altered cytochrome P450-associated activities in both male and female monkeys, two in females only, and one altered similar activities in males only. Frequently, significant treatment-related elevations in NADPH cytochrome c reductase and ethylmorphine N-demethylase were noted. When the results from all 10 studies were pooled, 14 cytochrome P450-associated activities were significantly increased and five were decreased in males compared to 15 significantly increased and three decreased in the females. Treatment-associated liver weight increases were noted in four studies. Except for hepatocellular hypertrophy in one study, no significant treatment-related microscopic changes in liver and no elevations of serum biomarkers commonly associated with liver toxicity were observed in any of the studies that demonstrated significant hepatic enzyme induction. Compared to parallel rat studies, one compound was an inducer only in monkeys and one was an inducer only in rats. Significant elevations of microsomal drug-metabolizing enzymes in the cynomolgus monkey liver are not accompanied by substantial hepatic changes except for hepatomegaly. These alterations in the hepatic drug-metabolizing enzyme system were benign based the absence of histopathological lesions and serum biomarkers of hepatobiliary toxicity. PMID:16274908

  9. 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

  10. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

    PubMed

    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

  11. 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

  12. A critique of biomarkers in environmental toxicology: A case study in birds

    SciTech Connect

    Bellward, G.D.

    1995-12-31

    The authors have been testing the hypothesis that exposure to elevated levels of 2,3,7,8-TCDD and similarly-acting compounds derived from pulp mill effluent adversely affects the reproductive capacity of colonies of great blue herons and double crested cormorants in the local area. Their objectives included developing quantitative TCDD dose-response curves for various toxicologically relevant endpoints in birds, with the goal of finding an appropriate environmental biomarker of dioxin exposure and toxicity. Potential biomarkers studied included ethoxyresorufin O-deethylase (EROD) as a measure of cytochrome P-450 1-A activity, and various hormonally-relevant end-points as measures of dioxin toxicity. The animal model used was the newly hatched chick, after in ovo exposure either in the laboratory or from the environment. Because the TEQ approach is based to a large extent on the use of in vitro and in vivo biomarkers, this study provides a useful example of one of the simplest in vivo models. The authors were able to construct hepatic EROD dose-response curves from the environmentally exposed heron and cormorant chicks, and from TCDD egg injections both early and late in the incubation period. Domestic chicken and pigeons were used as control species. The EROD induction data from the late injection pigeon study was very helpful for predicting appropriate doses for use in the early injection experiments, and for the wild avian species. However, the data was too limited to use for accurately predicting such endpoints as mortality, or effects at the lower end of the dose-response curves. Using various toxic equivalency factors, TEQs for the environmental data were calculated, and compared to the laboratory derived dose-response curves for TCDD. Using specific examples from this environmental case study, the strengths and weaknesses of the use of biomarkers and the TEQ approach will be discussed.

  13. Transcriptional profiling of reactive metabolites for elucidating toxicological mechanisms: a case study of quinoneimine-forming agents.

    PubMed

    Stamper, Brendan D

    2015-02-01

    Toxicogenomics can be broadly defined as the study of how the genetic material responds to toxicant exposure. This sub-discipline of toxicology utilizes numerous genomic technologies to relate adverse toxicologic effects with their associated changes in gene expression. The scope of this review will focus on microarray technology and its use in identifying key biomarkers at both the single gene and pathway levels to elucidate toxicologic mechanisms in the liver. Microarrays have been used to study global transcriptomic changes associated with toxicants for years; however, limited emphasis has been placed on what role their reactive metabolites play in this process. Reactive metabolites, which can be generated by normal oxidative metabolism, have the potential to react with endogenous biomolecules, alter their function, and elicit a toxicogenomic response. Quinoneimines are an example of such a species, eliciting toxicity through the generation of oxidative and electrophilic stress. Five compounds with differing toxicity profiles are evaluated herein that are capable of forming quinoneimine intermediates by cytochrome P450 enzymes. They include acetaminophen (APAP), amodiaquine, atorvastatin, carvedilol, and diclofenac. Perspectives on the consistency between the hepatic gene expression profiles of these quinoneimine-forming agents as well as the untapped value of structure-based transcriptome profiling are discussed in this review. PMID:25351209

  14. Inhalation developmental toxicology studies: Teratology study of 1,3-butadiene in mice: Final report

    SciTech Connect

    Hackett, P.L.; Sikov, M.R.; Mast, T.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.

    1987-11-01

    Maternal toxicity, reproductive performance and developmental toxicology were evaluated in CD-1 mice following whole-body, inhalation exposures to 0, 40, 200 and 1000 ppM of 1,3-butadiene. The female mice, which had mated with unexposed males were exposed to the chemical for 6 hours/day on 6 through 15 dg and sacrificed on 18 dg. Maternal animals were weighed prior to mating and on 0, 6, 11 and 18 dg; the mice were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. Live fetuses were weighed and subjected to external, visceral and skeletal examinations to detect growth retardation and morphologic anomalies. Significant concentration-related decreases were detected in a number of maternal body weight measures. There was a significant concentration-related depression of fetal body weights and placental weights. Body weights of male fetuses of all exposed groups were significantly lower than values for control fetuses; weights of female fetuses were significantly depressed in the mice exposed to 200 and 1000 ppM. In the 200- and 1000-ppM exposure groups, weights of placentas of male fetuses were significantly decreased, but placental weights of female fetuses were significantly affected only in litters exposed to the highest 1,3-butadiene concentration. This exposure regimen produced significant signs of maternal toxicity at concentrations of 200 and 1000 ppM 1,3-butadiene.

  15. Docking-based classification models for exploratory toxicology studies on high-quality estrogenic experimental data

    EPA Science Inventory

    Background: Exploratory toxicology is a new emerging research area whose ultimate mission is that of protecting human health and environment from risks posed by chemicals. In this regard, the ethical and practical limitation of animal testing has encouraged the promotion of compu...

  16. 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...

  17. [Reproduction toxicologic studies on rats following oral administration of benzopyrone preparations].

    PubMed

    Preuss-Ueberschär, C; Ueberschär, S; Grote, W

    1984-01-01

    The influence of the benzopyrone preparation Venalot (active substances: coumarin and troxerutin; in the following briefly called CT) on the fertility and teratogenicity as well as on the perinatal and postnatal development of a total of 3 generations was evaluated in a combined study. The 1-, 8-, 64-, and 128fold of the daily therapeutical doses for humans was suspended in tap water and administered orally by gavage to 95 male and 190 female SPF rats (Wistar) (test groups 2 to 5). 23 male and 46 female rats (test group 1) served as controls and were given tap water alone. The male animals were subjected to a pretreatment of 10, the female animals to one of 3 weeks. The treatment was continued during the phase of mating. The animals scheduled for cesarian section received the test substance until the day of the laparatomy (gestation day 20), those selected for littering throughout lactation (day 24 post partum). With the aid of a stepwise histological technique, the teratological examination could also disclose non lethal malformations of the organs. The treatment resulted in a decreased food consumption in the animals of group 5 and in a reduced gain of body weight as well as pathologic-anatomically and histologically demonstrable, definitely dose related hepatic lesions. The test substance had no effect on either the treated P generation nor the untreated F1 generation. As teratogenic effects could also not be demonstrated and the peri- and postnatal development of the filial generations 1 and 2 was undisturbed, the present study does not indicate a reproduction toxicological risk.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6542792

  18. 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

  19. Reproducibility of Results in Preclinical Studies: A Perspective From the Bone Field

    PubMed Central

    Manolagas, Stavros C.; Kronenberg, Henry M.

    2015-01-01

    The biomedical research enterpriseand the public support for itis predicated on the belief that discoveries and the conclusions drawn from them can be trusted to build a body of knowledge which will be used to improve human health. As in all other areas of scientific inquiry, knowledge and understanding grow by layering new discoveries upon earlier ones. The process self-corrects and distills knowledge by discarding false ideas and unsubstantiated claims. Although self-correction is inexorable in the long-term, in recent years biomedical scientists and the public alike have become alarmed and deeply troubled by the fact that many published results cannot be reproduced. The chorus of concern reached a high pitch with a recent commentary from the NIH Director, Francis S. Collins, and Principal Deputy Director, Lawrence A. Tabak, and their announcement of specific plans to enhance reproducibility of preclinical research that relies on animal models. In this invited perspective, we highlight the magnitude of the problem across biomedical fields and address the relevance of these concerns to the field of bone and mineral metabolism. We also suggest how our specialty journals, our scientific organizations, and our community of bone and mineral researchers can help to overcome this troubling trend. PMID:24916175

  20. 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-α 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

  1. Reproducibility of results in preclinical studies: a perspective from the bone field.

    PubMed

    Manolagas, Stavros C; Kronenberg, Henry M

    2014-10-01

    The biomedical research enterprise-and the public support for it-is predicated on the belief that discoveries and the conclusions drawn from them can be trusted to build a body of knowledge which will be used to improve human health. As in all other areas of scientific inquiry, knowledge and understanding grow by layering new discoveries upon earlier ones. The process self-corrects and distills knowledge by discarding false ideas and unsubstantiated claims. Although self-correction is inexorable in the long-term, in recent years biomedical scientists and the public alike have become alarmed and deeply troubled by the fact that many published results cannot be reproduced. The chorus of concern reached a high pitch with a recent commentary from the NIH Director, Francis S. Collins, and Principal Deputy Director, Lawrence A. Tabak, and their announcement of specific plans to enhance reproducibility of preclinical research that relies on animal models. In this invited perspective, we highlight the magnitude of the problem across biomedical fields and address the relevance of these concerns to the field of bone and mineral metabolism. We also suggest how our specialty journals, our scientific organizations, and our community of bone and mineral researchers can help to overcome this troubling trend. PMID:24916175

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

    PubMed

    Natesan, Sridhar; Reckless, Greg E; Barlow, Karen B L; Nobrega, Jos 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

  3. Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA)-power plant studies: assessment of cellular responses

    PubMed Central

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

    2013-01-01

    The Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA) project assessed primary and secondary particulate by simulating the chemical reactions that a plume from a source might undergo during atmospheric transport and added other atmospheric constituents that might interact with it. Three coal-fired power plants with different coal and different emission controls were used. Male Sprague-Dawley rats were exposed for 6 h to either filtered air or aged aerosol from the power plant. Four exposure scenarios were studied: primary particles (P); primary + secondary (oxidized) particles (PO); primary + secondary (oxidized) particles + SOA (POS); and primary + secondary (oxidized) particles neutralized + SOA (PONS). Exposure concentrations varied by scenario to a maximum concentration of 257.1 10.0 g/m3. Twenty-four hours after exposure, pulmonary cellular responses were assessed by bronchoalveolar lavage (BAL), complete blood count (CBC), and histopathology. Exposure to the PONS and POS scenarios produced significant increases in BAL total cells and macrophage numbers at two plants. The PONS and P scenarios were associated with significant increases in BAL neutrophils and the presence of occasional neutrophils and increased macrophages in the airways and alveoli of exposed animals. Univariate analyses and random forest analyses showed that increases in total cell count and macrophage cell count were significantly associated with neutralized sulfate and several correlated measurements. Increases in neutrophils in BAL were associated with zinc. There were no significant differences in CBC parameters or blood vessel wall thickness by histopathology. The association between neutrophils increases and zinc raises the possibility that metals play a role in this response. PMID:21466245

  4. Development of the dietary fiber functional food and studies on its toxicological and physiologic properties.

    PubMed

    Hong, Yan; Zi-Jun, Wang; Jian, Xiong; Ying-jie, Dai; Fang, Ma

    2012-09-01

    Dietary fiber (DF) obtained from wheat bran by microbial fermentation was used as a food additive to cookies. The cookies were evaluated sensorally through an orthogonal test to gain the optimized production conditions as follows: the suitable DF content 8%, leavening agent 1.5%, standing time 5 min, and baking time of the cookies is 8 min. A series of toxicological and physiological functions of the cookies were studied using KM mice as the experimental animal in this paper. No deaths or abnormal behaviors of mice occurred either in acute toxicity tests or in short-term feeding tests. Besides, the weight gains, food utilization ratios, blood and serum biochemical parameters, organ coefficients and the results of organ histopathology tests of all doses groups exhibited no significant differences with the control group. This reveals that the dietary fiber functional cookies made by this formula have no acute or sub-chronic toxicity. In terms of physiological function, compared with the control group, the total cholesterol (TC) and triglycerides (TG) were 17.0-21.7% and 18.7-35.0% lower in mice serum of all DF cookie doses groups, respectively, but this difference was not significant (P>0.05). Compared with positive control group, the Cd(2+) and Pb(2+) excretion ratios of DF group were 27.4% and 25.2% higher, respectively. Thus, a conclusion has been drawn that dietary fiber functional cookies made by this formula have no toxic or harmful actions on animals or humans, and the DF food was able to decrease TC and TG concentrations to some extent in serum and increase excretion of Cd(2+) and Pb(2+) in Feces. PMID:22609425

  5. Metabolic profiling studies on the toxicological effects of realgar in rats by (1)H NMR spectroscopy.

    PubMed

    Wei, Lai; Liao, Peiqiu; Wu, Huifeng; Li, Xiaojing; Pei, Fengkui; Li, Weisheng; Wu, Yijie

    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 (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. (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. PMID:19073202

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

    PubMed

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

    2013-12-01

    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

  8. The therapeutic potential of renin angiotensin aldosterone system (RAAS) in chronic pain: from preclinical studies to clinical trials.

    PubMed

    Bessaguet, Flavien; Magy, Laurent; Desmoulière, Alexis; Demiot, Claire

    2016-03-01

    The prevalence rate of chronic pain is 15% to 25% in adults while the therapeutic arsenal is still insufficient, especially in relieving neuropathic pain. Peripheral pain transmission is conducted by the small Aδ and C sensory nerve fibres. They express elements from the renin-angiotensin-aldosterone system (RAAS), a well-known blood pressure regulator. Recently, studies have demonstrated the role of angiotensin II, its derivatives and aldosterone in the modulation of pain perception, by interacting with receptors expressed by sensory nerve fibres or through the central nervous system. Here, we assess the effects of RAAS modulators in the conduction of pain with molecular, preclinical and clinical approaches, in normal or pathological conditions. Currently, some clinical studies have been carried out on the pain-relieving effect of RAAS modulators and suggest their potential in the management of chronic, inflammatory or neuropathic pain. PMID:26852820

  9. Are All Dentiform Teeth with Simulated Caries the Same? A Six-Year Retrospective Study in Preclinical Operative Dentistry.

    PubMed

    Delgado, Alex J; Walter, Ricardo; Behar-Horenstein, Linda S; Boushell, Lee W

    2015-11-01

    Dentiform teeth with simulated caries (DTSC), frequently used in preclinical courses, should show no variability in the amount of simulated caries from tooth to tooth. However, the level of caries variability among DTSC is currently unknown. The aim of this study was to assess the variation in simulated caries levels in one group of DTSC and determine whether variation among DTSC impacted the preclinical performance of dental students. In the study, 80 commercially available mandibular first molar DTSC with simulated mesio-occluso-distal caries were sectioned in coronal (n=40) and sagittal (n=40) planes where the caries depth/width was greatest. Section images were analyzed for variation in levels of simulated caries using image-processing software. Three years of practical performance data using DTSC were compared with three years of practical performance data using dentiform teeth without simulated caries, for a total of six years (students' performance on two exams, Practical 1 and Practical 2). The results showed that 70% of the coronally sectioned teeth had manufacturing defects that resulted in caries overextension at the dentino-enamel junctions (DEJs). Overextensions were found at the DEJ in 41.3% of the sagittally sectioned teeth. There was a statistically significant decrease in Practical 1 performance of the students who used DTSC as compared with students who used teeth without simulated caries (p=0.0001); there was no statistically significant difference on Practical 2 performance. Of the DTSC evaluated in this study, 56.6% contained manufacturing defects, and more than 80% were found to have excessive caries variation. Prediction of which DTSC will have caries overextension is not possible. Students preparing DTSC that contain caries overextension are therefore at increased risk of receiving undeserved negative summative assessment on practical examinations. PMID:26522639

  10. Analysis of machine perfusion benefits in kidney grafts: a preclinical study

    PubMed Central

    2011-01-01

    Background Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts. Methods We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia + 24 h hypothermic preservation). Endpoints were: function recovery, quality of function during follow up (3 month), inflammation, fibrosis, animal survival. Results ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and ?-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to-mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP. Conclusions With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits. PMID:21266040

  11. 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; Lin, Zhifen; Zhou, Xianghong; Yin, Daqiang

    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, ligandreceptor 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.

  12. NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics

    PubMed Central

    2014-01-01

    In May of 2014, the NIH Director together with the Director of the Office of Research on Womens Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner. PMID:25780556

  13. Two years later: journals are not yet enforcing the ARRIVE guidelines on reporting standards for pre-clinical animal studies.

    PubMed

    Baker, David; Lidster, Katie; Sottomayor, Ana; Amor, Sandra

    2014-01-01

    There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented. PMID:24409096

  14. (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

  15. Is Science the Only Driver in Species Selection? An Internal Study to Evaluate Compound Requirements in the Minipig Compared to the Dog in Preclinical Studies.

    PubMed

    Schaefer, Kai; Rensing, Susanne; Hillen, Heinz; Burkhardt, John E; Germann, Paul-Georg

    2016-04-01

    Dogs have been often chosen as a nonrodent species for preclinical development of small molecule drugs mainly due to availability and relative ease of handling. Recently, focus has increased on the minipig as a potential alternative to the dog, based on either scientific rationale or public opinion concerns. There are, however, other factors influencing nonrodent choices, in particular drug amount and synthesis time, which differ between species and therefore may impact the milestones of a drug development program. To assess the magnitude of compound need, a retrospective internal survey was conducted on drug amounts used in dog studies which were translated into the requirements for minipigs. Compound need approximately doubles if minipigs are used. Costs of compound are accordingly higher, and synthesis times are slightly increased. In our company, the differences were not considered significant enough to preclude the use of minipigs if the later preclinical program might benefit from improved human risk prediction. PMID:26839331

  16. Reducing attrition in drug development: smart loading preclinical safety assessment.

    PubMed

    Roberts, Ruth A; Kavanagh, Stefan L; Mellor, Howard R; Pollard, Christopher E; Robinson, Sally; Platz, Stefan J

    2014-03-01

    Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca's potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping ('stopping toxicities') showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase. This will reduce animal use overall, save significant R&D costs and improve drug pipeline quality. PMID:24269835

  17. 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. ...

  18. 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.

  19. The design of chronic toxicology studies of monoclonal antibodies: implications for the reduction in use of non-human primates.

    PubMed

    Chapman, Kathryn L; Andrews, Laura; Bajramovic, Jeffrey J; Baldrick, Paul; Black, Lauren E; Bowman, Christopher J; Buckley, Lorrene A; Coney, Lee A; Couch, Jessica; Maggie Dempster, A; de Haan, Lolke; Jones, Keith; Pullen, Nick; de Boer, Anne Seitske; Sims, Jennifer; Ian Ragan, C

    2012-03-01

    The changing environment of monoclonal antibody (mAb) development is impacting on the cost of drug development and the use of experimental animals, particularly non-human primates (NHPs). The drive to reduce these costs is huge and involves rethinking and improving nonclinical studies to make them more efficient and more predictive of man. While NHP use might be unavoidable in many cases because of the exquisite specificity and consequent species selectivity of mAbs, our increasing knowledge base can be used to improve drug development and maximise the output of experimental data. Data on GLP regulatory toxicology studies for 58mAbs were obtained from 10 companies across a wide range of therapeutic indications. These data have been used to investigate current practice and identify study designs that minimise NHP use. Our analysis shows that there is variation in the number of animals used for similar studies. This information has been used to develop practical guidance and make recommendations on the use of science-based rationale to design studies using fewer animals taking into account the current regulatory guidance. There are eight recommendations intended to highlight areas for consideration. They include guidance on the main group size, the inclusion of recovery groups and the number of dose groups used in short and long term chronic toxicology studies. PMID:22100994

  20. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995).

    PubMed

    Shaw, D; Leon, C; Kolev, S; Murray, V

    1997-11-01

    Since 1991, the Medical Toxicology Unit (MTU) at Guys' Hospital, London, has been assessing the toxicological problems associated with the use of traditional and herbal remedies and dietary supplements. This assessment was carried out by evaluating reports to the National Poisons Information Service (London) [NPIS(L)] which provides emergency information to medical professionals. Relevant telephone enquiries to NPIS(L) were identified. Further case details were obtained by follow-up questionnaire, clinical consultation, toxicological analysis of samples from patients and/or products and botanical identification of plant material. Of 1297 symptomatic enquiries evaluated there was a possible/confirmed association in 785 cases. Case series have been identified which substantiate previous reports, including liver problems following the use of Chinese herbal medicine for skin disorders, allergic reactions to royal jelly and propolis and heavy metal poisoning caused by remedies from the Indian subcontinent. Although the overall risk to public health appears to be low, certain groups of traditional remedies have been associated with a number of potentially serious adverse effects. Considering the extent of use of herbal remedies and food supplements a comprehensive surveillance system for monitoring the adverse health effects of these products is essential. Surveillance of a large population is needed for the complex task of identifying the uncommon and unpredictable adverse effects which are potentially serious. In the UK, the Medicines Control Agency responded to the MTU report by recognising the need for vigilance and by incorporating adverse reactions reporting on unlicensed herbal remedies into their drug reaction monitoring function. As a further step to safeguard the patients/consumers an effective single regulatory system is required which would ensure the safety and quality of all herbal remedies and food supplements available in the UK. PMID:9391777

  1. 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. PMID:26106427

  2. Efficacy of screens in removing long fibers from an aerosol stream--sample preparation technique for toxicology studies.

    PubMed

    Ku, Bon Ki; Deye, Gregory J; Turkevich, Leonid A

    2014-02-01

    Fiber dimension (especially length) and biopersistence are thought to be important variables in determining the pathogenicity of asbestos and other elongate mineral particles. In order to prepare samples of fibers for toxicology studies, it is necessary to develop and evaluate methods for separating fibers by length in the micrometer size range. In this study, we have filtered an aerosol of fibers through nylon screens to investigate whether such screens can efficiently remove the long fibers (L >20 m, a typical macrophage size) from the aerosol stream. Such a sample, deficient in long fibers, could then be used as the control in a toxicology study to investigate the role of length. A well-dispersed aerosol of glass fibers (a surrogate for asbestos) was generated by vortex shaking a Japan Fibrous Material Research Association (JFMRA) glass fiber powder. Fibers were collected on a mixed cellulose ester (MCE) filter, imaged with phase contrast microscopy (PCM) and lengths were measured. Length distributions of the fibers that penetrated through various screens (10, 20 and 60?m mesh sizes) were analyzed; additional study was made of fibers that penetrated through double screen and centrally blocked screen configurations. Single screens were not particularly efficient in removing the long fibers; however, the alternative configurations, especially the centrally blocked screen configuration, yielded samples substantially free of the long fibers. PMID:24417374

  3. The Application of Radiation Therapy to the Pediatric Preclinical Testing Program (PPTP): Results of a Pilot Study in Rhabdomyosarcoma

    PubMed Central

    Sommerfeld, Jim; Bondra, Kathryn; Lu, Lanchun; Leasure, Justin; Nguyen, Phuong; McHugh, Kelsey; Li, Ning; Chronowski, Christopher; Sebastian, Nikhil; Singh, Mamta; Kurmasheva, Raushan; Houghton, Peter; Pelloski, Christopher E.

    2016-01-01

    Background The Pediatric Preclinical Testing Program (PPTP) has been successfully used to determine the efficacy of novel agents against solid tumors by testing them within a mouse-flank in vivo model. To date, radiation therapy has not been applied to this system. We report on the feasibility and biologic outcomes of a pilot study using alveolar and embryonal rhabdomyosarcoma xeno-graft lines. Procedures We developed a high-throughput mouse-flank irradiation device that allows the safe delivery of radiotherapy in clinically relevant doses. For our pilot study, two rhabdomyosarcoma xenograft lines from the PPTP, Rh30 (alveolar) and Rh18 (embryonal) were selected. Using established methods, xenografts were implanted, grown to appropriate volumes, and were subjected to fractionated radiotherapy. Tumor response-rates, growth kinetics, and event-free survival time were measured. Results Once optimized, the rate of acute toxicity requiring early removal from study in 93 mice was only 3%. During the optimization phase, it was observed that the alveolar Rh30 xenograft line demonstrated a significantly greater radiation resistance than embryonal Rh18 in vivo. This finding was validated within the standardized 30 Gy treatment phase, resulting in overall treatment failure rates of 10% versus 60% for the embryonal versus alveolar subtype, respectively. Conclusions Our pilot study demonstrated the feasibility of our device which enables safe, clinically relevant focal radiation delivery to immunocompromised mice. It further recapitulated the expected clinical radiobiology. PMID:22692929

  4. Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS

    PubMed Central

    Streeter, Heather B.; Rigden, Rachel; Martin, Keith F.; Scolding, Neil J.

    2015-01-01

    Objective: The study was designed to test the efficacy of ATX-MS-1467 in a relevant preclinical model and to assess its safety for the treatment of patients with secondary progressive multiple sclerosis (SPMS). Methods: ATX-MS-1467 was tested for its ability to suppress experimental autoimmune encephalomyelitis (EAE) in the (Ob x DR2)F1 mouse both before and after disease onset. Safety was assessed by clinical assessment, MRI analysis, and the measurement of immune responses to self- and nonself-antigens in patients with SPMS. Results: ATX-MS-1467 displayed a dose-dependent inhibition of EAE and was more effective than glatiramer acetate in the treatment of ongoing disease in humanized mice. A phase 1 open-label dose-escalating study demonstrated that ATX-MS-1467 was safe and well-tolerated in a group of 6 patients with SPMS, up to a dose of 800 g. Conclusions: The results of this study support further development of ATX-MS-1467 in a clinical trial powered to investigate the immunologic and clinical benefits of treatment in relapsing-remitting MS. Classification of evidence: This study provides Class IV evidence that ATX-MS-1467 is safe and tolerated in a group of 6 patients with SPMS. PMID:25798453

  5. Preclinical study of using multiphoton microscopy to diagnose liver cancer and differentiate benign and malignant liver lesions

    NASA Astrophysics Data System (ADS)

    Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Wu, Xiufeng; Zhou, Dong; Xie, Shusen; Jiang, Jiahao; Ying, Mingang; Jia, Fan; Chen, Jianxin; Zhou, Jian

    2012-02-01

    Recently, the miniaturized multiphoton microscopy (MPM) and multiphoton probe allow the clinical use of multiphoton endoscopy for diagnosing cancer via ``optical biopsy''. The purpose of this study was to establish MPM optical diagnostic features for liver cancer and evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis. Firstly, we performed a pilot study to establish the MPM diagnostic features by investigating 60 surgical specimens, and found that high-resolution MPM images clearly demonstrated apparent differences between benign and malignant liver lesions in terms of their tissue architecture and cell morphology. Cancer cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, were identified by MPM images, which were comparable to hematoxylin-eosin staining images. Secondly, we performed a blinded study to evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis by investigating another 164 specimens, and found that the sensitivity, specificity, and accuracy of MPM diagnosis was 96.32%, 96.43%, and 96.34%, respectively. In conclusion, it is feasible to use MPM to diagnose liver cancer and differentiate benign and malignant liver lesions. This preclinical study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive ``optical biopsy'' for liver lesions in the near future.

  6. Does Bacillus anthracis Lethal Toxin Directly Depress Myocardial Function? A Review of Clinical Cases and Preclinical Studies.

    PubMed

    Suffredini, Dante A; Sampath-Kumar, Hanish; Li, Yan; Ohanjanian, Lernik; Remy, Kenneth E; Cui, Xizhong; Eichacker, Peter Q

    2015-01-01

    The US outbreak of B.anthracis infection in 2001 and subsequent cases in the US and Europe demonstrate that anthrax is a continuing risk for the developed world. While several bacterial components contribute to the pathogenesis of B. anthracis, production of lethal toxin (LT) is strongly associated with the development of hypotension and lethality. However, the mechanisms underlying the cardiovascular instability LT produces are unclear. Some evidence suggests that LT causes shock by impairing the peripheral vasculature, effects consistent with the substantial extravasation of fluid in patients dying with B. anthracis. Other data suggests that LT directly depresses myocardial function. However a clinical correlate for this latter possibility is less evident since functional studies and post-mortem examination in patients demonstrate absent or minimal cardiac changes. The purposes of this review were to first present clinical studies of cardiac functional and histologic pathology with B. anthracis infection and to then examine in vivo, in vitro, and ex vivo preclinical studies of LT's myocardial effects. Together, these data suggest that it is unclear whether that LT directly depresses cardiac function. This question is important for the clinical management and development of new therapies for anthrax and efforts should continue to be made to answer it. PMID:26703730

  7. Does Bacillus anthracis Lethal Toxin Directly Depress Myocardial Function? A Review of Clinical Cases and Preclinical Studies

    PubMed Central

    Suffredini, Dante A.; Sampath-Kumar, Hanish; Li, Yan; Ohanjanian, Lernik; Remy, Kenneth E.; Cui, Xizhong; Eichacker, Peter Q.

    2015-01-01

    The US outbreak of B.anthracis infection in 2001 and subsequent cases in the US and Europe demonstrate that anthrax is a continuing risk for the developed world. While several bacterial components contribute to the pathogenesis of B. anthracis, production of lethal toxin (LT) is strongly associated with the development of hypotension and lethality. However, the mechanisms underlying the cardiovascular instability LT produces are unclear. Some evidence suggests that LT causes shock by impairing the peripheral vasculature, effects consistent with the substantial extravasation of fluid in patients dying with B. anthracis. Other data suggests that LT directly depresses myocardial function. However a clinical correlate for this latter possibility is less evident since functional studies and post-mortem examination in patients demonstrate absent or minimal cardiac changes. The purposes of this review were to first present clinical studies of cardiac functional and histologic pathology with B. anthracis infection and to then examine in vivo, in vitro, and ex vivo preclinical studies of LT’s myocardial effects. Together, these data suggest that it is unclear whether that LT directly depresses cardiac function. This question is important for the clinical management and development of new therapies for anthrax and efforts should continue to be made to answer it. PMID:26703730

  8. Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study

    PubMed Central

    Rivulgo, Virginia; Sparo, Mnica; Ceci, Mnica; Fumuso, Elida; Confalonieri, Alejandra; Snchez Bruni, Sergio F.

    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

  9. Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: The case experience with preclinical mechanistic and early clinical-translational studies

    SciTech Connect

    Miller, Janine D.; Scull, Heather

    2007-11-01

    Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.

  10. Preclinical studies of N3-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H22-bearing mice

    PubMed Central

    Zhang, Juan; Li, Min; Liu, Zhihong; Wang, Lili; Liu, Yongjun; Zhang, Na

    2014-01-01

    Purpose N3-O-toluyl-fluorouracil (TFU) is a potential antitumor prodrug of 5-fluorouracil (5-FU), but its poor solubility has limited its use in clinic. This study aimed to improve the bioavailability of TFU by preparing TFU-loaded lipid-based nanosuspensions (TFU-LNS) and perform a preclinical evaluation. Methods TFU-LNS were prepared through high-pressure homogenization and were lyophilized afterwards. For in vitro test, the physicochemical properties and cytotoxicity against HegG2 cells were conducted. For in vivo evaluation, the pharmacokinetics, tissue distribution, and antitumor efficacy were investigated in H22-bearing Kunming mice. Results TFU showed different degradability in four media; in particular, nearly all of it converted to an equimolar amount of 5-FU in blank plasma of Wistar rats. The lyophilized TFU-LNS had a mean particle size of 180.03±3.11 nm and zeta potential of −8.02±1.43 mV and showed no discernible changes after storage at 4°C for 3 months. In the in vivo antitumor study, the antitumor efficacy of TFU-LNS was consistent with that of 5-FU injection. Furthermore, TFU-LNS released a lower concentration of 5-FU in heart and kidney throughout the tissue distribution studies. Conclusion TFU-LNS exhibited convincing antitumor activity and easy scale-up opportunity, which suggests that TFU-LNS might be a promising drug delivery system for cancer therapy. PMID:24920908

  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. [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

  13. Re-evaluate the effect of hyperbaric oxygen therapy in cancer - a preclinical therapeutic small animal model study.

    PubMed

    Pande, Sneha; Sengupta, Amit; Srivastava, Anurag; Gude, Rajiv P; Ingle, Arvind

    2012-01-01

    Tumor hypoxia is a known driver of angiogenesis that also facilitates tumor growth. Moreover, poorly oxygenated central tumor area remains relatively radio or chemo resistant. HBO therapy is known to elevate the levels of dissolved oxygen and eliminates tumor hypoxia. It has been one of the modalities in cancer treatment; therefore its optimization is important. In this experimental study, no cancer enhancing effect was seen during the course of HBO therapy; however, post therapy there was an accelerated growth and progression of tumor. HBO treated mice lived shorter and the response to therapy was dose & tumor volume dependent. HBO therapy probably exert its effect on the cancer proliferating cells through multiple pathways such as increased DNA damage, apoptosis & geno-toxicity leading to slow cancer progression while post therapy tumorigenic effect could be due to impaired DNA repair mechanism, mutagenic effect & aneuploidy as well as altered blood supply & nutrients. Tumor growth reached plateau with time and this finding validated theoretical model predicting tumor reaching an asymptotic limit. While, marked asymmetry observed in tumor volume progression or cancer cell proliferation rate in each of the experimental C3H mouse suggested a need for an alternate small animal pre-clinical cancer therapeutic model. PMID:23144880

  14. BLOCKING CANNABINOID CB1 RECEPTORS FOR THE TREATMENT OF NICOTINE DEPENDENCE: INSIGHTS FROM PRECLINICAL AND CLINICAL STUDIES

    PubMed Central

    Le Foll, Bernard; Forget, Benoit; Aubin, Henri-Jean; Goldberg, Steven R.

    2009-01-01

    Tobacco use is one of the leading preventable causes of death in developed countries. Since existing medications are only partially effective in treating tobacco smokers, there is a great need for improved medications for smoking cessation. It has been recently proposed that cannabinoid CB1 receptor antagonists represent a new class of therapeutic agents for drug dependence, and, notably, nicotine dependence. Here, we will review current evidence supporting the use of this class of drugs for smoking cessation treatment. Preclinical studies indicate that nicotine exposure produces changes in endocannabinoid content in the brain. In experimental animals, Rimonabant (SR141716) and AM251, two cannabinoid CB1 receptor antagonists, block nicotine self-administration behavior, an effect that may be related to the blockade of the dopamine-releasing effects of nicotine in the brain. Rimonabant also seems efficacious in decreasing the influence of nicotine-associated stimuli over behavior, suggesting that it may act on two distinct neuronal pathways, those implicated in drug-taking behavior and those involved in relapse phenomena. The utility of Rimonabant has been evaluated in several clinical trials. It seems that Rimonabant is an efficacious treatment for smoking cessation, although its efficacy doesn’t exceed that of nicotine replacement therapy and its use may be limited by emotional side effects (nausea, anxiety and depression, mostly). Rimonabant also appears to decrease relapse rates in smokers. These findings indicate significant, but limited, utility of Rimonabant for smoking cessation. PMID:18482433

  15. Case study: the role of mechanistic network models in systems toxicology.

    PubMed

    Hoeng, Julia; Talikka, Marja; Martin, Florian; Sewer, Alain; Yang, Xiang; Iskandar, Anita; Schlage, Walter K; Peitsch, Manuel C

    2014-02-01

    Twenty first century systems toxicology approaches enable the discovery of biological pathways affected in response to active substances. Here, we briefly summarize current network approaches that facilitate the detailed mechanistic understanding of the impact of a given stimulus on a biological system. We also introduce our network-based method with two use cases and show how causal biological network models combined with computational methods provide quantitative mechanistic insights. Our approach provides a robust comparison of the transcriptional responses in different experimental systems and enables the identification of network-based biomarkers modulated in response to exposure. These advances can also be applied to pharmacology, where the understanding of disease mechanisms and adverse drug effects is imperative for the development of efficient and safe treatment options. PMID:23933191

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

    PubMed Central

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

    2015-01-01

    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

  17. Reform in Teaching Preclinical Pathophysiology

    ERIC Educational Resources Information Center

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-01-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

  18. Reform in Teaching Preclinical Pathophysiology

    ERIC Educational Resources Information Center

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-01-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. Biomarkers in Computational Toxicology

    EPA Science Inventory

    Biomarkers are a means to evaluate chemical exposure and/or the subsequent impacts on toxicity pathways that lead to adverse health outcomes. Computational toxicology can integrate biomarker data with knowledge of exposure, chemistry, biology, pharmacokinetics, toxicology, and e...

  5. 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...

  6. Prazosin addition to fluvoxamine: A preclinical study and open clinical trial in OCD.

    PubMed

    Feenstra, Matthijs G P; Klompmakers, André; Figee, Martijn; Fluitman, Sjoerd; Vulink, Nienke; Westenberg, Herman G M; Denys, Damiaan

    2016-02-01

    The efficacy of selective serotonin reuptake inhibitors (SRIs) in psychiatric disorders may be "augmented" through the addition of atypical antipsychotic drugs. A synergistic increase in dopamine (DA) release in the prefrontal cortex has been suggested to underlie this augmentation effect, though the mechanism of action is not clear yet. We used in vivo microdialysis in rats to study DA release following the administration of combinations of fluvoxamine (10mg/kg) and quetiapine (10mg/kg) with various monoamine-related drugs. The results confirmed that the selective 5-HT1A antagonist WAY-100635 (0.05mg/kg) partially blocked the fluvoxamine-quetiapine synergistic effect (maximum DA increase dropped from 325% to 214%). A novel finding is that the α1-adrenergic blocker prazosin (1mg/kg), combined with fluvoxamine, partially mimicked the effect of augmentation (maximum DA increase 205%; area-under-the-curve 163%). As this suggested that prazosin augmentation might be tested in a clinical study, we performed an open clinical trial of prazosin 20mg addition to SRI in therapy-resistant patients with obsessive-compulsive disorder applying for neurosurgery. A small, non-significant reduction in Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores was observed in 10 patients and one patient was classified as a responder with a reduction in Y-BOCS scores of more than 25%. We suggest that future clinical studies augmenting SRIs with an α1-adrenergic blocker in less treatment resistant cases should be considered. The clinical trial "Prazosin in combination with a serotonin reuptake inhibitor for patients with Obsessive Compulsive disorder: an open label study" was registered at 24/05/2011 under trial number ISRCTN61562706: http://www.controlled-trials.com/ISRCTN61562706. PMID:26712326

  7. Preclinical studies of the potent and selective nicotinic ?4?2 receptor ligand VMY-2-95.

    PubMed

    Kong, Hyesik; Song, Jun-ke; Yenugonda, Venkata Mahidhar; Zhang, Li; Shuo, Tian; Cheema, Amrita K; Kong, Yali; Du, Guan-hua; Brown, Milton L

    2015-02-01

    The discovery and development of small molecules that antagonize neuronal nicotinic acetylcholine receptors may provide new ligands for evaluation in models of depression or addiction. We discovered a small molecule, VMY-2-95, a nAChR ligand with picomolar affinity and high selectivity for ?4?2 receptors. In this study, we investigated its preclinical profile in regards to solubility, lipophilicity, metabolic stability, intestinal permeability, bioavailability, and drug delivery to the rat brain. Metabolic stability of VMY-2-952HCl was monitored on human liver microsomes, and specific activity of VMY-2-952HCl on substrate metabolism by CYP1A2, 2C9, 2C19, 2D6, and 3A4 was tested in a high-throughput manner. The intestinal transport of VMY-2-952HCl was studied through Caco-2 cell monolayer permeability. VMY-2-952HCl was soluble in water and chemically stable, and the apparent partition coefficient was 0.682. VMY-2-952HCl showed significant inhibition of CYP2C9 and 2C19, but weak or no effect on 1A2, 2D6, and 3A4. The Caco-2 cell model studies revealed that VMY-2-952HCl was highly permeable with efflux ratio of 1.11. VMY-2-952HCl achieved a maximum serum concentration of 0.56 mg/mL at 0.9 h and was orally available with a half-life of ?9 h. Furthermore, VMY-2-952HCl was detected in the rat brain after 3 mg/kg oral administration and achieved a maximal brain tissue concentration of 2.3 ?g/g within 60 min. Overall, the results demonstrate that VMY-2-952HCl has good drug like properties and can penetrate the blood-brain barrier with oral administration. PMID:25533629

  8. Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study

    PubMed Central

    Grunfeld, C.; Delaney, J.A.C.; Wanke, C.; Currier, J.S.; Scherzer, R.; Biggs, M. L.; Tien, P.; Shlipak, M.; Sidney, S.; Polak, J.F.; O'Leary, D.; Bacchetti, P.; Kronmal, R.

    2010-01-01

    Background Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. Methods Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors. Results For internal carotid, mean IMT was 1.170.50mm for HIV-infected participants and 1.060.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm). Conclusions Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking. PMID:19455012

  9. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review.

    PubMed

    Gulin, Julián Ernesto Nicolás; Rocco, Daniela Marisa; García-Bournissen, Facundo

    2015-11-01

    Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction. PMID:26587586

  10. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review

    PubMed Central

    Gulin, Julián Ernesto Nicolás; Rocco, Daniela Marisa; García-Bournissen, Facundo

    2015-01-01

    Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction. PMID:26587586

  11. 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.

  12. Inhalation developmental toxicology studies: Teratology study of methyl ethyl ketone in mice: Final report

    SciTech Connect

    Mast, T.J.; Dill, J.A.; Evanoff, J.J.; Rommereim, R.L.; Weigel, R.J.; Westerberg, R.B.

    1989-02-01

    Methyl ethyl ketone (MEK) is a widely used industrial solvent which results in considerable human exposure. In order to assess the potential for MEK to cause developmental toxicity in rodents, four groups of Swiss (CD-1) mice were exposed to 0, 400, 1000 or 3000 ppM MEK vapors, 7 h/day, 7 dy/wk. Ten virgin females and approx.30 plug-positive females per group were exposed concurrently for 10 consecutive days (6--15 dg for mated mice). Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice on 18 dg. Uterine implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. Exposure of pregnant mice to these concentrations of MEK did not result in apparent maternal toxicity, although there was a slight, treatment-correlated increase in liver to body weight ratios which was significant for the 3000-ppM group. Mild developmental toxicity was evident at 3000-ppM as a reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease in mean fetal body weight was the same for both sexes. 17 refs., 4 figs., 10 tabs.

  13. Inhalation developmental toxicology studies: Teratology study of isoprene in mice and rats: Final report

    SciTech Connect

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

    1989-01-01

    Isoprene, a reactive, branched diene, is used in large quantities in the manufacture of polyisoprene and as a copolymer in the synthesis of butyl rubber. The potential for isoprene to cause developmental toxicity was assessed in rodents, by exposing four groups each of Sprague-Dawley rats and Swiss (CD-1) mice to 0, 280, 1400, or 7000 ppM isoprene vapors, 6 h/day, 7 day/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.30 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 31 refs., 6 figs., 19 tabs.

  14. Inhalation developmental toxicology studies: Teratology study of acetone in mice and rats: Final report

    SciTech Connect

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

    1988-11-01

    Acetone, an aliphatic ketone, is a ubiquitous industrial solvent and chemical intermediate; consequently, the opportunity for human exposure is high. The potential for acetone to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 440, 2200, or 11000 ppm, and in Swiss (CD-1) mice exposed to 0, 440, 2200, and 6600 ppm acetone vapors, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and approx.32 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 46 refs., 6 figs., 27 tabs.

  15. Current approaches toward chemical mixture studies at the National Institute of Environmental Health Sciences and the U.S. National Toxicology Program.

    PubMed

    Bucher, J R; Lucier, G

    1998-12-01

    The National Institute of Environmental Health Sciences (NIEHS) has several new initiatives involving chemical mixtures and has recognized the need to develop new experimental approaches to enhance our efforts in this area. Responding to recent increases in nominations of complex occupational exposures for toxicologic assessment by the U.S. National Toxicology Program, the NIEHS and the National Institute for Occupational Safety and Health have begun a program to characterize exposures through field studies, identify biomarkers of exposure in workers, and recreate relevant mixed exposures in a laboratory setting. A second initiative with the National Center for Environmental Health/Centers for Disease Control and Prevention will examine blood samples from the U.S. National Health and Nutrition Examination Survey population surveys for selected endocrine-disrupting agents and for common patterns of persistent xenobiotics, providing critical information for the design of animal studies to assess risks of relevant chemical mixtures to humans. New toxicology testing methods (lower cost, faster) will enhance our ability to study chemical mixtures (e.g., dioxin and dioxinlike chemicals, combination AIDS therapies). Ongoing method development efforts involve in vitro functional toxicology assays, screens for estrogenic activity, and carcinogenesis studies in transgenic mice. A major scientific initiative with mixtures involves studies of individual and mixtures of dioxin and dioxinlike chemicals to determine if toxic equivalence factors predict carcinogenic potency in traditional and transgenic bioassays. Complementing these studies is an increased emphasis on physiologically based pharmacokinetic modeling, an activity central to the proper interpretation of chemical mixture studies. PMID:9860884

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

    PubMed Central

    Aboody, Karen S.; Najbauer, Joseph; Metz, Marianne Z.; DApuzzo, 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

  17. Evaluation of novel acute urinary rat kidney toxicity biomarker for subacute toxicity studies in preclinical trials.

    PubMed

    Fuchs, Tobias Christian; Frick, Katharina; Emde, Barbara; Czasch, Stephanie; von Landenberg, Friedrich; Hewitt, Philip

    2012-10-01

    Novel urinary protein biomarkers for the detection of acute renal damage, recently accepted by the U.S. Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency (Japan), now have to be validated in practice. Limited data regarding the performance of these acute markers after subacute or subchronic treatment are publicly available. To increase the area of applicability of these markers, it is important to evaluate the ability to detect them after 28 days of treatment or even longer. Wistar rats were treated with three doses of cisplatin, vancomycin, or puromycin to induce renal damage. Twelve candidate proteins were measured by Luminex xMAP-based WideScreen assays, MesoScale Discovery-based MULTI-SPOT technology, or RENA-strip dipstick assay after 28 days. Treatment with all three model compounds resulted in a dose-dependent increase in urinary biomarkers, specific for the observed areas within the nephron, determined histopathologically. The most promising biomarkers in this study were NGAL, Kim-1, osteopontin, clusterin, RPA-1, and GSTYb1, detected by multiplexing technologies. The RENA-strip dipstick assay delivered good diagnostic results for vancomycin-treated but not for cisplatin- or puromycin-treated rats. Taken together, the data show that these new biomarkers are robust and measurable for longer term studies to predict different types of kidney toxicities. PMID:22581810

  18. 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

  19. 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

  20. Systematic Approach to Remediation in Basic Science Knowledge for Preclinical Students: A case study

    NASA Astrophysics Data System (ADS)

    Amara, Francis

    Remediation of pre-clerkship students for deficits in basic science knowledge should help them overcome their learning deficiencies prior to clerkship. However, very little is known about remediation in basic science knowledge during pre-clerkship. This study utilized the program theory framework to collect and organize mixed methods data of the remediation plan for pre-clerkship students who failed their basic science cognitive examinations in a Canadian medical school. This plan was analyzed using a logic model narrative approach and compared to literature on the learning theories. The analysis showed a remediation plan that was strong on governance and verification of scores, but lacked: clarity and transparency of communication, qualified remedial tutors, individualized diagnosis of learner's deficits, and student centered learning. Participants admitted uncertainty about the efficacy of the remediation process. A remediation framework is proposed that includes student-centered participation, individualized learning plan and activities, deliberate practice, feedback, reflection, and rigorous reassessment.

  1. Irinotecan delivery by microbubble-assisted ultrasound - A pilot preclinical study

    NASA Astrophysics Data System (ADS)

    Escoffre, Jean-Michel; Novell, Anthony; Serrire, Sophie; Bouakaz, Ayache

    2012-11-01

    Irinotecan is conventionally used for the treatment of colorectal cancer. However, its administration is associated with severe side effects. Targeted drug delivery using ultrasound (US) combined with microbubbles offers new opportunities to increase the therapeutic effectiveness of antitumor treatment and to reduce toxic exposure to healthy tissues. The objective of this study is to investigate the safety and efficacy of in-vivo delivery of irinotecan by microbubble-assisted US in human glioblastoma model (U-87 MG). In order to validate the potential of this new method in-vivo, subcutaneous tumors were implanted in the flank of nude mouse and treated when they reached a volume of 100 mm3. In the first study, the measured volumes with caliper and anatomic ultrasound imaging were compared for the monitoring and the quantification of tumor growth during 27 days. Ultrasound imaging measurements were positively correlated to caliper measurements. The tumor treatment consisted of an i.v. injection of irinotecan (20 mg/kg) followed one hour later by i.v. administration of MM1 microbubble and an US insonation using a single-element transducer operating at 1MHz (400 kPa, 10 kHz PRF 40% DC, 3 min). The therapeutic efficacy was evaluated for 39 days by measuring the tumor volume before and after treatment using a caliper and based on ultrasound images using an 18 MHz probe (Vevo 2100). Our results showed that anatomical ultrasound imaging was as efficient as caliper for the monitoring and the quantification of tumor growth. Moreover, irinotecan delivery by sonoporation induced a significant decrease of glioblastoma tumor volume and an increase of tumor-doubling time compared to the tumor treated by irinotecan alone. In conclusion, this novel therapeutic approach has promising features since it can be used to reduce the injected drug dose and to achieve a better therapeutic efficacy.

  2. A Preclinical Study of Laryngeal Motor-Evoked Potentials as a Marker Vagus Nerve Activation.

    PubMed

    Grimonprez, Annelies; Raedt, Robrecht; De Taeye, Leen; Larsen, Lars Emil; Delbeke, Jean; Boon, Paul; Vonck, Kristl

    2015-12-01

    Vagus nerve stimulation (VNS) is a treatment for refractory epilepsy and depression. Previous studies using invasive recording electrodes showed that VNS induces laryngeal motor-evoked potentials (LMEPs) through the co-activation of the recurrent laryngeal nerve and subsequent contractions of the laryngeal muscles. The present study investigates the feasibility of recording LMEPs in chronically VNS-implanted rats, using a minimally-invasive technique, to assess effective current delivery to the nerve and to determine optimal VNS output currents for vagal fiber activation. Three weeks after VNS electrode implantation, signals were recorded using an electromyography (EMG) electrode in the proximity of the laryngeal muscles and a reference electrode on the skull. The VNS output current was gradually ramped up from 0.1 to 1.0 mA in 0.1 mA steps. In 13/27 rats, typical LMEPs were recorded at low VNS output currents (median 0.3 mA, IQR 0.2-0.3 mA). In 11/27 rats, significantly higher output currents were required to evoke electrophysiological responses (median 0.7 mA, IQR 0.5-0.7 mA, [Formula: see text]). The latencies of these responses deviated significantly from LMEPs ([Formula: see text]). In 3/27 rats, no electrophysiological responses to simulation were recorded. Minimally invasive LMEP recordings are feasible to assess effective current delivery to the vagus nerve. Furthermore, our results suggest that low output currents are sufficient to activate vagal fibers. PMID:26510476

  3. Ultra-high-resolution imaging of small animals: implications for preclinical and research studies.

    PubMed

    Weber, D A; Ivanovic, M

    1999-01-01

    Recent developments in the use of pinhole SPECT and dedicated PET for UHR small animal imaging have identified the technology that can be used to provide images with spatial resolution of the order of 1 to 3 mm. In SPECT imaging, rotating camera pinhole SPECT has provided the means to use existing equipment to achieve UHR images. It has the disadvantages of low sensitivity and requires special image software to reconstruct tomographic slices. However, with minimal additional cost to an imaging laboratory, pinhole SPECT can provide a quantitatively accurate imaging technique for small-animal studies. New detector technology offers considerable promise; however, more studies are required before any one system can be singled out as offering major advantages over the pinhole SPECT method for general purpose small-animal SPECT imaging. The search for the means to achieve better sensitivity with UHR continues. In PET imaging, with few exceptions, the general trend has been to design systems dedicated to small-animal imaging to achieve UHR images with satisfactory sensitivity for quantitative UHR imaging. Several of the ring configuration, small-animal PET imaging systems provide good sensitivity and high spatial resolution. The cost of many of these systems, however, is relatively high, and investigators continue to explore different detector materials and imaging geometries to develop an instrument with acceptable levels of sensitivity with UHR imaging capability. We believe that both small-animal SPECT and PET imaging techniques now offer practical UHR imaging methods for quantitative small-animal imaging. As these tools are implemented in the investigation of new radiopharmaceuticals, we expect the utility of in vivo small animal assays will support further research in optimizing this technology. PMID:10385189

  4. Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris.

    PubMed

    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

  5. Virtual reality, augmented reality, and robotics applied to digestive operative procedures: from in vivo animal preclinical studies to clinical use

    NASA Astrophysics Data System (ADS)

    Soler, Luc; Marescaux, Jacques

    2006-04-01

    Technological innovations of the 20 th century provided medicine and surgery with new tools, among which virtual reality and robotics belong to the most revolutionary ones. Our work aims at setting up new techniques for detection, 3D delineation and 4D time follow-up of small abdominal lesions from standard mecial images (CT scsan, MRI). It also aims at developing innovative systems making tumor resection or treatment easier with the use of augmented reality and robotized systems, increasing gesture precision. It also permits a realtime great distance connection between practitioners so they can share a same 3D reconstructed patient and interact on a same patient, virtually before the intervention and for real during the surgical procedure thanks to a telesurgical robot. In preclinical studies, our first results obtained from a micro-CT scanner show that these technologies provide an efficient and precise 3D modeling of anatomical and pathological structures of rats and mice. In clinical studies, our first results show the possibility to improve the therapeutic choice thanks to a better detection and and representation of the patient before performing the surgical gesture. They also show the efficiency of augmented reality that provides virtual transparency of the patient in real time during the operative procedure. In the near future, through the exploitation of these systems, surgeons will program and check on the virtual patient clone an optimal procedure without errors, which will be replayed on the real patient by the robot under surgeon control. This medical dream is today about to become reality.

  6. Preclinical Studies of YK-4-272, an Inhibitor of Class II Histone Deacetylases by Disruption of Nucleocytoplasmic Shuttling

    PubMed Central

    Kong, Hye-Sik; Tian, Shuo; Kong, Yali; Du, Guanhua; Zhang, Li; Jung, Mira; Dritschilo, Anatoly

    2013-01-01

    Purpose The HDAC shuttling inhibitor, YK-4-272 functions by restricting nuclear shuttling of Class II HDACs. Pre-clinical investigations of YK-4-272 bioavailability, pharmacokinetics, in vivo toxicity and tumor growth inhibition were performed to determine its potential as an HDAC shuttling disruptor for use in clinical applications. Methods The solubility, lipophilicity, in vitro metabolic stability, in vitro intestinal permeability, and in vivo pharmacokinetics of YK-4-272 were determined by HPLC methods. The anti-tumor activity of YK-4-272 was determined by monitoring athymic Balb/c nude mice bearing PC-3 xenografts. Results Oral bioavailability of YK-4-272 is supported by its solubility (0.537 mg/mL) and apparent partition coefficient of 2.0. The compound was chemically and metabolically stable and not a substrate for CYP450. In Caco-2 cell transport studies, YK-4-272 was highly permeable. The time-concentration profile of YK- 4-272 in plasma resulted in a Cmax of 2.47 µg/mL at 0.25 h with a AUC of 3.304 µg×h/mL. Treatment of PC-3 tumor xenografts with YK-4-272 showed significant growth delay. Conclusions YK-4-272 is stable and bio-available following oral administration. Growth inhibition of cancer cells and tumors was observed. These studies support advancing YK-4-272 for further evaluation as a novel HDAC shuttling inhibitor for use in cancer treatment. PMID:22836184

  7. A Preclinical Study Combining the DNA Repair Inhibitor Dbait with Radiotherapy for the Treatment of Melanoma1

    PubMed Central

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

    2014-01-01

    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 67days] or the radical protocol (TGD by 3.2-fold; median survival: 221 vs 109days). 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

  8. Synthesis, characterization and preclinical studies of two-photon-activated targeted PDT therapeutic triads

    NASA Astrophysics Data System (ADS)

    Spangler, C. W.; Starkey, J. R.; Rebane, A.; Meng, F.; Gong, A.; Drobizhev, M.

    2006-02-01

    Photodynamic therapy (PDT) continues to evolve into a mature clinical treatment of a variety of cancer types as well as age-related macular degeneration of the eye. However, there are still aspects of PDT that need to be improved in order for greater clinical acceptance. While a number of new PDT photo-sensitizers, sometimes referred to as second- or third- generation therapeutic agents, are currently under clinical investigation, the direct treatment through the skin of subcutaneous tumors deeper than 5 mm remains problematic. Currently approved PDT porphyrin photo-sensitizers, as well as several modified porphyrins (e.g. chlorins, bacteriochlorins, etc.) that are under clinical investigation can be activated at 630-730 nm, but none above 800 nm. It would be highly desirable if new PDT paradigms could be developed that would allow photo-activation deep in the tissue transparency window in the Near-infrared (NIR) above 800 nm to reduce scattering and absorption phenomena that reduce deep tissue PDT efficacy. Rasiris and MPA Technologies have developed new porphyrins that have greatly enhanced two-photon absorption ( P A ) cross-sections and can be activated deep in the NIR (ca. 780-850 nm). These porphyrins can be incorporated into a therapeutic triad that also employs an small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR onephoton imaging agent that allows tracking the delivery of the triad to the tumor site, as well as clearance of excess triad from healthy tissue prior to the start of PDT treatment. We are currently using these new triads in efficacy studies with a breast cancer cell line that has been transfected with luciferase genes that allow implanted tumor growth and post- PDT treatment efficacy studies in SCID mouse models by following the rise and decay of the bioluminescence signal. We have also designed highly absorbing and scattering collagen breast cancer phantoms in which we have demonstrated dramatic cell kill to a depth of at least 4 cm. We have also demonstrated that at the wavelength and laser fluences used in the treatment of implanted tumors in the mouse mammary fat pads, there is little, if any, damage to the skin or internal mouse organs. In addition, we have also demonstrated that the implanted tumors can be treated to a depth of more than 1 cm by direct radiation through the dorsal side of the mouse.

  9. Toxicology and Carcinogenesis Studies of Hexachloroethane (CAS No. 67-72-1) in F344/N Rats (Gavage Studies).

    PubMed

    1989-08-01

    Hexachloroethane is used in organic synthesis as a retarding agent in fermentation, as a camphor substitute in nitrocellulose, in pyrotechnics and smoke devices, in explosives, and as a solvent. In previous long-term gavage studies with B6C3F1 mice and Osbourne-Mendel rats (78 weeks of exposure followed by 12-34 weeks of observation), hexachloroethane caused increased incidences of hepatocellular carcinomas in mice. However, survival of low and high dose rats was reduced compared with that of vehicle controls, and the effects on rats were inconclusive. Therefore, additional toxicology and carcinogenesis studies were conducted in F344/N rats by administering hexachloroethane (approximately 99% pure) in corn oil by gavage to groups of males and females for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Urinalysis was performed in conjunction with the 13-week studies. Sixteen-Day Studies: In the 16-day studies (dose range, 187-3,000 mg/kg), all rats that received 1,500 or 3,000 mg/kg and 1/5 males and 2/5 females that received 750 mg/kg died before the end of the studies. Final mean body weights of rats that received 750 mg/kg were 25% lower than that of vehicle controls for males and 37% lower for females. Compound-related clinical signs seen at 750 mg/kg or more included dyspnea, ataxia, prostration, and excessive lacrimation. Other compound-related effects included hyaline droplet formation in the tubular epithelial cells in all dosed males and tubular cell regeneration and granular casts in the tubules at the corticomedullary junction in the kidney in males receiving 187 and 375 mg/kg. Thirteen-Week Studies: In the 13-week studies (dose range, 47-750 mg/kg), 5/10 male rats and 2/10 female rats that received 750 mg/kg died before the end of the studies. The final mean body weight of male rats that received 750 mg/kg was 19% lower than that of vehicle controls. Compound-related clinical signs for both sexes included hyperactivity at doses of 94 mg/kg or higher and convulsions at doses of 375 or 750 mg/kg. The relative weights of liver, heart, and kidney were increased for exposed males and females. Kidney lesions were seen in all dosed male groups, and the severity increased with dose. Papillary necrosis and tubular cell necrosis and degeneration in the kidney and hemorrhagic necrosis in the urinary bladder were observed in the five male rats that received 750 mg/kg and died before the end of the studies; at all lower doses, hyaline droplets, tubular regeneration, and granular casts were present in the kidney. No chemical-related kidney lesions were observed in females. Foci of hepatocellular necrosis were observed in several male and female rats at doses of 188 mg/kg or higher. Dose selection for the 2-year studies was based primarily on the lesions of the kidney in males and of the liver in females. Studies were conducted by administering hexachloroethane in corn oil by gavage at 0, 10, or 20 mg/kg body weight, 5 days per week, to groups of 50 male rats. Groups of 50 female rats were administered 0, 80, or 160 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were slightly (5%-9%) lower than those of vehicle controls toward the end of the studies. No significant differences in survival were observed between any groups of rats (male: vehicle control, 31/50; 10 mg/kg, 29/50; 20 mg/kg, 26/50; female: vehicle control, 32/50; 80 mg/kg, 27/50; 160 mg/kg, 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Incidences of kidney mineralization (vehicle control, 2/50; low dose, 15/50; high dose, 32/50) and hyperplasia of the pelvic transitional epithelium (0/50; 7/50; 7/50) were increased in dosed male rats. Renal tubule hyperplasia was observed at an increased incidence in high dose male rats (2/50; 4/50; 11/50). These lesions have been described as characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generateted with an accumulation of liver-generated a2μ-globulin in the cytoplasm of tubular epithelial cells. The severity of nephropathy was increased in high dose male rats (moderate vs. mild), and the incidences and severity of nephropathy were increased in dosed females (22/50; 42/50; 45/50). The incidences of adenomas (1/50; 2/50; 4/50), carcinomas (0/50; 0/50; 3/50), and adenomas or carcinomas (combined) (1/50; 2/50; 7/50) of the renal tubule were also increased in the high dose male group. One of the carcinomas in the high dose group metastasized to the lung. No compound-related neoplasms were observed in females. The incidence of pheochromocytomas of the adrenal gland in low dose male rats was significantly greater than that in vehicle controls (15/50; 28/50; 21/49), and the incidences for both dosed groups were greater than the mean historical control incidence (28% ± 11%). Genetic Toxicology: Hexachloroethane was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with and without exogenous metabolic activation. In CHO cells, hexachloroethane did not induce chromosomal aberrations with or with out metabolic activation but did produce sister chromatid exchanges in the presence of exogenous metabolic activation. Audit: The data, documents, and pathology materials from the 2-year studies of hexachloroethane have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of hexachloroethane for male F344/N rats, based on the increased incidences of renal neoplasms. The marginally increased incidences of pheochromocytomas of the adrenal gland may have been related to hexachloroethane administration to male rats. There was no evidence of carcinogenic activity of hexachloroethane for female F344/N rats administered 80 or 160 mg/kg by gavage for 103 weeks. The severity of nephropathy and incidences of linear mineralization of the renal papillae and hyperplasia of the transitional epithelium of the renal pelvis were increased in dosed male rats. The incidences and severity of nephropathy were increased in dosed female rats. Synonyms: carbon hexachloride; ethane hexachloride; hexachlorethane; hexachloroethylene; 1,1,1,2,2,2-hexachloroethane; perchloroethane Trade Names: Avlothane; Distokal; Distopan; Distopin; Egitol; Falkitol; Fasciolin; Mottenhexe; Phenohep PMID:12695780

  10. 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...

  11. Contributions of GABA to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

    PubMed Central

    Silveri, Marisa M.

    2015-01-01

    There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol abuse disorders. PMID:24631274

  12. Preclinical studies of vascular acting photosensitizer bacteriopheophorbide for the treatment of prostate cancer

    NASA Astrophysics Data System (ADS)

    Hetzel, Fred W.; Chen, Qun; Luck, David; Beckers, Jill; Huang, Zheng

    2004-06-01

    Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. In vivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the IV infused photosensitizer drug. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week post PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Prostate lesions could be detected by MRI scan as early as 48 h post PDT. Maximum lesion size of 1.5 cm3 and 2.9 cm3 could be achieved at 50 J/cm and 100 J/cm, respectively, with interstitial treatment using a single 1-cm diffuser fiber, suggesting the Tookad-PDT is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat localized prostate cancer.

  13. Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats

    PubMed Central

    Lin, Chien-Min; Tsai, Jo-Ting; Chang, Chen Kuei; Cheng, Juei-Tang; Lin, Jia-Wei

    2015-01-01

    Background Decrease of peroxisome proliferator-activated receptors-δ (PPARδ) expression has been observed after spinal cord injury (SCI). Increase of PPARδ may improve the damage in SCI. Telmisartan, the antihypertensive agent, has been mentioned to increase the expression of PPARδ. Thus, we are going to screen the effectiveness of telmisartan in SCI for the development of it in clinical application. Methods In the present study, we used compressive SCI in rats. Telmisartan was then used to evaluate the influence in rats after SCI. Change in PPARδ expression was identified by Western blots. Also, behavioral tests were performed to check the recovery of damage. Results Recovery of damage from SCI was observed in telmisartan-treated rats. Additionally, this action of telmisartan was inhibited by GSK0660 at the dose sufficient to block PPARδ. However, metformin at the dose enough to activate adenosine monophosphate-activated protein kinase failed to produce similar action as telmisartan. Thus, mediation of adenosine monophosphate-activated protein kinase in this action of telmisartan can be rule out. Moreover, telmisartan reversed the expressions of PPARδ in rats with SCI. Conclusion The obtained data suggest that telmisartan can improve the damage of SCI in rats through an increase in PPARδ expression. Thus, telmisartan is useful to be developed as an agent in the therapy of SCI. PMID:26316709

  14. 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

  15. Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study.

    PubMed

    Li, Chenwen; Fu, Ruoqiu; Yu, Caiping; Li, Zhuoheng; Guan, Haiyan; Hu, Daqiang; Zhao, Dehua; Lu, Laichun

    2013-01-01

    In this study, a mixture of poly(vinyl alcohol) (PVA) and chitosan oligosaccharides (COS) was electrospun with silver nanoparticles (AgNPs) to produce fibrous mats for use in wound healing. The AgNPs were reduced by COS prior to electrospinning or Ag(+) was reduced via ultraviolet irradiation in nanofibers. The morphologies of the PVA/COS/AgNO3 and PVA/COS-AgNP nanofibers were analyzed by scanning electron microscopy. Formation of the AgNPs was investigated by field emission transmission electron microscopy, ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. We also evaluated the biocompatibility of the nanofibers, particularly their cytotoxicity to human skin fibroblasts and potential to cause primary skin irritation. The in vitro antibacterial activity and in vivo wound healing capacity of the nanofibers were also investigated. The nanofibers had a smooth surface with an average diameter of 130-192 nm. The diameters of the AgNPs were in the range of 15-22 nm. The nanofibers significantly inhibited growth of Escherichia coli and Staphylococcus aureus bacteria. PVA/COS-AgNP nanofibers accelerated the rate of wound healing over that of the control (gauze). The results of our in vitro and in vivo animal experiments suggest that PVA/COS-AgNP nanofibers should be of greater interest than PVA/COS/AgNO3 nanofibers for clinical use as a bioactive wound dressing. PMID:24204142

  16. Khat (Catha edulis F.) and cannabinoids: Parallel and contrasting behavioral effects in preclinical and clinical studies.

    PubMed

    Geresu, Berhanu

    2015-11-01

    After a brief outline of Catha edulis F. (khat) and the cannabinoid systems, the interactions between the pharmacological effects of khat and cannabinoids will be reviewed. Khat chewing is a widespread habit that has a deep-rooted sociocultural tradition in Africa and the Middle East. Experimental studies conducted to investigate khat's central and peripheral effects have revealed an amphetamine-like mechanism of action mediated through the dopaminergic system. The endocannabinoid system comprises the receptors, the endogenous agonists and the related biochemical machinery responsible for synthesizing these substances and terminating their actions. Endocannabinoids are synthesized "on demand" from membrane phospholipids and then rapidly cleared by cellular uptake and enzymatic degradation. Khat and cannabinoids produce a body of parallel and contrasting behavioral effects. Concurrent consumption of khat and cannabinoids may increase the risk of getting or precipitating psychosis, has rewarding and motivational effect, increases the threshold of pain perception and impairs learning and memory. On the other hand, the action of cannabis to enhance food intake is likely to reduce khat's appetite suppressant effects. PMID:26469212

  17. Reduction in muscular motility by selective focused cold therapy: a preclinical study.

    PubMed

    Hsu, Michael; Stevenson, Fang-Feng

    2014-01-01

    Application of freezing temperatures to the temporal branch of the facial nerve can temporarily inhibit motor nerve conduction, resulting in inhibition of voluntary contraction of the frontalis and glabella muscle groups. This feasibility study demonstrates the reduction in motility of muscle groups through application of low temperatures to nerves in a rat model. Twenty-seven adult female Sprague-Dawley rats received cryotreatment to the tibial nerve of the hind limb, and the contralateral limb was left untreated as a negative control. The use of a cold temperature application (-59 ± 8 °C for 60 s) onto the rat tibial nerve resulted in temporary reduction of physiological function of the hind limb. Histological observations of the nerve revealed demyelination and axonal degeneration by 2 weeks post-treatment followed by complete axonal regeneration and remyelination at 16 weeks. Application of low temperatures to peripheral motor nerves resulted in temporary denervation and loss of function of the treated hind limb. Low temperature treatment on motor nerves did not result in any permanent or long-term changes to function and structure of the nerves. PMID:23917804

  18. Use of electrogastrography in preclinical studies of cholinergic and anticholinergic agents in experimental pigs.

    PubMed

    Květina, J; Tachecí, I; Pavlík, M; Kopáčová, M; Rejchrt, S; Douda, T; Kuneš, M; Bureš, J

    2016-01-01

    Electrogastrography (EGG) is a non-invasive method for the assessment of gastric myoelectrical activity. Porcine EGG is comparable with human one. The purpose of this study was to evaluate the effect of atropine and neostigmine on the EGG in experimental pigs. Adult female pigs were administrated atropine (1.5 mg i.m., n=6) and neostigmine (0.5 mg i.m., n=6) after the baseline EGG, followed by a 90-min trial recording (MMS, Enschede, the Netherlands). Running spectral analysis was used for the evaluation. The results were expressed as dominant frequency of slow waves and EGG power (areas of amplitudes). Neostigmine increased continuously the dominant frequency and decreased significantly the EGG power. Atropine did not change the dominant frequency significantly. However, atropine increased significantly the EGG power (areas of amplitudes) from basal values to the maximum at the 10-20-min interval. After that period, the areas of amplitudes decreased significantly to the lowest values at the 60-90-min interval. In conclusion, cholinergic and anticholinergic agents affect differently EGG in experimental pigs. PMID:26674291

  19. Preclinical Studies on Neurobehavioral and Neuromuscular Effects of Cocaine Hydrolase Gene Therapy in Mice

    PubMed Central

    Murthy, Vishakantha; Gao, Yang; Geng, Liyi; LeBrasseur, Nathan; White, Thomas; Brimijoin, Stephen

    2014-01-01

    Cocaine hydrolase gene transfer of mutated human butyrylcholinesterase (BChE) is evolving as a promising therapy for cocaine addiction. BChE levels after gene transfer can be 1,500-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. Because mutated BChE is approximately 70 % as efficient in hydro-lyzing acetylcholine as wild-type enzyme, it is important to examine the impact on cholinergic function. Here, we focused on memory and cognition (Stone T-maze), basic neuromuscular function (treadmill endurance and grip strength), and coordination (Rotarod). BALB/c mice were given adeno-associated virus vector or helper-dependent adenoviral vector encoding mouse or human BChE optimized for cocaine. Age-matched controls received saline or luciferase vector. Despite high doses (up to 1013 particles per mouse) and high transgene expression (1,000-fold above baseline), no deleterious effects of vector treatment were seen in neurobehavioral functions. The vector-treated mice performed as saline-treated and lucif-erase controls in maze studies and strength tests, and their Rotarod and treadmill performance decreased less with age. Thus, neither the viral vectors nor the large excess of BChE caused observable toxic effects on the motor and cognitive systems investigated. This outcome justifies further steps toward an eventual clinical trial of vector-based gene transfer for cocaine abuse. PMID:24085526

  20. A 3-week pre-clinical study of 2?-fucosyllactose in farm piglets.

    PubMed

    Hanlon, Paul R; Thorsrud, Bjorn A

    2014-12-01

    One of the most abundant oligosaccharides found in human milk is 2?-fucosyllactose, a trisaccharide composed of fucose and lactose, and multiple studies have demonstrated a health benefit to this compound. Recent advances have allowed for the large-scale production of oligosaccharides via fermentation, including 2?-fucosyllactose. A neonatal piglet model was used to evaluate the tolerability of 2?-fucosyllactose, produced through this process, in order to demonstrate the suitability of this compound for human infants under 12 weeks of age. Crossbred farm piglets, at lactation day 2, were assigned to one of four treatment groups receiving a liquid diet containing 0, 200, 500 or 2000?mg/L of 2?-fucosyllactose. The calculated consumption of 2?-fucosyllactose corresponded to dose levels of 29.37, 72.22 and 291.74?mg/kg/day, respectively, in males and 29.30, 74.31, and 298.99?mg/kg/day, respectively in females. Piglets were administered diet for 3 weeks; and there were no test article-related effects on growth and development (clinical observations, body weight and food consumption), clinical pathology parameters (hematology, clinical chemistry, coagulation and urinalysis), or any histopathologic changes. Therefore, dietary exposure to 2?-fucosyllactose at concentrations up to 2000?mg/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. PMID:25445760

  1. 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

  2. Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study

    PubMed Central

    Li, Chenwen; Fu, Ruoqiu; Yu, Caiping; Li, Zhuoheng; Guan, Haiyan; Hu, Daqiang; Zhao, Dehua; Lu, Laichun

    2013-01-01

    In this study, a mixture of poly(vinyl alcohol) (PVA) and chitosan oligosaccharides (COS) was electrospun with silver nanoparticles (AgNPs) to produce fibrous mats for use in wound healing. The AgNPs were reduced by COS prior to electrospinning or Ag+ was reduced via ultraviolet irradiation in nanofibers. The morphologies of the PVA/COS/AgNO3 and PVA/COS-AgNP nanofibers were analyzed by scanning electron microscopy. Formation of the AgNPs was investigated by field emission transmission electron microscopy, ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. We also evaluated the biocompatibility of the nanofibers, particularly their cytotoxicity to human skin fibroblasts and potential to cause primary skin irritation. The in vitro antibacterial activity and in vivo wound healing capacity of the nanofibers were also investigated. The nanofibers had a smooth surface with an average diameter of 130–192 nm. The diameters of the AgNPs were in the range of 15–22 nm. The nanofibers significantly inhibited growth of Escherichia coli and Staphylococcus aureus bacteria. PVA/COS-AgNP nanofibers accelerated the rate of wound healing over that of the control (gauze). The results of our in vitro and in vivo animal experiments suggest that PVA/COS-AgNP nanofibers should be of greater interest than PVA/COS/AgNO3 nanofibers for clinical use as a bioactive wound dressing. PMID:24204142

  3. 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

  4. Photoacoustic spectroscopy in the monitoring of breast tumor development: a pre-clinical study

    NASA Astrophysics Data System (ADS)

    Priya, Mallika; Rao, Bola Sadashiva Satish; Ray, Satadru; Mahato, Krishna Kishore

    2014-03-01

    Breast cancer is the most frequently diagnosed cancer type and its detection at an early stage can reduce the mortality rate substantially. With the aim to detect breast cancer early, by studying tumor progression in nude mice, a pulsed laser induced photoacoustic spectroscopy set up has been designed and developed. MCF-7 cells xenografts were developed using six to eight weeks old female nude mice and tumor tissues were extracted on different days (10th, 15th and 20th Day) post injection and the corresponding photoacoustic spectra were recorded at 281nm excitation. A total of 144 time domain spectra were recorded from 36 animals belonging to the three time points (10th, 15th and 20th day post injection) and converted into frequency domains by Fast Fourier Transform (FFT) tools of the MATLAB algorithms and analyzed. The frequency patterns of the tumor masses on 10th, 15th and 20th day of tumor development showed a gradual increase in intensity at certain frequencies, 5.93 x103 Hz, 15.9 x103 Hz, 29.69 x103 Hz and 32.5 x103 Hz in the FFT patterns indicating that these frequencies were more sensitive towards tumor development. Further analysis of the data yielded a clear variation in the spectral parameters with progression of the disease suggesting that the technique may be suitable for early detection of the disease. Thus, we expect that the developed setup may be useful in assessing the different phases of tumor development which may have clinical implications.

  5. Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study

    PubMed Central

    Nayagam, David A. X.; Williams, Richard A.; Allen, Penelope J.; Shivdasani, Mohit N.; Luu, Chi D.; Salinas-LaRosa, Cesar M.; Finch, Sue; Ayton, Lauren N.; Saunders, Alexia L.; McPhedran, Michelle; McGowan, Ceara; Villalobos, Joel; Fallon, James B.; Wise, Andrew K.; Yeoh, Jonathan; Xu, Jin; Feng, Helen; Millard, Rodney; McWade, Melanie; Thien, Patrick C.; Williams, Chris E.; Shepherd, Robert K.

    2014-01-01

    Purpose To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. Methods Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. Results All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 kΩ during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. Conclusions Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents. PMID:24853376

  6. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders

    PubMed Central

    Chiu, Chi-Tso; Chuang, De-Maw

    2011-01-01

    Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium’s therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium’s main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington’s, Alzheimer’s, and Parkinson’s diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium’s neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases. PMID:20705090

  7. Microrobotized blasting improves the bone-to-textured implant response. A preclinical in vivo biomechanical study.

    PubMed

    Coelho, Paulo G; Gil, Luiz F; Neiva, Rodrigo; Jimbo, Ryo; Tovar, Nick; Lilin, Thomas; Bonfante, Estevam A

    2016-03-01

    This study evaluated the effect of microrobotized blasting of titanium endosteal implants relative to their manually blasted counterparts. Two different implant systems were utilized presenting two different implant surfaces. Control surfaces (Manual) were fabricated by manually grit blasting the implant surfaces while experimental surfaces (Microblasted) were fabricated through a microrobotized system that provided a one pass grit blasting routine. Both surfaces were created with the same ~50µm average particle size alumina powder at ~310KPa. Surfaces were then etched with 37% HCl for 20min, washed, and packaged through standard industry procedures. The surfaces were characterized through scanning electron microscopy (SEM) and optical interferometry, and were then placed in a beagle dog radius model remaining in vivo for 3 and 6 weeks. The implant removal torque was recorded and statistical analysis evaluated implant system and surface type torque levels as a function of time in vivo. Histologic sections were qualitatively evaluated for tissue response. Electron microscopy depicted textured surfaces for both manual and microblasted surfaces. Optical interferometry showed significantly higher Sa, Sq, values for the microblasted surface and no significant difference for Sds and Sdr values between surfaces. In vivo results depicted that statistically significant gains in biomechanical fixation were obtained for both implant systems tested at 6 weeks in vivo, while only one system presented significant biomechanical gain at 3 weeks. Histologic sections showed qualitative higher amounts of new bone forming around microblasted implants relative to the manually blasted group. Microrobotized blasting resulted in higher biomechanical fixation of endosteal dental implants and should be considered as an alternative for impant surface manufacturing. PMID:26703231

  8. 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

  9. Fiber optic fluorescence detection of low-level porphyrin concentrations in preclinical and clinical studies

    NASA Astrophysics Data System (ADS)

    Mang, Thomas S.; McGinnis, Carolyn; Khan, S.

    1990-07-01

    A significant clinical problem in the local treatment of cutaneous metastases of breast cancer (by any modality--surgery, radiation therapy or photodynainic therapy) is the fact that the disease almost always extends beyond the boundary of visible lesions in the form of microscopic deposits. These deposits may be distant from the site of visible disease but are often in close proximity to it and are manifested sooner or later by the development of recurrent lesions at the border of the treated area, thus the "marginal miss" in radiation therapy, the "rim recurrence" in photodynamic therapy, and the "incisional recurrence" following surgical excision. More intelligent use of these treatment modalities demands the ability to detect microscopic deposits of tumor cells using non-invasive methodology. In vivo fluorescence measurements have been made possible by the development of an extremely sensitive fiber optic in vivo fluorescence photometer. The instrument has been used to verify that fluorescence correlated with injected porphyrin levels in various tissues. The delivery of light to excite and detect background fluorescence as well as photosensitizer fluorescence in tissues has been accomplished using two HeNe lasers emitting at 632.8 nm and 612 nm delivered through a single quartz fiber optic. Chopping at different frequencies, contributions of fluorescence may be separated. Fluorescence is picked up via a 400 micron quartz fiber optic positioned appropriately near the target tissue. Validation of these levels was made by extraction of the drug from the tissues with resultant quantitation. Recently, an extensive study was undertaken to determine if fluorescence could be used for the detection of occult, clinically non-palpable metastases in the lymph node of rats. This unique model allowed for the detection of micrometastases in lymph nodes using very low injected doses of the photosensitizer Photofrin II. Data obtained revealed the ability to detect on the order of 50-100 cells using 0.25 mg/kg of sensitizer, a level 20 times lower than normally used for treatment of animal tumors. These results indicate that Photofrin II could be used for fluorescence detection of small metastatic tumors, while substantially reducing the major side effect of PDT; namely, prolonged photosensitivity. Results to be presented demonstrate the ability of this technique to detect microscopic deposits of malignant tumor cells in patients with metastatic breast cancer. These deposits were found in clinically negative areas of the chest wall.

  10. Bone metastasis imaging with SPECT/CT/MRI: a preclinical toolbox for therapy studies.

    PubMed

    Sanches, Pedro Gomes; Peters, Steffie; Rossin, Raffaella; Kaijzel, Eric L; Que, Ivo; Lwik, Clemens W G M; Grll, Holger

    2015-06-01

    Bone is one of the most common metastatic target sites in breast cancer, with more than 200 thousand new cases of invasive cancer diagnosed in the US alone in 2011. We set out to establish a multimodality imaging platform for bone metastases in small animals as a tool to non-invasively quantify metastasis growth, imaging the ensuing bone lesions and possibly the response to treatment. To this end, a mouse model of osteolytic metastatic bone tumors was characterized with SPECT/CT and MRI over time. A cell line capable of forming bone metastases, MDA-MB-231, was genetically modified to stably express the reporter gene herpes simplex virus-1 thymidine kinase (hsv-1 tk). The intracellular accumulation of the radiolabeled tracer [(123)I]FIAU promoted by HSV-1 TK specifically pinpoints the location of tumor cells which can be imaged in vivo by SPECT. First, a study using tumors implanted subcutaneously was performed. The SPECT/MRI overlays and the ex vivo ?-counting showed a linear correlation in terms of %ID/cm(3) (R(2)=0.93) and %ID/g (R(2)=0.77), respectively. Then, bone metastasis growth was imaged weekly by SPECT/CT and T2-weighted MRI over a maximum of 40 days post-intracardiac injection of tumor cells. The first activity spots detectable with SPECT, around day 20 post-cell injection, were smaller than 2mm(3) and not yet visible by MRI and increased in volume and in %ID over the weeks. Osteolytic bone lesions were visible by CT (in vivo) and ?CT (ex vivo). The SPECT/MRI overlays also showed a linear correlation in terms of %ID/cm(3) (R(2)=0.86). In conclusion, a new multimodality imaging platform has been established that non-invasively combines images of active tumor areas (SPECT), tumor volume (MRI) and the corresponding bone lesions (CT and ?CT). To our knowledge this is the first report where the combination of soft tissue information from MRI, bone lesions by CT, and reporter gene imaging by SPECT is used to non-invasively follow metastatic bone lesions. PMID:25680341

  11. Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours

    PubMed Central

    Martin-Liberal, J; Gil-Martín, M; Sáinz-Jaspeado, M; Gonzalo, N; Rigo, R; Colom, H; Muñoz, C; Tirado, O M; García del Muro, X

    2014-01-01

    Background: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine. Methods: Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m−2 on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted. Results: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment. Conclusions: Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m−2. Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing. PMID:25003665

  12. Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer's Disease: What are the Roadblocks and How Can They Be Overcome?

    PubMed

    Banik, Avijit; Brown, Richard E; Bamburg, James; Lahiri, Debomoy K; Khurana, Dheeraj; Friedland, Robert P; Chen, Wei; Ding, Ying; Mudher, Amritpal; Padjen, Ante L; Mukaetova-Ladinska, Elizabeta; Ihara, Masafumi; Srivastava, Sudhir; Padma Srivastava, M V; Masters, Colin L; Kalaria, Raj N; Anand, Akshay

    2015-01-01

    Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress. PMID:26401762

  13. 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; Sprssel, 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 2025% 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-1792 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

  14. The prevalence and correlations of medical student burnout in the pre-clinical years: a cross-sectional study.

    PubMed

    Mazurkiewicz, Rebecca; Korenstein, Deborah; Fallar, Robert; Ripp, Jonathan

    2012-01-01

    Burnout is a psychological syndrome of emotional exhaustion, depersonalization, and impaired personal accomplishment induced by repeated workplace stressors. Current research suggests that physician burnout may have its origins in medical school. The consequences of medical student burnout include both personal and professional distress, loss of empathy, and poor health. We hypothesized that burnout occurs prior to the initiation of the clinical years of medical education. This was a cross-sectional survey administered to third-year medical students at the Mount Sinai School of Medicine (MSSM) in New York, New York (a traditional-style medical school with a marked division between pre-clinical and clinical training occurring at the beginning of the third year). Survey included an instrument used to measure job burnout, a sleep deprivation screen, and questions related to demographic information, current rotation, psychiatric history, time spent working/studying, participation in extracurricular activities, social support network, autonomy and isolation. Of the 86 medical students who participated, 71% met criteria for burnout. Burnt out students were significantly more likely to suffer from sleep deprivation (p=0.0359). They were also more likely to disagree with the following statements: "I have control over my daily schedule" (p=0.0286) and "I am confident that I will have the knowledge and skills necessary to become an intern when I graduate" (p=0.0263). Our findings show that burnout is present at the beginning of the third year of medical school, prior to the initiation of the clinical years of medical training. Medical student burnout is quite common, and early efforts should be made to empower medical students to both build the knowledge and skills necessary to become capable physicians, as well as withstand the emotional, mental, and physical challenges inherent to medical school. PMID:21781020

  15. Monte Carlo simulation on pre-clinical irradiation: A heterogeneous phantom study on monoenergetic kilovoltage photon beams

    NASA Astrophysics Data System (ADS)

    Chow, James C. L.

    2012-10-01

    This study investigated radiation dose variations in pre-clinical irradiation due to the photon beam energy and presence of tissue heterogeneity. Based on the same mouse computed tomography image dataset, three phantoms namely, heterogeneous, homogeneous and bone homogeneous were used. These phantoms were generated by overriding the relative electron density of no voxel (heterogeneous), all voxel (homogeneous) and the bone voxel (bone homogeneous) to one. 360 photon arcs with beam energies of 50 - 1250 keV were used in mouse irradiations. Doses in the above phantoms were calculated using the EGSnrc-based DOSXYZnrc code through the DOSCTP. Monte Carlo simulations were carried out in parallel using multiple nodes in a high-performance computing cluster. It was found that the dose conformity increased with the increase of the photon beam energy from the keV to MeV range. For the heterogeneous mouse phantom, increasing the photon beam energy from 50 keV to 1250 keV increased seven times the dose deposited at the isocenter. For the bone dose enhancement, the mean dose was 2.7 times higher when the bone heterogeneity was not neglected using the 50 keV photon beams in the mouse irradiation. Bone dose enhancement affecting the mean dose was found in the photon beams with energy range of 50 - 200 keV and the dose enhancement decreased with an increase of the beam energy. Moreover, the MeV photon beam had a higher dose at the isocenter, and a better dose conformity compared to the keV beam.

  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 β-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. Genetic toxicology assessment of HI-6 dichloride

    SciTech Connect

    Putman, D.; San, R.H.; Bigger, C.A.; Levine, B.S.; Jacobson-Kram, D.

    1996-08-01

    The oxime HI-6 dichloride (1-(2 hydroxyiminomethyl- 1-pyridino)-3- (4-carbamoyl-1- pyridino)-2-oxapropane dichloride monohydrate) has shown to be a potent reactivator of cholinesterase activity and may have efficacy for the treatment of organo-phosphate intoxication (SIPRI, 1976; Schenk et al.; Arch Toxicol 36:71-81, 1976). As part of a pre-clinical safety assessment program, the genetic toxicology of HI-6 dichloride was evaluated in a series of assays designed to measure induction of gene mutations and chromosomal aberrations. HI-6 dichloride gave negative responses in the Salmonella mutagenicity assay and in the CHO/HGPRT gene mutation assay. Dose-dependent increases in the frequency of chromosomal aberrations when HI-6 dichloride was tested in cultured CHO cells and in cultured human peripheral blood lymphocytes. The mouse lymphoma gene mutation assay, reputed to measure both gene mutations and chromosomal deletions, was negative in the absence of metabolic activation. Depending on the criteria employed, a negative or equivocal response was seen in the presence of rat liver-derived S-9 mix. An in vivo rat bone marrow metaphase assay performed to further investigate the in vitro clastogenic responses was negative. The results from these studies indicate that HI-6 dichloride does not induce gene mutations in vitro; however, it is clastogenic in vitro but does not appear to be clastogenic in vivo.

  18. Toxicology and Carcinogenesis Studies of Ochratoxin A (CAS No. 303-47-9) in F344/N Rats (Gavage Studies).

    PubMed

    1989-05-01

    Ochratoxin A is a naturally occurring fungal toxin that is a contaminant in corn, peanuts, storage grains, cottonseed, meats, dried fish, and nuts. Toxicology and carcinogenesis studies were conducted by administering ochratoxin A (98% pure) in corn oil by gavage to groups of F344/N rats of each sex for 16 days, 13 weeks, 9 months, 15 months, or 2 years. Only rats were studied because ochratoxin A has been shown to be carcinogenic in mice. Genetic toxicology tests were performed with bacterial and mammalian cells. Urinalysis, hematologic and serum chemical analyses, and bone marrow cellularity determinations were conducted at 9, 15, and 24 months in the 2-year studies. Sixteen-Day and Thirteen-Week Studies: Rats were administered 0, 1, 4, or 16 mg/kg ochratoxin A in corn oil by gavage 5 days per week for a total of 12 doses over 16 days. All rats that received 16 mg/kg ochratoxin A died within 6 days. Rats that received 4 mg/kg lost weight. Compound-related lesions in rats included bone marrow hyperplasia, thymic atrophy, necrosis and hyperplasia of the forestomach epithelium, renal tubular cell degenerative and regenerative changes (nephropathy), and adrenal gland hemorrhage. Renal tubular changes were most severe in animals that received 4 mg/kg. Rats that received 16 mg/kg had less severe renal lesions than those at 4 mg/kg, perhaps because the acute toxicity and early death did not allow sufficient time for full development of lesions. No compound-related deaths occurred in the 13-week studies (doses were 0 and 0.0625 to 1 mg/kg). The final mean body weight of rats that received 0.25, 0.5, or 1 mg/kg was 7%, 11%, or 19% lower than that of vehicle controls for males and 3%, 4%, or 9% lower for females. Compound-related lesions in the kidney were characterized as degeneration and regeneration of the epithelium of the proximal convoluted tubules with individual cell necrosis of moderate severity (see page 3 of the Technical Report). Karyomegaly of tubular epithelial cells was widespread but most pronounced in the straight portion of the tubules just above the corticomedullary junction. Karyomegaly was present in all dosed groups, and the severity increased as the dose increased. At lower doses, atrophy of the straight portions of the tubules at the corticomedullary junction and in the medulla was observed. Based on mortality and on the presence and severity of renal lesions, groups of 80 rats per sex and dose group were administered 0, 21, 70, or 210 ug/kg ochratoxin A in corn oil by gavage 5 days per week for up to 2 years. Groups of 15 rats per sex and dose were killed at 9 or at 15 months and the remaining animals at 2 years. Nine-Month and Fifteen-Month Studies: Administration of ochratoxin A by gavage for 9 months or 15 months to F344/N rats was associated with increased incidences of renal tubular cell neoplasms in males and hyperplasia, degeneration, and karyomegaly of renal tubular epithelial cells in both males and females (see page 4 of the Technical Report). Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were generally 4%-7% lower than those of vehicle controls. No significant differences in survival were observed between any groups of female rats (vehicle control, 32/50; low dose, 23/51; mid dose, 35/50; high dose, 34/50). Survival was decreased after 77 weeks in high dose male rats and after 96 weeks in low and mid dose male rats (39/50; 26/51; 26/51; 23/50). Clinical Pathology: Minor differences were observed for hematologic values between dosed and vehicle control animals, but these were not considered to be of biologic significance. Results of serum chemistry analysis were not clearly compound related. Ochratoxin A-dosed animals had slight increases compared with vehicle controls in urine volume and decreases in urine specific gravity in concentration tests, suggesting that exposure resulted in mild to moderate decreases in the ability to concentrate urine. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: A spectrum of degenerative and proliferative cho-Year Studies: A spectrum of degenerative and proliferative changes occurred in the kidney of male and female rats given ochratoxin A for 2 years. Degeneration of the renal tubular epithelium with formation of tubular cysts, proliferation of the tubular epithelium, and karyomegaly of the nuclei of tubular epithelial cells occurred at increased incidences in dosed rats (see page 5 of the Technical Report). Hyperplasia of the renal tubular epithelium and renal tubular adenomas and carcinomas also occurred at increased incidences in the dosed rats; the tumors were frequently multiple within a single kidney or were bilateral, and many metastasized to other organs. The incidence of fibroadenomas of the mammary gland in high dose female rats was significantly greater than that in vehicle controls (vehicle control, 17/50; low dose, 23/51; mid dose, 22/50; high dose, 28/50). Multiple fibroadenomas of the mammary gland were observed at an increased incidence in high dose female rats (4/50; 4/51; 5/50; 14/50). One mammary gland adenoma was seen in a mid dose female, and two mammary gland adenocarcinomas were seen in each dosed group; one adenocarcinoma was seen in the vehicle control group. An adenoma of the pars intermedia of the pituitary gland was observed in one mid dose female rat, and a carcinoma was observed in a second mid dose female rat. Squamous cell papillomas of the tongue were seen in two low dose and two mid dose male rats. Neither the pituitary neoplasms nor the papillomas of the tongue were considered related to ochratoxin A exposure. Genetic Toxicology: Ochratoxin A was not mutagenic in four strains of Salmonella typhimurium (TA97, TA98, TA100, or TA1535) when tested both with and without exogenous metabolic activation. In cultured Chinese hamster ovary (CHO) cells, ochratoxin A induced sister chromatid exchanges (SCEs) in the presence, but not the absence, of metabolic activation; it did not significantly increase the number of chromosomal aberrations in these cells. Audit: The data, documents, and pathology materials from the 2-year studies of ochratoxin A have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of ochratoxin A for male F344/N rats as shown by substantially increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney. There was clear evidence of carcinogenic activity for female F344/N rats shown by increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney and by increased incidences and multiplicity of fibroadenomas of the mammary gland. Ochratoxin A administration also caused nonneoplastic renal changes including tubular cell hyperplasia, tubular cell proliferation, cytoplasmic alteration, karyomegaly, and degeneration of the renal tubular epithelium. Synonym: (R)-N-[(5-chloro-3,4-dihydro-8-hydroxy-3-methyl-1-oxo-1H-2-enzopyran-7-yl)-carbonyl](-L-)phenylalanine PMID:12695783

  19. 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...

  20. CAVEATS REGARDING THE USE OF THE LABORATORY RATS AS A MODEL FOR ACUTE TOXICOLOGICAL STUDIES: MODULATION OF THE TOXIC RESPONSE VIA PHYSIOLOGICAL AND BEHAVIORAL MECHANISMS

    EPA Science Inventory

    The rodent, specifically the inbred laboratory rat, is the primary experimental animal used in toxicology testing. Despite its popularity, recent studies from our laboratory and others raise a number of questions concerning the rat's appropriateness as an animal model for toxicol...

  1. 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

  2. Education Predicts Incidence of Preclinical Mobility Disability in Initially High-Functioning Older Women. The Women’s Health and Aging Study II

    PubMed Central

    Gregory, Patricia C.; Xue, Qian-Li; Tian, Jing; Thorpe, Roland J.; Fried, Linda P.

    2011-01-01

    Background. To examine the impact of educational attainment on the incidence of preclinical mobility disability (PCD). Methods. The Women's Health and Aging II Study is a prospective observational cohort study of 436 initially high-functioning community-dwelling women aged 70–79 years at baseline in Baltimore, Maryland. We measured the association of highest attained education level with preclinical mobility disability (PCD) over an 11-year period. PCD is defined as self-reported modification in any of four tasks without reporting difficulty in those tasks. The tasks were walking ½ mile, climbing up steps, doing heavy housework, and getting in/out of bed or chair. Results. Participants with less than 9 years of education were more likely to acquire incident PCD (hazard ratio: 3.1, 95% confidence interval = 1.2–7.7) than their counterparts with more education after adjusting for income, marital status, number of diseases, and high self-efficacy. Conclusions. Lower education level is an independent predictor of incident preclinical mobility disability. This association has important implications for primary and secondary prevention and can be easily assessed in clinical encounters. PMID:21382883

  3. Toxicology and Carcinogenesis Studies of 8-Methoxypsoralen (CAS No. 298-81-7) in F344/N Rats (Gavage Studies).

    PubMed

    1989-07-01

    Oral administration of 8-methoxypsoralen followed by exposure to longwave ultraviolet light (primarily ultraviolet A, 320-400 nm) is used in the treatment of vitiligo and psoriasis. 8-Methoxypsoralen also occurs naturally in a variety of vegetables. Toxicology and carcinogenesis studies of 8-methoxypsoralen without ultraviolet A were conducted by administering USP-grade 8-methoxypsoralen (99% pure) in corn oil by gavage to groups of F344/N rats once or for 16 days, 13 weeks, or 2 years. In vitro genetic toxicology tests were performed with bacteria and mammalian cells. Single-Administration, Sixteen-Day, and Thirteen-Week Studies: In the single-administration studies, the chemical was administered at doses of 0 and 63-1,000 mg/kg. Four of five male rats and 5/5 female rats that received 1,000 mg/kg 8-methoxypsoralen died within 2 days. In the 16-day studies, the chemical was administered at doses of 0 and 50-800 mg/kg. All rats receiving 800 mg/kg died within 5 days, and one male and one female at 400 mg/kg and one female at 200 mg/kg also died before the end of the studies. The final mean body weights of animals at 200 or 400 mg/kg were 14% or 30% lower than those of vehicle controls. No compound-related effects were observed at necropsy. In the 13-week studies, the chemical was administered at doses of 0 and 25-400 mg/kg. Six of 10 male rats and 8/10 female rats that received 400 mg/kg died before the end of the studies. The final mean body weight of male rats that received 100, 200, or 400 mg/kg was 12%, 22%, or 45% lower than that of vehicle controls. The final mean body weight of female rats that received 200 or 400 mg/kg was 15% or 35% lower than that of vehicle controls. The liver weight to body weight ratios for all dosed groups of rats except the lowest (25 mg/kg) were greater than those for vehicle controls. Compound-related effects included fatty change in the liver in males and females and atrophy of the testis, seminal vesicles, and prostate. Based on these results, 2-year studies were conducted by administering 0, 37.5 or 75 mg/kg 8-methoxypsoralen in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex. Body Weight and Survival in the Two-Year Studies: The mean body weights of dosed male rats were generally 3%-14% lower than those of vehicle controls, and the mean body weights of high dose female rats were 5%-17% lower. The survival of both the low and the high dose groups of male rats was lower than that of the vehicle controls (male: vehicle control, 30/50; low dose, 16/50; high dose, 16/50; female: 39/50; 33/50; 36/50), likely because of kidney toxicity and neoplasia. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Mineralization of the renal papilla was observed in high dose male rats (vehicle control, 0/50; low dose, 0/50; high dose, 31/49). The severity of nephropathy was increased in dosed male rats. Focal hyperplasia of renal tubular cells was observed in dosed male rats (0/50; 8/50; 8/49). The incidences of tubular cell adenomas (1/50; 11/50; 8/49), adenocarcinomas (0/50; 1/50; 3/49), and adenomas or adenocarcinomas (combined) (1/50; 12/50; 11/49) were increased in dosed male rats. Hyperplasia of the parathyroid glands (2/49; 22/47; 18/48) and fibrous osteodystrophy (2/50; 10/50; 12/49) in male rats were secondary to chronic nephropathy. The incidences of carcinomas or squamous cell carcinomas (combined) of the Zymbal gland were increased in dosed male rats (1/50; 7/50; 4/49). The mean historical incidence for carcinomas or squamous cell carcinomas (combined) in corn oil vehicle control male F344/N rats is 0.8% (16/1,949); the highest incidence in any one group is 4% (2/49). Fibromas of the subcutaneous tissue in male rats occurred with a positive trend (1/50; 5/50; 7/49). An additional high dose male had a sarcoma. The mean historical incidence of fibromas or fibrosarcomas (combined) of subcutaneous tissue in corn oil vehicle control male F344/N rats is 9% (171/1,949). Alveolar/bronchiolar adenomas occurred with a positive trend in male rats (4t

  4. Inhalation developmental toxicology studies of 1,3-butadiene in the rat: Final report

    SciTech Connect

    Hackett, P.L.; Sikov, M.R.; Mast, T.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.

    1987-11-01

    Maternal toxicity, reproductive performance and developmental toxicology were evaluated in Sprague-Dawley-derived rats during and following 6 hours/day, whole-body, inhalation exposures to 0, 40, 200, and 1000 ppM of 1,3-butadiene. The female rats (Ns = 24 to 28), which had mated with unexposed males, were exposed to the chemical from 6 through 15 dg and sacrificed on 20 dg. Maternal animals were weighed prior to mating and on 0, 6, 11, 16 and 20 dg; the rats were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. Live fetuses were weighed and subjected to external, visceral and skeletal examinations to detect growth retardation and morphologic anomalies. There were no significant differences among treatment groups in maternal body weights or extragestational weights of rats exposed to 1,3-butadiene concentrations of 40 or 200 ppM, but, in animals exposed to 1000 ppM, significantly depressed body weight gains were observed during the first 5 days of exposure and extragestational weight gains tended to be lower than control values. These results, and the absence of clinical signs of toxicity, were considered to indicate that there was no maternal toxicity at exposure levels of 200 ppM or lower. The percentage of pregnant animals and the number of litters with live fetuses were unaffected by treatment. Under the conditions of this exposure regimen, there was no evidence for a teratogenic response to 1,3-butadiene exposure.

  5. 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

  6. Pharmacotherapy of cocaine abuse: preclinical development.

    PubMed

    Witkin, J M

    1994-01-01

    Preclinical models of behavioral and toxic effects of cocaine are reviewed and their potential for predicting compounds with efficacy and safety in the medical management of cocaine abuse and toxicity is assessed. Many of the existing models appear to be good predictors of the effects of compounds against specific behavioral or toxicological actions of cocaine. However, the utility of the models for prediction of the efficacy of new therapeutic entities must await clinical validation as no accepted or standard pharmacotherapy currently exists. Preclinical data generated by these models with drugs currently under clinical investigation for cocaine abuse treatment as well as with other compounds are reviewed. These compounds include buprenorphine, bromocriptine, desmethylimipramine, carbamazepine, dopaminergic agonists, antagonists and partial agonists, dopamine reuptake inhibitors, sigma ligands, serotonin antagonists, and excitatory amino acid antagonists. Preclinical information on several drug classes appears sufficiently promising to warrant further evaluation. These include dopamine agonists and partial agonists, D1 receptor antagonists, selective sigma ligands, and modulators of the N-methyl-D-aspartate subtype glutamate receptor. PMID:8170620

  7. Preclinical Studies of the Potent and Selective Nicotinic α4β2 Receptor Ligand VMY-2-95

    PubMed Central

    2015-01-01

    The discovery and development of small molecules that antagonize neuronal nicotinic acetylcholine receptors may provide new ligands for evaluation in models of depression or addiction. We discovered a small molecule, VMY-2-95, a nAChR ligand with picomolar affinity and high selectivity for α4β2 receptors. In this study, we investigated its preclinical profile in regards to solubility, lipophilicity, metabolic stability, intestinal permeability, bioavailability, and drug delivery to the rat brain. Metabolic stability of VMY-2-95·2HCl was monitored on human liver microsomes, and specific activity of VMY-2-95·2HCl on substrate metabolism by CYP1A2, 2C9, 2C19, 2D6, and 3A4 was tested in a high-throughput manner. The intestinal transport of VMY-2-95·2HCl was studied through Caco-2 cell monolayer permeability. VMY-2-95·2HCl was soluble in water and chemically stable, and the apparent partition coefficient was 0.682. VMY-2-95·2HCl showed significant inhibition of CYP2C9 and 2C19, but weak or no effect on 1A2, 2D6, and 3A4. The Caco-2 cell model studies revealed that VMY-2-95·2HCl was highly permeable with efflux ratio of 1.11. VMY-2-95·2HCl achieved a maximum serum concentration of 0.56 mg/mL at 0.9 h and was orally available with a half-life of ∼9 h. Furthermore, VMY-2-95·2HCl was detected in the rat brain after 3 mg/kg oral administration and achieved a maximal brain tissue concentration of 2.3 μg/g within 60 min. Overall, the results demonstrate that VMY-2-95·2HCl has good drug like properties and can penetrate the blood–brain barrier with oral administration. PMID:25533629

  8. Applications of Proteomic Technologies to Toxicology

    EPA Science Inventory

    Proteomics is the large-scale study of gene expression at the protein level. This cutting edge technology has been extensively applied to toxicology research recently. The up-to-date development of proteomics has presented the toxicology community with an unprecedented opportunit...

  9. Reproductive Toxicology Testing with EDCS

    EPA Science Inventory

    An introduction to reproductive toxicology: the basic approaches to testing chemicals for adverse effects using multigenerational studies with rats and how the regulatory agencies used the data in risk assessments. Case studies were presented of how endocrine or genomic data were...

  10. 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

  11. Aquatic toxicology: fact or fiction

    SciTech Connect

    Macek, K.J.

    1980-02-01

    The science of aquatic toxicology is a relatively new science. The development of the field of aquatic toxicology since 1930 is traced. The state of the art of aquatic toxicology compared with that of classical toxicology is evaluated. The science of aquatic toxicology is expected to undergo a significant period of rapid growth and development, leading ultimately to the formation of a mature science.

  12. Validation of murine and human placental explant cultures for use in sex steroid and phase II conjugation toxicology studies

    PubMed Central

    Sato, Brittany L.; Ward, Monika A.; Astern, Joshua M.; Kendal-Wright, Claire E.; Collier, Abby C.

    2014-01-01

    Human primary placental explant culture is well established for cytokine signaling and toxicity, but has not been validated for steroidogenic or metabolic toxicology. The technique has never been investigated in the mouse. We characterized human and mouse placental explants for up to 96hr in culture. Explant viability (Lactate dehydrogenase) and sex steroid levels were measured in media using spectrophotometry and ELISA, respectively. Expression and activities of the steroidogenic (3β-hydroxysteroid dehydrogenase, Cytochrome P45017A1, Cytochrome P45019), conjugation (UDP-glucuronosyltransferase, sulfotransferase (SULT)), and regeneration (β-glucuronidase, arylsulfatase C (ASC)) enzymes were determined biochemically in tissues with fluorimetric and spectrophotometric assays, and western blot. Explants were viable up to 96hr, but progesterone, estrone, and 17β-estradiol secretion decreased. Steroidogenic enzyme expression and activities were stable in mouse explants and similar to levels in freshly isolated tissues, but were lower in human explants than in fresh tissue (P<0.01). Human and mouse explants exhibited significantly less conjugation after 96hr, SULT was not detected in the mouse, and neither explants had active ASC, although proteins were expressed. Mouse explants may be useful for steroid biochemistry and endocrine disruption studies, but not metabolic conjugation. In contrast, human explants may be useful for studying conjugation for <48hr, but not for steroid/endocrine studies. PMID:25283089

  13. 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

    2016-02-17

    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' (ECVAM) 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

  14. Nanotechnology: Toxicologic Pathology

    PubMed Central

    Hubbs, Ann F.; Sargent, Linda M.; Porter, Dale W.; Sager, Tina M.; Chen, Bean T.; Frazer, David G.; Castranova, Vincent; Sriram, Krishnan; Nurkiewicz, Timothy R.; Reynolds, Steven H.; Battelli, Lori A.; Schwegler-Berry, Diane; McKinney, Walter; Fluharty, Kara L.; Mercer, Robert R.

    2015-01-01

    Nanotechnology involves technology, science, and engineering in dimensions less than 100 nm. A virtually infinite number of potential nanoscale products can be produced from many different molecules and their combinations. The exponentially increasing number of nanoscale products will solve critical needs in engineering, science, and medicine. However, the virtually infinite number of potential nanotechnology products is a challenge for toxicologic pathologists. Because of their size, nanoparticulates can have therapeutic and toxic effects distinct from micron-sized particulates of the same composition. In the nanoscale, distinct intercellular and intracellular translocation pathways may provide a different distribution than that obtained by micron-sized particulates. Nanoparticulates interact with subcellular structures including microtubules, actin filaments, centrosomes, and chromatin; interactions that may be facilitated in the nanoscale. Features that distinguish nanoparticulates from fine particulates include increased surface area per unit mass and quantum effects. In addition, some nanotechnology products, including the fullerenes, have a novel and reactive surface. Augmented microscopic procedures including enhanced dark-field imaging, immunofluorescence, field-emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy are useful when evaluating nanoparticulate toxicologic pathology. Thus, the pathology assessment is facilitated by understanding the unique features at the nanoscale and the tools that can assist in evaluating nanotoxicology studies. PMID:23389777

  15. Preclinical models of pancreatic ductal adenocarcinoma.

    PubMed

    Hwang, Chang-Il; Boj, Sylvia F; Clevers, Hans; Tuveson, David A

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. Despite intensive efforts, the translation of findings in preclinical studies has been ineffective, due partially to the lack of preclinical models that faithfully recapitulate features of human PDA. Here, we review current preclinical models for human PDA (eg human PDA cell lines, cell line-based xenografts and patient-derived tumour xenografts). In addition, we discuss potential applications of the recently developed pancreatic ductal organoids, three-dimensional culture systems and organoid-based xenografts as new preclinical models for PDA. Copyright 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:26419819

  16. Sources of variation in the design of preclinical studies assessing the effects of amphetamine-type stimulants in pregnancy and lactation.

    PubMed

    McDonnell-Dowling, Kate; Kelly, John P

    2015-02-15

    The prevalence of drug use during pregnancy has increased in recent years and the amount of drug-exposed babies has therefore increased. In order to assess the risk associated with this there has been an increase in the amount of preclinical studies investigating the effects of prenatal and postnatal drug exposure on the offspring. There are many challenges associated with investigating the developmental and behavioural effects of drugs of abuse in animal models and ensuring that such models are appropriate and clinically relevant. The purpose of this review is to illustrate the variation in the design of preclinical studies investigating the effects of the amphetamine-type stimulants taken during pregnancy and/or lactation in animal models. Methamphetamine, methylendioxymethamphetamine and amphetamine were included in this review. The protocols used for exploring the effects of these drugs when taking during pregnancy and/or lactation were investigated and summarised into maternal experimental variables and offspring experimental variables. Maternal experimental variables include animals used, mating procedures and drug treatment and offspring experimental variables include litter standardisation, cross fostering, weaning and behaviours and parameters assessed. The findings in this paper suggest that there is a large diversity and little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. For this reason, the importance of steering the preclinical studies in a direction that is most clinically relevant will be an important future recommendation. This will also allow us to be more confident in the results obtained and confident that the human situation is being replicated as closely as possible. PMID:25449844

  17. A New Stochastic Kriging Method for Modeling Multi-Source ExposureResponse Data in Toxicology Studies

    PubMed Central

    2015-01-01

    One of the most fundamental steps in risk assessment is to quantify the exposureresponse 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 exposureresponse 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., dosetimeresponse 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 SKQs ability to efficiently model exposureresponse 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

  18. Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases.

    PubMed

    Schildknecht, Stefan; Karreman, Christiaan; Pltl, Dominik; Efrmova, Liudmila; Kullmann, Cornelius; Gutbier, Simon; Krug, Anne; Scholz, Diana; Gerding, Hanne R; Leist, Marcel

    2013-01-01

    Human differentiated cell types, such as neurons or hepatocytes, are of limited availability, and their use for experiments requiring ectopic gene expression is challenging. Using the human conditionally-immortalized neuronal precursor line LUHMES, we explored whether genetic modification in the proliferating state could be used for experiments in the differentiated post-mitotic neurons. First, alpha-synuclein (ASYN), a gene associated with the pathology of Parkinson's disease, was overexpressed. Increased amounts of the protein were tolerated without change of phenotype, and this approach now allows further studies on protein variants. Knockdown of ASYN attenuated the toxicity of the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP+). Different lentiviral constructs then were tested: cells labeled ubiquitously with green (GFP) or red fluorescent protein (RFP) allowed the quantification of neurite growth and of its disturbance by toxicants; expression of proteins of interest could be targeted to different organelles; production of two different proteins from a single read-through construct was achieved successfully by an expression strategy using a linker peptide between the two proteins, which is cleaved by deubiquitinases; LUHMES, labeled with GFP in the cytosol and RFP in the mitochondria, were used to quantify mitochondrial mobility along the neurites. MPP+ reduced such organelle movement before any other detectable cellular change, and this toxicity was prevented by simultaneous treatment with the antioxidant ascorbic acid. Thus, a strategy has been outlined here to study new functional endpoints, and subtle changes of structure and proteostasis relevant in toxicology and biomedicine in post-mitotic human cells. PMID:24173167

  19. Toxicological evaluation of an Allium-based commercial product in a 90-day feeding study in Sprague-Dawley rats.

    PubMed

    Mellado-García, P; Puerto, M; Pichardo, S; Llana-Ruiz-Cabello, M; Moyano, R; Blanco, A; Jos, A; Cameán, A M

    2016-04-01

    Proallium AP(®) is a commercial Allium extract intended to be used in active food packaging as the antibacterial and antioxidant effects of some organosulfur compounds are well known. However, there is little information on its toxicity and the Scientific Committee on Food (UE) requires the safety assessment of substances used in food contact materials. Thus, the aim of this study was to conduct for the first time a subchronic oral toxicity study of Proallium AP(®) with groups of 10 males and 10 females Sprague-Dawley rats fed a diet containing 0, 25, 100, 400 mg/kg/d for 90 days. No treatment-related clinical signs or mortality were noted. Besides, no treatment-related effects with regard to any of the toxicological biomarkers considered were observed, including biochemical, haematological and histopathology parameters. In conclusion, the non-observed-adverse-effect-level (NOAEL) for Proallium AP(®) in rats was determined to be a dietary dose of 400 mg/kg/d under the present experimental conditions, a value 500-fold higher than the exposure derived from its potential use in active packaging. PMID:26827789

  20. Pulmonary Edema Due to Oral Gavage in a Toxicological Study Related to Aquaporin-1, -4 and -5 Expression

    PubMed Central

    Singha, Ornuma; Kengkoom, Kanchana; Chaimongkolnukul, Khuanjit; Cherdyu, Sompong; Pongponratn, Emsri; Ketjareon, Taweesak; Panavechkijkul, Yaowaluk; Ampawong, Sumate

    2013-01-01

    A one-time oral gavage can be enough to cause of alveologenic edema with higher expression of AQP-1 and -4 than that with repeated-dose oral gavage, which caused both profound perivascular edema and hydrostatic pressure edema, while AQP-5 was similarly expressed. The alteration of AQPs expression was probably related to alveolar fluid clearance across the alveolar and bronchiolar epithelium in different stages of lung injury. The results clarified the type of lung edema in acute and sub-chronic toxicity studies without treatment related effect of tested material. The pathogenesis of pulmonary edema due to oral gavage toxicological study is associated with the cellular immune response to the reflux materials. Mast cell and leukocyte accumulation may contribute to increase vascular permeability leading to permeability edema. The increase in alveolar septum epithelium, perivascular and peribronchial cuffing, accumulation alveolar lipid containing macrophage and medial hyperplasia of the pulmonary artery might have been caused to increase airway resistance, which resulted in hydrostatic pressure edema. PMID:24155561

  1. Application of metabolomics to toxicology of drugs of abuse: A mini review of metabolomics approach to acute and chronic toxicity studies.

    PubMed

    Zaitsu, Kei; Hayashi, Yumi; Kusano, Maiko; Tsuchihashi, Hitoshi; Ishii, Akira

    2016-02-01

    Metabolomics has been widely applied to toxicological fields, especially to elucidate the mechanism of action of toxicity. In this review, metabolomics application with focus on the studies of chronic and acute toxicities of drugs of abuse like stimulants, opioids and the recently-distributed designer drugs will be presented in addition to an outline of basic analytical techniques used in metabolomics. Limitation of metabolomics studies and future perspectives will be also provided. PMID:26613805

  2. Toxicology of brotizolam

    PubMed Central

    Hewett, C.; Kreuzer, H.; Köllmer, H.; Niggeschulze, A.; Stötzer, H.

    1983-01-01

    1 Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents > 10,000 and > 900 mg/kg, respectively). 2 Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. 3 Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. 4 Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams were treated with 400 mg/kg, litter mortality was markedly increased. 5 Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. 6 Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. 7 Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. 8 The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose. PMID:6686462

  3. 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...

  4. NTP Toxicology and Carcinogenesis Studies of Diallylphthalate (CAS No. 131-17-9) in F344/N Rats (Gavage Studies).

    PubMed

    1985-08-01

    Diallylphthalate is widely used as a crosslinking agent for unsaturated polyesters. Diallylphthalate or diallylphthalate polyester blends are used primarily as plasticizers and carriers for adding catalysts and pigments to polyesters and in molding, electrical parts, laminating compounds, and impregnation of metal castings. Rubber compounds, epoxy formulations, and polyurethane foams may also contain diallylphthalate. Precise figures are not currently available, although annual production of diallylphthalate in the United States is known to exceed 5,000 pounds, and an estimated 57,000 pounds were imported into the United States in 1982. Toxicology and carcinogenesis studies of diallylphthalate (approximately 99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 0 (vehicle control), 50, or 100 mg/kg 5 days per week for 103 weeks. The diallylphthalate doses used in the 2-year studies were chosen on the basis of 13-week studies, wherein doses of 200 or 400 mg/kg caused death, reductions in body weight gains, or periportal hepatocellular necrosis and fibrosis in both sexes. Mean body weights and survival of male and female rats administered diallylphthalate were essentially the same as those of the vehicle controls throughout the 2-year studies, although hepatotoxicity was produced in both sexes by the 100 mg/kg dose. Based on the results of the prechronic studies and the effects on the liver in the 2-year studies, the doses used in the 2-year studies were considered to be adequate for carcinogenicity testing. Male and female rats receiving the 100 mg/kg dose of diallylphthalate in the 2-year studies developed chronic liver diseases characterized by periportal fibrosis, periportal accumulation of pigment, and severe bile duct hyperplasia. Pigment accumulation also occurred at the 50 mg/kg dose in both sexes. Diallylphthalate administration increased the occurrence of mononuclear cell leukemia in female rats (P<0.05 by trend tests), and the increase in the 100 mg/kg dose female rats was greater (Pstudy (NTP TR 242) reported an increased incidence of lymphomas in male B6C3F1 mice receiving diallylphthalate by gavage for 2 years at doses of 0, 150, or 300 mg/kg. This increase was considered to be equivocally related to diallylphthalate administration. The incidences of hyperplasia and inflammatory lesions of the forestomach were increased in a dose-related fashion in both sexes of mice in that study, and uncommon forestomach papillomas were observed in 0%, 2%, and 4% of both sexes of mice. Because of the numerical increase in forestomach papillomas, the concomitant presence of forestomach hyperplasia, and the rarity of forestomach papillomas in vehicle control (corn oil gavage) B6C3F1 mice, the development of these proliferative lesions of the forestomach in mice may have been related to diallylphthalate administration. In the current study in rats, a squamous cell carcinoma was found in one high dose male rat. Diallylphthalate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by a 9,000 x g supernatant fraction from the livers of Aroclor 1254-treated male Sprague-Dawley rats or Syrian hamsters. Diallylphthalate did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenicity studies on diallylphthalate. No data discrepancies were found that influenced the final interpretations. Under the conditions of this study, the administration of diallylphthalate by gavage in corn oil to male and female F344/N rats for 2 years caused chronic liver disease characterized by periportal fibrosis and pigment accumulation and an inc

  5. Toxicology studies with recombinant staphylokinase and with SY 161-P5, a polyethylene glycol-derivatized cysteine-substitution mutant.

    PubMed

    Moons, L; Vanlinthout, I; Roelants, I; Moreadith, R; Collen, D; Rapold, H J

    2001-01-01

    SY 161-P5, a polyethylene glycol derivatized (PEGylated) mutant of the recombinant Staphylokinase (rSak) variant SakSTAR, exhibiting reduced antigenicity is in clinical development for treatment of acute myocardial infarction as a single bolus injection. A series of safety studies were performed in vivo as a routine toxicology program with SY 161-P5 (PEG-rSakSTAR) and with the recombinant Staphylokinase variant Sak42D (rSak42D). For both compounds, intravenous single bolus injections of up to 100-fold therapeutic equivalent, as well as repeated injections during 7 to 28 days revealed no significant pathological findings in mice, rats or hamsters. However, New Zealand white rabbits developed clinically silent, multifocal myocarditis following single or repeat doses of SY 161-P5 or of Sak42D. These findings were dose-independent and reversible. A similar species-specific cardiotoxic effect has previously been described for other proteolytic proteins, including the approved drugs Streptokinase and Acetylated Plasminogen Streptokinase Complex (APSAC). The large experience with these drugs, as well as the clinical data accumulated both with PEGylated and non-PEGylated rSak variants to date, do not indicate cardiotoxic hazards associated with the use of these drugs in humans. PMID:11442014

  6. Performance characterization of a new CZT-based preclinical SPECT system: a comparative study of different collimators

    NASA Astrophysics Data System (ADS)

    Yu, A. R.; Park, S.-J.; Choi, Y. Y.; Kim, K. M.; Kim, H.-J.

    2015-09-01

    Triumph X-SPECT is a newly released CZT-based preclinical small-animal SPECT system with interchangeable collimators. The purpose of this work was to evaluate and systematically compare the imaging performances of three different collimators in the CZT-based preclinical small-animal system: a single-pinhole collimator (SPH), a multi-pinhole collimator (MPH) and a parallel-hole collimator. We measured the spatial resolutions and sensitivities of the three collimators with 99mTc sources, considering three distinct energy window widths (5, 10, and 20%), and used the NEMA NU4-2008 Image Quality phantom to test the imaging performance of the three collimators in terms of uniformity and spill-over ratio (SOR) for each energy window. With a 10% energy window width at a radius of rotation (ROR) of 30 mm, the system resolution of the SPH, MPH and parallel-hole collimators was 0.715, 0.855 and 3.270 mm FWHM, respectively. For the same energy window, the sensitivity of the system with SPH, MPH and parallel-hole collimators was 32.860, 152.514 and 49.205 counts/sec/MBq at a 100 mm source-to-detector distance and 6.790, 33.376 and 49.038 counts/sec/MBq at a 130 mm source-to-detector distance, respectively. The image noise and SORair for the three collimators were 20.137, 12.278 and 11.232 (%STDunif) and 0.106, 0.140 and 0.161, respectively. Overall, the results show that the SPH had better spatial resolution than the other collimators. The MPH had the highest sensitivity at 100 mm source-to-collimator distance, and the parallel-hole collimator had the highest sensitivity at 130 mm-source-to-detector distance. Therefore, the proper collimator for Triumph X-SPECT system must be determined by the task. These results provide valuable reference data and insight into the imaging performance of various collimators in CZT-based preclinical small-animal SPECT.

  7. Simvastatin Hydroxy Acid Fails to Attain Sufficient Central Nervous System Tumor Exposure to Achieve a Cytotoxic Effect: Results of a Preclinical Cerebral Microdialysis Study.

    PubMed

    Patel, Yogesh T; Jacus, Megan O; Davis, Abigail D; Boulos, Nidal; Turner, David C; Vuppala, Pradeep K; Freeman, Burgess B; Gilbertson, Richard J; Stewart, Clinton F

    2016-04-01

    3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were potent hits against a mouse ependymoma cell line, but their effectiveness against central nervous system tumors will depend on their ability to cross the blood-brain barrier and attain a sufficient exposure at the tumor. Among 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that had activity in vitro, we prioritized simvastatin (SV) as the lead compound for preclinical pharmacokinetic studies based on its potential for central nervous system penetration as determined from in silico models. Furthermore, we performed systemic plasma disposition and cerebral microdialysis studies of SV (100 mg/kg, p.o.) in a murine model of ependymoma to characterize plasma and tumor extracellular fluid (tECF) pharmacokinetic properties. The murine dosage of SV (100 mg/kg, p.o.) was equivalent to the maximum tolerated dose in patients (7.5 mg/kg, p.o.) based on equivalent plasma exposure of simvastatin acid (SVA) between the two species. SV is rapidly metabolized in murine plasma with 15 times lower exposure compared with human plasma. SVA exposure in tECF was <33.8 ± 11.9 µg/l per hour, whereas the tumor to plasma partition coefficient of SVA was <0.084 ± 0.008. Compared with in vitro washout IC50 values, we did not achieve sufficient exposure of SVA in tECF to suggest tumor growth inhibition; therefore, SV was not carried forward in subsequent preclinical efficacy studies. PMID:26802130

  8. 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.

  9. ISO 12189 standard for the preclinical evaluation of posterior spinal stabilization devices - II: A parametric comparative study.

    PubMed

    La Barbera, Luigi; Costa, Francesco; Villa, Tomaso

    2016-02-01

    The International Standardization Organization (ISO) 12189 standard was recently introduced to preclinically evaluate and compare the mechanical properties of posterior stabilization devices. This scenario presents some new significant steps ahead over the vertebrectomy model recommended by American Society for Testing and Materials (ASTM) F1717 standard: the modular anterior support allows for describing a closer scenario to the effective clinical use as well as to test very flexible and dynamic posterior stabilization devices. Despite these significant advantages, ISO 12189 received little attention in the literature. Anatomical parameters depending on the spinal level were compared to the published data or original measurements on biplanar stereoradiography on 13 patients. Other mechanical variables, describing the test set-up design, were considered and all parameters were investigated using a numerical parametric finite element model. Stress values were calculated by also considering their worst-case combination. The standard set-up represents quite well the anatomy of an instrumented average thoracolumbar segment. The parametric comparative analysis demonstrates a significant (even beyond +350%) maximum increase in the stress on the device, compared to the standard currently in use. The anterior support stiffness plays the most detrimental effect (maximum stress increases up to 396%). The initial precompression step has an important role in determining the final stress values achieved at peak load (up to +76%). Moreover, when combining these two contributions, an even higher stress increase may be achieved (up to 473%). Despite the other anatomical parameters playing a secondary role, their worst-case combination demonstrates that a device could potentially undergo higher stresses than those reached according to standard suggestions (maximum increase of 22.4% at L1). Any user/designer should be aware of these effects when using ISO 12189 standard for the preclinical evaluation of posterior spinal stabilization devices. PMID:26673809

  10. 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. PMID:25677784

  11. The influence of storage parameters on measurement of survival motor neuron (SMN) protein levels: implications for pre-clinical studies and clinical trials for spinal muscular atrophy.

    PubMed

    Hunter, Gillian; Roche, Sarah L; Somers, Eilidh; Fuller, Heidi R; Gillingwater, Thomas H

    2014-11-01

    Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN) protein. A growing number of potential therapeutic strategies for SMA are entering pre-clinical and clinical testing, including gene therapy and antisense oligonucleotide-based approaches. For many such studies SMN protein levels are used as one major readout of treatment efficacy, often necessitating comparisons between samples obtained at different times and/or using different protocols. Whether differences in tissue sampling strategies or storage parameters have an influence on measurable SMN levels remains to be determined. We assessed murine SMN protein immunoreactivity over time and under differing tissue storage conditions. SMN protein levels, measured using sensitive quantitative fluorescent western blotting, declined rapidly over a period of several days following sample collection, especially when protein was extracted immediately and stored at -20°C. Storage of samples at lower temperatures (-80°C), and as intact tissue, led to significantly better preservation of SMN immunoreactivity. However, considerable deterioration in measurable SMN levels occurred, even under optimal storage conditions. These issues need to be taken into consideration when designing and interpreting pre-clinical and clinical SMA studies where SMN protein levels are being measured. PMID:25047670

  12. 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

  13. GENOMIC ADAPTATION OF THE EMBRYONIC STEM CELL TEST (EST) FOR A TOXICOLOGICAL STUDY OF DRINKING WATER DISINFECTION BY-PRODUCTS

    EPA Science Inventory

    Among the many promised and potential applications of embryonic stem cells, in vitro toxicology is one area in which ES cells have already proven their utility. In 2003, the Embryonic Stem Cell Test (EST) protocol was validated in Europe as an in vitro alternative to live animal...

  14. 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

  15. [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

  16. 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

  17. 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; Bdker, Julie Stve; Schmitz, Alexander; Kjeldsen, Malene Krag; Srensen, Suzette; Madsen, Jakob; El-Galaly, Tarec Christoffer; Bgsted, Martin; Dybkr, 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

  18. MINING ENVIRONMENTAL TOXICOLOGY INFORMATION WEB RESOURCES

    EPA Science Inventory

    Environmental toxicology is the study of the ecological effects of anthropogenic substances released into the environment. It is a relatively diverse field addressing impacts to aquatic and terrestrial organisms and communities. The determination of potential risk associated with...

  19. IMPAIRED GAMETE FUNCTION: IMPLICATIONS FOR REPRODUCTIVE TOXICOLOGY

    EPA Science Inventory

    The invited symposium chapter reviews methods for evaluating sperm function in laboratory rodents and humans, and presents strategies for incorporating both in vivo and in vitro fertilization assessments into reproductive toxicology studies. The EPA Program Offices may encounter ...

  20. Impact of study design and database parameters on NOAEL distributions used for toxicological concern (TTC) values.

    PubMed

    Zarn, Jrg A; Hnggi, Emanuel; Engeli, Barbara E

    2015-08-01

    TTC values for chemicals with unknown toxicity but known structure are derived from 5th percentiles of NOAEL distributions from compounds with known toxicity. The impact of chemical structures on TTC values was repeatedly investigated but not the impact of parameters such as study numbers per compound and differences in study design. Recently, study design parameters such as application route with related dose-decrements, dose-spacing and number of animals per group but not exposure duration were found to affect NOAEL distributions. Here, the impact of study design parameters on lowest NOAEL distributions and consequently on TTC values was analyzed in a database on 423 Cramer class III pesticides. Using NOAELs related to lowest LOAELs instead of lowest NOAELs, excluding studies with a dose spacing >8, and standardizing NOAELs to the initial dose animals received shifted the 5th percentile of NOAEL distributions from 0.22 to 0.5mg/kg body weight per day. In contrast, weighting of NOAELs for the study numbers per compound shifts 5th percentiles downwards to lower values by 10-20%. The results show that database and study design parameters influence NOAEL distributions to a minor degree and derived TTC values therefore can be considered reliable in that perspective. PMID:26001586

  1. A toxicological study of 1,2,4-triazole-5-one

    SciTech Connect

    London, J.

    1988-12-01

    The acute oral LD/sub 50/ values for 1,2,4-triazole-5-one (TO) are greater than 5g/kg. According to classical guidelines, the material would be considered only slightly toxic or practically nontoxic in both rats and mice. The sensitization study in the guinea pig did not show TO to have potential sensitizing effects. Skin application studies on the rabbit demonstrated it was cutaneously nonirritating. This material was also nonirritating in the rabbit eye application studies. 4 refs., 1 tab.

  2. 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; Li Xiaojing Pei Fengkui Li Weisheng; Wu Yijie

    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.

  3. 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

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

    PubMed

    Schoeny, R

    1996-05-01

    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

  5. Preliminary toxicology study of 3,6-diamino-1,2,4,5-tetrazine

    SciTech Connect

    London, J.E.

    1993-03-01

    The calculated acute oral LD 30/50 (lethal dose for 50% of the animals occurring within 30 days after compound administration) value for 3,6-diamino-1,2,4,5-tetrazine (DATZ) was 863 mg/kg in rats. According to classical guidelines, DATZ would be considered slightly to moderately toxic for rats. The calculated acute oral LD [sub 30/50] value was 2,288 mg/kg in mice and would be considered slightly to moderately toxic for mice. Skin application studies using rabbits demonstrated DATZ to be a nonirritant. The eye study using rabbits disclosed DATZ to be a very mild irritant. The sensitization study using guinea pigs did not show DATZ to have potential sensitizing properties.

  6. Preliminary toxicology study of 3,6-diamino-1,2,4,5-tetrazine

    SciTech Connect

    London, J.E.

    1993-03-01

    The calculated acute oral LD 30/50 (lethal dose for 50% of the animals occurring within 30 days after compound administration) value for 3,6-diamino-1,2,4,5-tetrazine (DATZ) was 863 mg/kg in rats. According to classical guidelines, DATZ would be considered slightly to moderately toxic for rats. The calculated acute oral LD {sub 30/50} value was 2,288 mg/kg in mice and would be considered slightly to moderately toxic for mice. Skin application studies using rabbits demonstrated DATZ to be a nonirritant. The eye study using rabbits disclosed DATZ to be a very mild irritant. The sensitization study using guinea pigs did not show DATZ to have potential sensitizing properties.

  7. Toxicology and carcinogenesis studies of hexachloroethane (CAS No. 67-72-1) in F344/N rats (gavage studies). Technical report

    SciTech Connect

    Eastin, W.C.

    1989-08-01

    Toxicology and carcinogenesis studies were conducted by administering doses of 0, 10, or 20 mg/kg hexachloroethane in corn oil by gavage 5 days per week for 103 weeks to groups of 50 male rats. Groups of 50 female rats were administered 0, 80, or 160 mg/kg on the same schedule. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of hexachloroethane for male F344/N rats, based on the increased incidences of renal neoplasms. The marginally increased incidences of pheochromocytomas of the adrenal gland may have been related to hexachloroethane administration to male rats. There was no evidence of carcinogenic activity of hexachloroethane for female F344/N rats administered 80 or 160 mg/kg by gavage for 103 weeks.

  8. 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 ...

  9. Toward a Checklist for Exchange and Interpretation of Data froma Toxicology Study

    EPA Science Inventory

    With the advent of toxicogenomics came the need to share data across interdisciplinary teams and to deposit data associated with publications into public data repositories. Within a single institution, many variables associated with a study are standardized, for instance diet, an...

  10. STUDY OF THE CHEMICAL AND BEHAVIORAL TOXICOLOGY OF SUBSTITUTE CHEMICALS IN MICROTINE RODENTS

    EPA Science Inventory

    Acute oral LD50 and 30-day dietary subacute LC50 studies of 10 selected pesticides were evaluated in microtine rodents. As a means to developing new animal model systems, four species of microtine rodents including Microtus ochrogaster (MO), Microtus canicaudus (MC), Microtus pen...

  11. 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...

  12. 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...

  13. Inhalation developmental toxicology studies: Developmental toxicity of chloroprene vapors in New Zealand white rabbits. Final report

    SciTech Connect

    Mast, T.J.; Evanoff, J.J.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.

    1994-04-01

    Chloroprene, 2-chloro-1,3-butadiene, is a colorless liquid with a pungent ethereal odor that is primarily used as an intermediate in the manufacture of neoprene rubber, and has been used as such since about 1930. This study addressed the potential for chloroprene to cause developmental toxicity in New Zealand white rabbits following gestational exposure to 0, 10, 40, or 175 ppm chloroprene vapors, 6h/dy, 7dy/wk. Each treatment group consisted of 15 artificially inseminated females exposed on 6 through 28 days of gestation (dg). Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice on 29 dg. Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. There were no overt signs of maternal toxicity and the change in maternal body weight over the course of the study was not affected. Exposure of pregnant rabbits to chloroprene vapors on 6-28 dg had no effect on the number of implantation, the mean percent of live pups per litter, or on the incidence of resorptions per litter. The incidence of fetal malformations was not increased by exposure to chloroprene. Results of this study indicate that gestational exposure of New Zealand white rabbits to 10, 40, or 175 ppm chloroprene did not result in observable toxicity to either the dam or the offspring.

  14. Assessment of male rodent fertility in general toxicology 6-month studies.

    PubMed

    Mitchard, Terri; Jarvis, Philip; Stewart, Jane

    2012-12-01

    An outcome and statistical review of male reproductive performance assessed by including a mating phase within 6-month general toxicity studies in the Han Wistar rat was undertaken. The basic study design was 16-20 animals per group dosed for approximately 9 weeks before pairing the male rats with undosed females. This design provides opportunity for remating and automatically includes general toxicity parameters. The dose levels used in the 1- and 6-month studies show that male reproduction was assessed at generally similar doses. The majority of males (compound-dosed and controls) mated within 7 days. All vehicle-dosed males mated and 98.5% of these females were pregnant. Modeling shows that a pregnancy rate of less than 14 out of 16 pregnant animals is very unlikely to occur due to biological variability. Power calculations based on vehicle control data show that group sizes of >10 males have a >80% power of detecting a decrease in median of three embryos per group compared with the control group. Even if the number of pregnancies decreased by a third, a group size of ?12 would still detect a decrement in the median of three embryos with >80% power. Based on the statistical modeling and inherent strengths of the study design, this review indicates that decrements in male reproductive function can be successfully detected by incorporating a mating phase into a 6-month rat study and that a group size of 12-16 is generally adequate rather than the 16-20 group size indicated as a generic default within ICHS5(R2). PMID:23213047

  15. Systems toxicology: modelling biomarkers of glutathione homeostasis and paracetamol metabolism.

    PubMed

    Stahl, Simone H; Yates, James W; Nicholls, Andrew W; Kenna, J Gerry; Coen, Muireann; Ortega, Fernando; Nicholson, Jeremy K; Wilson, Ian D

    2015-08-01

    One aim of systems toxicology is to deliver mechanistic, mathematically rigorous, models integrating biochemical and pharmacological processes that result in toxicity to enhance the assessment of the risk posed to humans by drugs and other xenobiotics. The benefits of such 'in silico' models would be in enabling the rapid and robust prediction of the effects of compounds over a range of exposures, improving in vitro-in vivo correlations and the translation from preclinical species to humans. Systems toxicology models of organ toxicities that result in high attrition rates during drug discovery and development, or post-marketing withdrawals (e.g., drug-induced liver injury (DILI)) should facilitate the discovery of safe new drugs. Here, systems toxicology as applied to the effects of paracetamol (acetaminophen, N-acetyl-para-aminophenol (APAP)) is used to exemplify the potential of the approach. PMID:26464084

  16. Shellfish: Toxicology studies. (Latest citations from the NTIS Bibliographic database). Published Search

    SciTech Connect

    Not Available

    1993-12-01

    The bibliography contains citations concerning the effects of toxic substances on shellfish. Petroleum products, solvents, sewage, copper, mercury, chromium, dredged materials, and organic chemicals are among the toxic substances studied. Reproductive impairment, molting behavior, and population reduction caused by toxic chemicals are discussed. Shellfish as bioindicators and shellfish tolerance to toxic substances are briefly considered. (Contains 250 citations and includes a subject term index and title list.)

  17. 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

  18. 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

  19. Toxicological assessment of combined lead and cadmium: acute and sub-chronic toxicity study in rats.

    PubMed

    Yuan, Guiping; Dai, Shujun; Yin, Zhongqiong; Lu, Hongke; Jia, Renyong; Xu, Jiao; Song, Xu; Li, Li; Shu, Yang; Zhao, Xinghong

    2014-03-01

    The exposure to chemical mixtures is a common and important determinant of toxicity and receives concern for their introduction by inhalation and ingestion. However, few in vivo mixture studies have been conducted to understand the health effects of chemical mixtures compared with single chemicals. In this study, the acute and 90day sub-chronic toxicity tests of combined Pb and Cd were conducted. In the acute toxicity test, the LD50 value of Pb(NO3)2 and CdCl2 mixture by the oral route was 2696.54mg/kg by Bliss method. The sub-chronic treatment revealed that the low-dose combination of Pb and Cd exposures can significantly change the physiological and biochemical parameters of the blood of Sprague-Dawley (SD) rats with dose-response relationship and causes microcytic hypochromic anemia and the damages of liver and kidney of the SD rats to various degrees. Histopathological exams showed that the target organs of Pb and Cd were testicle, liver, and kidneys. These observations suggest that Pb and Cd are practically additive-toxic for the SD rats in oral acute toxicity studies. The lowest observed adverse-effect level in rats may be lower than a dose of 29.96mg/(kgbwday) when administered orally for 90 consecutive days. PMID:24394482

  20. INACTIVATION OF LACTATE DEHYDROGENASE BY SEVERAL CHEMICALS: IMPLICATIONS FOR IN VITRO TOXICOLOGY STUDIES

    PubMed Central

    Kendig, Derek M.; Tarloff, Joan B.

    2007-01-01

    Lactate dehydrogenase (LDH) release is frequently used as an end-point for cytotoxicity studies. We have been unable to measure LDH release during studies using para-aminophenol (PAP) in LLC-PK1 cells. When LLC-PK1 cells were incubated with either PAP (010 mM) or menadione (01000 ?M), viability was markedly reduced when assessed by alamar Blue or total LDH activity but not by release of LDH into the incubation medium. In addition, we incubated cells with PAP or menadione and compared LDH activity using two different assays. Both assays confirmed our observation of decreased LDH activity in cell lysates without corresponding increases in LDH activity in incubation media. Using purified LDH and 10 mM PAP, we that PAP produced loss of LDH activity that was inversely proportional to the amount of LDH initially added. In additional experiments, we incubated 0.5 units of LDH for 1 h with varying concentrations of PAP, menadione, hydrogen peroxide (H2O2) or cisplatin. All four chemicals produced concentration-dependent decreases in LDH activity. In previous experiments, inclusion of antioxidants such as reduced glutathione (GSH) and ascorbate protected cells from PAP toxicity. GSH (1 mM) preserved LDH activity in the presence of toxicants while ascorbate (1 mM) only prevented LDH loss induced by PAP. These studies suggest that LDH that is released into the incubation medium is susceptible to degradation when reactive chemicals are present. PMID:17079110

  1. Effect of Stem Cell Therapy on Bone Mineral Density: A Meta-Analysis of Preclinical Studies in Animal Models of Osteoporosis

    PubMed Central

    Li, Feng; Zhou, Changlin; Xu, Liang; Tao, Shuqing; Zhao, Jingyi; Gu, Qun

    2016-01-01

    Background Preclinical studies of the therapeutic role of stem cell based therapy in animal models of osteoporosis have largely yielded inconsistent results. We performed a meta-analysis to provide an overview of the currently available evidence. Methods Pubmed, Embase and Cochrane Library databases were systematically searched for relevant controlled studies. A random-effect model was used for pooled analysis of the effect of stem cell based therapy on bone mineral density (BMD). Stratified analyses were performed to explore the effect of study characteristics on the outcomes. Results Pooled results from 12 preclinical studies (110 animals in stem cell treatment groups, and 106 animals in control groups) indicated that stem cell based treatment was associated with significantly improved BMD (standardized mean difference [SMD] = 1.29, 95% Confidence Interval [CI]: 0.84–1.74, P < 0.001) with moderate heterogeneity (Cochrane’s Q test: P = 0.02, I2 = 45%) among the constituent studies. Implantation of bone marrow cells, bone marrow mesenchymal stem cells, adipose-derived stem cells, and human umbilical cord blood-derived CD34+ cells, were all associated with improved BMD as compared to that in the controls (P < 0.05 for all); the only exception being the use of embryonic stem cell transplantation (P > 0.05). Egger’s test detected potential publication bias (P = 0.055); however, ‘trim and fill’ analysis yielded similar results after statistically incorporating the hypothetical studies in the analysis (SMD = 1.24, 95% CI: 0.32–2.16, P < 0.001). Conclusions Stem cell transplantation may improve BMD in animal models of osteoporosis. Our meta-analysis indicates a potential therapeutic role of stem cell based therapy for osteoporosis, and serves to augment the rationale for clinical studies. PMID:26882451

  2. [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.

  3. [A retrospective study analysis of urinary hippuric acid levels in occupational toxicology exams].

    PubMed

    Gonzalez, Kelly Cristina; Sagebin, Fernando Rodrigues; Oliveira, Paola Garcia; Glock, Luiz; Thiesen, Flavia Vallado

    2010-06-01

    Hippuric acid is the primary metabolite of toluene, a solvent widely used in industrial processes with considerable toxic effects, a fact which justifies regularly monitoring individuals with occupational exposure to this solvent. This work aims at evaluating urinary hippuric acid levels found in workers subject to biological monitoring. A retrospective study was carried out with data referring from 2002 to 2005, in which exams results and employment status were analyzed (periodic, post-employment, and pre-employment exams). Results indicate a significant reduction in hippuric acid levels for 2005. Periodic exams presented higher results than pre-employment and post-employment exams. No significant difference was found in individuals grouped according to their status in each of the established intervals, their reference numbers, and maximum biological levels allowed. Hippuric acid levels detected indicate low risk of toluene exposure for the population under evaluation, probably due to a growing concern with the deployment of measures regarding occupational hygiene. PMID:20640325

  4. [Animal experimento-toxicologic studies of protein isolates in sunflower seeds].

    PubMed

    Hoernicke, E; Lewerenz, H J; Mieth, G

    1988-01-01

    Safety evaluations of sunflower protein isolates (SPI) obtained by various processes were performed in subchronic (90-day) feeding studies using male and female rats as experimental animals. General appearance, food consumption and efficiency, haematology, kidney function and urine analysis, serum chemistry including determinations of enzyme activities, organ weights and macro- and microscopic pathology were used as criteria to disclose adverse effects. Feeding graded levels of SPI as supplements up to 75% of the total protein of the diet revealed no morphologic and functional changes attributable to toxic effects of the test product at daily intakes up to 13 g/kg body weight. The evaluations of the SPI-variants tested were similar. PMID:3231256

  5. S 17092: a prolyl endopeptidase inhibitor as a potential therapeutic drug for memory impairment. Preclinical and clinical studies.

    PubMed

    Morain, Philippe; Lestage, Pierre; De Nanteuil, Guillaume; Jochemsen, Roeline; Robin, Jean-Loc; Guez, David; Boyer, Pierre-Alain

    2002-01-01

    Any treatment that could positively modulate central neuropeptides levels would provide a promising therapeutic approach to the treatment of cognitive deficits associated with aging and/or neurodegenerative diseases. Therefore, based on the activity in rodents, S 17092 (2S,3aS,7aS)-1][(R,R)-2-phenylcyclopropyl]carbonyl]-2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole) has been selected as a potent inhibitor of cerebral prolyl-endopeptidase (PEP). By retarding the degradation of neuroactive peptides, S 17092 was successfully used in a variety of memory tasks. These tasks explored short-term, long-term, reference and working memory in aged mice, as well as in rodents and monkeys with chemically induced amnesia or spontaneous memory deficits. S 17092 has also been safely administered to humans, and showed a clear peripheral expression of its mechanism of action through its inhibitory effect upon PEP activity in plasma. S 17092 exhibited central effects, as evidenced by EEG recording in healthy volunteers, and could improve a delayed verbal memory task. Collectively, the preclinical and clinical effects of S 17092 have suggested a promising role for this compound as an agent for the treatment of cognitive disorders associated with cerebral aging. PMID:12070525

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

    PubMed Central

    Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

    2014-01-01

    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, tumor accumulation, and biodistribution. 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. PMID:25202689

  7. Monitoring of anti-cancer treatment with 18F-FDG and 18F-FLT PET: a comprehensive review of pre-clinical studies

    PubMed Central

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

    Functional imaging of solid tumors with positron emission tomography (PET) imaging is an evolving field with continuous development of new PET tracers and discovery of new applications for already implemented PET tracers. During treatment of cancer patients, a general challenge is to measure treatment effect early in a treatment course and by that to stratify patients into responders and non-responders. With 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) and 3’-deoxy-3’-[18F]fluorothymidine(18F-FLT) two of the cancer hallmarks, altered energy metabolism and increased cell proliferation, can be visualized and quantified non-invasively by PET. With 18F-FDG and 18F-FLT PET changes in energy metabolism and cell proliferation can thereby be determined after initiation of cancer treatment in both clinical and pre-clinical studies in order to predict, at an early time-point, treatment response. It is hypothesized that decreases in glycolysis and cell proliferation may occur in tumors that are sensitive to the applied cancer therapeutics and that tumors that are resistant to treatment will show unchanged glucose metabolism and cell proliferation. Whether 18F-FDG and/or 18F-FLT PET can be used for prediction of treatment response has been analyzed in many studies both following treatment with conventional chemotherapeutic agents but also following treatment with different targeted therapies, e.g. monoclonal antibodies and small molecules inhibitors. The results from these studies have been most variable; in some studies early changes in 18F-FDG and 18F-FLT uptake predicted later tumor regression whereas in other studies no change in tracer uptake was observed despite the treatment being effective. The present review gives an overview of pre-clinical studies that have used 18F-FDG and/or 18F-FLT PET for response monitoring of cancer therapeutics. PMID:26550536

  8. Toxicological and phytochemical studies of Aspidosperma subincanum Mart. stem bark (Guatambu).

    PubMed

    Santos, S R; Rangel, E T; Lima, J C S; Silva, R M; Lopes, L; Noldin, V F; Cechinel Filho, V; Delle Monache, F; Martins, D T O

    2009-12-01

    Aspidosperma subincanum Mart. is widely used in Brazilian folk medicine to treat digestive disorders. In this study, acute and subchronic toxicity and cytotoxicity of stem bark ethanolic extract of Aspidosperma subincanum (EEAs) have been evaluated. In addition, phytochemical analysis was performed. The EEAs had low acute toxicity in mice with LD50 =1129 +/- 154mg/kg p.o. and 397 +/- 15 mg/kg i.p. The LC50 was 1340 +/- 428 microg/mL in the brine shrimp assay. There was no relevance of serious changes in behavioral, hematological and biochemical parameters and no deleterious effect on vital organs of rats that resulted after 30 days daily exposure to 5 and 100 mg/kg of EEAs. Phytochemical analysis of stem bark of A. subincanum revealed the presence of indole alkaloids, saponins, terpenoids, steroids and tannins and resulted in the isolation of oleic acid and guatambuine as major constituents. Using the method of the dose by factor approach, the human safe dose was 210 mg/70 kg/day. The EEAs appears to be safe and non-toxic in low doses in rodents and domestic preparations used by population have relatively security. PMID:20095144

  9. Development toxicology study in rats exposed to 60-Hz horizontal magnetic fields. Final report

    SciTech Connect

    Anderson, L.E.

    1997-09-01

    A replicate study using large numbers of animals was conducted to determine if 60 Hz magnetic fields would produce developmental toxicity in rats. Systems used previously for electric field exposures were retrofitted to provide magnetic field exposures to small laboratory animals. Large coils, separated from the rat cages, were energized by computer-controlled function generators providing a relatively pure, 1,000--{micro}T (10 G), 60-Hz, horizontal magnetic field for the high exposure group. Leakage fields to a second system provided a second exposure group with average exposures of 0.61 {micro}T (6.1 mG). Ambient fields within a third (control) system were 0.09 {micro}T (0.9 mG). Replicate experiments were conducted in which female rats were mated, and sperm-positive females were randomly distributed among the three exposure groups: (0.09, 0.61, and 1,000 {micro}T). Pregnant animals were exposed to 60 Hz horizontal magnetic fields for 20 hr/day from mating until very near term, 20 days later.

  10. Nanoemulsion formulations for anti-cancer agent piplartine-Characterization, toxicological, pharmacokinetics and efficacy studies.

    PubMed

    Fofaria, Neel M; Qhattal, Hussaini Syed Sha; Liu, Xinli; Srivastava, Sanjay K

    2016-02-10

    Piplartine (PL) is an alkaloid found in black-pepper and known for its anticancer activity, however, due to poor solubility and lack of proper formulation, its use for oral administration is a challenge. The objective of this study was to formulate PL into nanoemulsion drug delivery system for oral delivery and thereafter evaluate toxicity, pharmacokinetics and therapeutic efficacy. Optimized nanoemulsions were formulated by self-emulsification as well as by homogenization-sonication method. Two nanoemulsions enhanced the solubility of PL with low polydispersity index and high stability. Both PL loaded nanoemulsions exhibited enhanced dissolution, cellular permeability and cytotoxic effects as compared to pure PL. Formulation of PL into nanoemulsions did not obstruct its cellular uptake in cancer cells. Blank or PL loaded nanoemulsions did not exhibited toxicity in mice upon daily oral administration for 60 days. Pharmacokinetics of PL followed a two-compartment model after intravenous administration. PL loaded nanoemulsions showed 1.5-fold increase in oral bioavailability as compared to free PL. Finally, PL loaded nanoemulsions showed marked anti-tumor activity at a dose of 10mg/kg in melanoma tumor bearing mice. In conclusion, for the first time we have developed a stable nanoemulsion delivery system for oral administration of PL, which enhanced its solubility, oral bioavailability and anti-tumor efficacy. PMID:26642946

  11. Toxicological study of the Anam River in Otuocha, Anambra State, Nigeria.

    PubMed

    Igwilo, Innocent O; Afonne, Onyenmechi Johnson; Maduabuchi, Ugwuona John-Moses; Orisakwe, Orish Ebere

    2006-01-01

    The authors studied the quality of water and soil samples from the Anam River in Nigeria. Using an atomic absorption spectrophotometer, they analyzed levels of lead, cadmium, copper, and nickel. They also analyzed sulfates, nitrates, biological oxygen demand, total hardness, total dissolved solids, pH values, electrical conductivity, chloride, and salinity. The ranges of detected metals were 0.002-0.005 mg/L for cadmium, 0.008-0.016 mg/L for lead, and 0.580-1.345 mg/L for copper. In the soil samples, the authors detected cadmium (0.07-3.45 ppm), copper (4.38-13.54 ppm), lead (0.59-7.34 ppm), and nickel (0.36-5.64 ppm). The mean values of the chemical parameters were 11.34 +/- 1.20 mg/L for total hardness, 4.43 +/- 1.54 mg/L for biological oxygen demand, 20.00 +/- 0.00 mg/L for total dissolved solids, and 0.22 +/- 0.05 mg/L for nitrates. Chloride, salinity, electrical conductivity, and pH values were 8.00 +/- 1.73 mg/L, 14.44 +/- 3.13 mg/L, 19.33 +/- 0.67 ps cm-L, and 7.09 +/- 0.05, respectively. The World Health Organization guidelines for the parameters in soil were exceeded. PMID:17891888

  12. 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 methods 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

  13. Toxicological Studies of 212Pb Intravenously or Intraperitoneally Injected into Mice for a Phase 1 Trial

    PubMed Central

    Milenic, Diane E.; Molinolo, Alfredo A.; Solivella, Mara S.; Banaga, Eileen; Torgue, Julien; Besnainou, Sarah; Brechbiel, Martin W.; Baidoo, Kwamena E.

    2015-01-01

    Faced with the novelty of a 212Pb-labeled monoclonal antibody (mAb) for clinical translation, concerns were expressed by the Food and Drug Administration (FDA) regarding 212Pb prematurely released from the mAb-chelate conjugate. The objective of this study was to simulate the worst case scenario of such a failure. Groups of Balb/c mice (n = 920) were administered 212Pb by intraperitoneal (0.09251.85 MBq) or intravenous (0.09251.11 MBq) injection and then euthanized at 7 or 90 days to assess acute or chronic effects. Weights were recorded prior to injection of the 212Pb and at the end of the observation periods. Blood samples were collected for clinical chemistry and blood cell analysis. Thirty tissues were harvested and formalin fixed for histopathological examination. Treatment related effects of the 212Pb were observed in the bone marrow, spleen, kidneys and the liver. Histological alterations in these organs were considered mild to moderate, indicating low grade toxicity, and not considered severe enough to affect function. This data was presented to the FDA and determined to be acceptable. The clinical trial with 212Pb-TCMC-trastuzumab was approved in January 2011 and the trial opened at the University of Alabama at Birmingham (UAB) in July. PMID:26213947

  14. 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

  15. In vitro and in vivo genetic toxicology studies with diethylene glycol monohexyl ether.

    PubMed

    Ballantyne, B; Vergnes, J S

    2001-01-01

    Diethylene glycol monohexyl ether (DEGHE; CAS no. 112-59-4), an industrial chemical, was investigated for the potential to produce genotoxic effects using three in vitro and two in vivo tests. No mutagenic activity occurred in either the absence or presence of metabolic activation with a Salmonella typhimurium reverse assay using strains TA98, TA100, TA1535, TA1537 and TA1538. In a Chinese hamster ovary (CHO) forward gene mutation test (HGPRT locus) there was an increase in the mutation frequencies, which were relatively small compared with the solvent control values, somewhat inconsistent between duplicate cultures and occurred particularly in the presence of metabolic activation. Linear regression analysis indicated a marginally significant trend for dosage versus mutation frequency, suggesting that DEGHE was weakly positive in this test. A sister chromatid exchange test in CHO cells showed no significant dosage-related effects in the presence or absence of metabolic activation. A peripheral blood micronucleus test in mice by dosing with an intraperitoneal injection of DEGHE did not show any potential for DEGHE to increase the incidence of micronucleated polychromatophilic erythrocytes. In a first femoral bone marrow chromosome aberration test in the rat by peroral dosing, DEGHE did not cause any increase in aberrations for 12-h and 24-h samples with males and females or with females at 48-h sampling. However, with males at 48 h the two lowest doses showed an increased number of aberrations, but not at the high doses. A repeat study in males with a larger number of doses and 24-h and 48-h samples did not replicate this finding. It is concluded that DEGHE may have limited weak mutagenic activity in vitro but is devoid of clastogenic potential. PMID:11746191

  16. Development of Nutraceutical Emulsions as Risperidone Delivery Systems: Characterization and Toxicological Studies.

    PubMed

    Igarta, Daniela Edith; Calienni, Mara Natalia; Feas, Daniela Agustina; Chiaramoni, Nadia Silvia; Valle Alonso, Silvia Del; Prieto, Mara Jimena

    2015-12-01

    Emulsions are gaining increasing interest to be applied as drug delivery systems. The main goal of this work was the formulation of an oil/water nutraceutical emulsion (NE) for oral administration, enriched in omega 3 (?3) and omega 6 (?6), and able to encapsulate risperidone (RISP), an antipsychotic drug widely used in the treatment of autism spectrum disorders (ASD). RISP has low solubility in aqueous medium and poor bioavailability because of its metabolism and high protein binding. Coadministration of ?3, ?3, and vitamin E complexed with RISP might increase its bioavailability and induce a synergistic effect on the treatment of ASD. Here, we developed an easy and quick method to obtain NEs and then optimized them. The best formulation was chosen after characterization by particle size, defects of the oil-in-water interface, zeta potential (ZP), and in vitro drug release. The formulation selected was stable over time, with a particle size of around 3 ?m, a ZP lower than -20 mV and controlled drug release. To better understand the biochemical properties of the formulation obtained, we studied in vitro toxicity in the Caco-2 cell line. After 4 h of treatment, an increase in cellular metabolism was observed for all RISP concentrations, but emulsions did not change their metabolic rate, except at the highest concentration without drug (25 ?g/mL), which showed a significant reduction in metabolism respect to the control. Additionally, locomotor activity and heart rate in zebrafish were measured as parameters of in vivo toxicity. Only the highest concentration (0.625 ?g/mL) showed a cardiotoxic effect, which corresponds to the decrease in spontaneous movement observed previously. As all the materials contained in the formulations were US FDA approved, the NE selected would be good candidate for clinical trials. 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:4142-4152, 2015. PMID:26359783

  17. 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...

  18. The isolation, Characterization and Preclinical Studies of Metal Complex of Thespesia populnea for the Potential Peroxisome Proliferator-activated Receptors-γ Agonist Activity

    PubMed Central

    Phanse, Mohini Ashok; Patil, Manohar Janardhan; Abbulu, Konde

    2015-01-01

    Background: Diabetes mellitus is an international public health problem since ancient days. The condition is predominantly more severe in developing countries like India where, life is more sedentary due to the even changing lifestyles in this fast-paced global scenario. Thespesia populnea is widely used in the ayurvedic system of medicine for treatment of diabetes mellitus in India for years. The aim of this work is to explore the anti-diabetic activity of the isolated compound. Materials and Methods: The sesquiterpene isolated from hexane fraction of bark of T. populnea modified synthetically then identified by using analytical techniques such as electron paramagnetic resonance spectra for confirmation and the anti-diabetic activity was evaluated by anti-hyperglycemic, hypoglycemic potential. Result: In the present work, we have studied the anti-hyperglycemic and hypoglycemic activity of the vanadium complex in glucose loaded and normal animals were shown significantly decreased in plasma blood glucose level. The results derived from preclinical studies confirm the potential of new sesquiterpene. Conclusion: The findings could provide evidence regarding the anti-diabetic potential of T. populnea by lowering blood glucose level. SUMMARY Thespesia populnea is widely used in the ayurvedic system of medicine for treatment of diabetes in India. Present study aimed to explore the anti diabetic potential of isolated compound. Isolation of sesquiterpene from hexane fraction of bark of Thespesia populnea and modified synthetically then authenticated by using analytical techniques such as electron paramagnetic resonance spectra for confirmation. The modified complex was further assessed for its anti diabetic property in glucose loaded rats. Vanadium complex demonstrated significant reduction in plasma blood glucose level in glucose loaded animals. The results derived from preclinical studies confirm the potential of new sesquiterpene. The present findings conclude that anti diabetic potential of Thespesia populnea could be due to lowering blood glucose level by acting on PPAR-γ receptor. PMID:26929578

  19. 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.

  20. Zebrafish as a genetic model in pre-clinical drug testing and screening.

    PubMed

    Gibert, Y; Trengove, M C; Ward, A C

    2013-01-01

    The traditional drug discovery pipeline for the identification and development of compounds that selectively target specific molecules to ameliorate disease remains a major focus for medical research. However, the zebrafish is increasingly providing alternative strategies for various components of this pipeline. Zebrafish and their embryos are small, easily accessible and relatively low cost, making them applicable to high-throughput, small molecule screening. Zebrafish can also be manipulated by a range of forward and reverse genetics techniques to facilitate gene discovery and functional studies. Moreover, their physiological and developmental complexity provides accurate models of human disease to underpin mechanism of action and in vivo validation studies. Finally, several of these biological characteristics make zebrafish eminently suitable for toxicity testing, including eco-toxicology. Here we review the application of zebrafish to preclinical drug development and toxicity testing, including recent advances in mutant generation, drug screening and toxicology that serve to further enhance the capabilities of this valuable model organism in drug discovery. PMID:23521675

  1. 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 Central

    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 approachesfrom basic neurobiological approaches to human studiesmight 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

  2. Post-mortem toxicology.

    PubMed

    Drummer, Olaf H

    2007-01-17

    Studies examining post-mortem processes are difficult to conduct since changes will have already occurred when the body arrives at the mortuary. While control of collection site for blood can minimize changes in concentration it is very difficult to conduct experiments in humans aimed at understanding the mechanisms and determining the extent of such changes. The use of appropriate animal models can be useful in this regard providing the species and conditions are carefully chosen. Pharmacokinetic studies in humans are also very useful for understanding the changes in drug concentration with time in blood (and other fluids) and also for improving our understanding of drug effects. Unfortunately, doses of illicit drugs that can be given are relatively low to guarantee safety hence extrapolations are made to real life situations. Individual case studies can be useful to describe an unusual or particularly interesting circumstances but little useful information can be obtained when trying to ascertain the role of competing factors, e.g. role of individual drugs when multiple drugs are present, varying toxicity between route of administration, and the role of age or natural disease when drugs are also present. Epidemiological approaches by reviewing large numbers of related cases are the most powerful tool to obtain this information. All of these studies need to operate under the ethical and legal framework appropriate for a jurisdiction. This paper discusses the relative merits of scientific approaches to research in post-mortem toxicology and provides guidance on the most appropriate techniques for future studies. PMID:16781104

  3. Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist.

    PubMed

    Wong, Harvey; Gould, Stephen E; Budha, Nageshwar; Darbonne, Walter C; Kadel, Edward E; La, Hank; Alicke, Bruno; Halladay, Jason S; Erickson, Rebecca; Portera, Chia; Tolcher, Anthony W; Infante, Jeffery R; Mamounas, Michael; Flygare, John A; Hop, Cornelis E C A; Fairbrother, Wayne J

    2013-12-01

    The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process. GDC-0917 [(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)pyrrolidine-2-carboxamide] is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitro-in vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED50 and ED90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process. PMID:24041744

  4. Preclinical Pharmacology and Opioid Combinations

    PubMed Central

    Pasternak, Gavril W.

    2012-01-01

    Although effective alone, opioids are often used in combination with other drugs for relief of moderate to severe pain. Guidelines for acute perioperative pain recommend the use of multimodal therapy for pain management although combinations of opioids are not specifically recommended. Mu opioid drugs include morphine, heroin, fentanyl, methadone, and morphine 6?-glucuronide (M6G). Their mechanism of action is complex, resulting in subtle pharmacological differences among them and with unpredictable differences in their potency, effectiveness, and tolerability among patients. Highly selective mu opioids do not bind to a single receptor. Rather, they interact with a large number of mu receptor subtypes with different activation profiles for the various drugs. Thus, mu-receptor-based drugs are not all the same and it may be possible utilize these differences for enhanced pain control in a clinical setting. These differences among the drugs raise the question of whether combinations might result in better pain relief with fewer side effects. This concept already has been demonstrated between two mu opioids in preclinical studies and clinical trials other combinations are ongoing. This article reviews the current state of knowledge about mu opioid receptor pharmacology, summarizes preclinical evidence for synergy from opioid combinations, and highlights the complex nature of the mu opioid receptor pharmacology. PMID:22420604

  5. 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

  6. 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 reproduciblein 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

  7. 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.

  8. Comparative Effectiveness of 3-Dimensional vs 2-Dimensional and High-Definition vs Standard-Definition Neuroendoscopy: A Preclinical Randomized Crossover Study

    PubMed Central

    Hughes-Hallett, Archie; Cundy, Thomas P.; Di Marco, Aimee; Pratt, Philip; Nandi, Dipankar; Darzi, Ara; Yang, Guang-Zhong

    2013-01-01

    BACKGROUND: Although the potential benefits of 3-dimensional (3-D) vs 2-dimensional (2-D) and high-definition (HD) vs standard-definition (SD) endoscopic visualization have long been recognized in other surgical fields, such endoscopes are generally considered too large and bulky for use within the brain. The recent development of 3-D and HD neuroendoscopes may therefore herald improved depth perception, better appreciation of anatomic details, and improved overall surgical performance. OBJECTIVE: To compare simultaneously the effectiveness of 3-D vs 2-D and HD vs SD neuroendoscopy. METHODS: Ten novice neuroendoscopic surgeons were recruited from a university hospital. A preclinical randomized crossover study design was adopted to compare 3-D vs 2-D and HD vs SD neuroendoscopy. The primary outcomes were time to task completion and accuracy. The secondary outcomes were perceived task workload using the NASA (National Aeronautics and Space Administration) Task Load Index and subjective impressions of the endoscopes using a 5-point Likert scale. RESULTS: Time to task completion was significantly shorter when using the 3-D vs the 2-D neuroendoscopy (P = .001), and accuracy of probe placement was significantly greater when using the HD vs the SD neuroendoscopy (P = .009). We found that 3-D endoscopy significantly improved perceived depth perception (P < .001), HD endoscopy significantly improved perceived image quality (P < .001), and both improved participants’ overall impression (P < .001). CONCLUSION: Three-dimensional neuroendoscopy and HD neuroendoscopy have differing but complementary effects on surgical performance, suggesting that neither alone can completely compensate for the lack of the other. There is therefore strong preclinical evidence to justify 3-D HD neuroendoscopy. ABBREVIATIONS: HD, high definition SD, standard definition PMID:24220007

  9. Preclinical Operative Dentistry Courses in Northern Europe and Scandinavia.

    ERIC Educational Resources Information Center

    Wilson, N. H. F.; And Others

    1993-01-01

    This study compares teaching methods, time spent, and materials used in the existing preclinical teaching efforts of dental schools in 11 Northern European states (Belgium, Denmark, Eire, Finland, France, Germany, Netherlands, Norway, Sweden, Switzerland, and United Kingdom). Results reveal considerable variation in the teaching of preclinical

  10. Aviation combustion toxicology: an overview.

    PubMed

    Chaturvedi, Arvind K

    2010-01-01

    Aviation combustion toxicology is a subspecialty of the field of aerospace toxicology, which is composed of aerospace and toxicology. The term aerospace, that is, the environment extending above and beyond the surface of the Earth, is also used to represent the combined fields of aeronautics and astronautics. Aviation is another term interchangeably used with aerospace and aeronautics and is explained as the science and art of operating powered aircraft. Toxicology deals with the adverse effects of substances on living organisms. Although toxicology borrows knowledge from biology, chemistry, immunology, pathology, physiology, and public health, the most closely related field to toxicology is pharmacology. Economic toxicology, environmental toxicology, and forensic toxicology, including combustion toxicology, are the three main branches of toxicology. In this overview, a literature search for the period of 1960-2007 was performed and information related to aviation combustion toxicology collected. The overview included introduction; combustion, fire, and smoke; smoke gas toxicity; aircraft material testing; fire gases and their interactive effects; result interpretation; carboxyhemoglobin and blood cyanide ion levels; pyrolytic products of aircraft engine oils, fluids, and lubricants; and references. This review is anticipated to be an informative resource for aviation combustion toxicology and fire-related casualties. PMID:20109297

  11. National Toxicology Program: Annual plan for Fiscal Year 1991

    SciTech Connect

    Not Available

    1991-06-01

    The NTP Board of Scientific Counselors reviewed and reports on research programs of the NIEHS Experimental Toxicology Branch including both contract efforts and inhouse research and methods development activities for work groups in chemical disposition, general toxicology, toxicologic pathology, mutagenesis, and clinical pathology. The Board reviewed and approved seven concept proposals for collaborative studies having to do testing, methods development or validation activities in general or reproductive toxicology or germ cell mutagenesis. The Board also reviewed and made recommendations for further action on 13 chemicals nominated for NTP study.

  12. Toxicology of mycotoxins.

    PubMed

    Paterson, Robert R M; Lima, Nelson

    2010-01-01

    Humans are exposed to mycotoxins via ingestion, contact and inhalation. This must have occurred throughout human history and led to severe outbreaks. Potential diseases range from akakabio-byo to stachybotryotoxicosis and cancer. The known molecular bases of toxicology run the gamut of 23 compounds, from aflatoxins (AFs) to zearalenone, ochratoxin A and deoxynivalenol. Ergotism is one of the oldest recognized mycotoxicosis, although mycotoxin science only commenced in the 1960s with the discovery of AFs in turkey feed. AFs are carcinogenic. Some others are suspected carcinogens. The effects of mycotoxins are acute or chronic in nature. Mycotoxins are well known in the scientific community, although they have a low profile in the general population. An incongruous situation occurs in United States where mycotoxins from "moldy homes" are considered to be a significant problem, although there is a general debate about seriousness. This contrasts with the thousands of deaths from mycotoxins that occur, even now, in the technologically less developed countries (e.g., Indonesia, China, and Africa). Mycotoxins are more toxic than pesticides. Studies are moving from whole animal work to investigating the biochemical mechanisms in isolated cells, and the mechanisms of toxicity at the molecular level are being elucidated. The stereochemical nature of AFs has been shown to be important. In addition, the effect of multiple mycotoxins is being increasingly investigated, which will more accurately represent the situation in nature. It is anticipated that more fungal metabolites will be recognized as dangerous toxins and permitted statutory levels will decrease in the future. PMID:20358681

  13. Alternative methods in toxicology: CFU assays application, limitation and future prospective.

    PubMed

    Yadav, Navneet Kumar; Shukla, Pooja; Omer, Ankur; Singh, Poonam; Singh, R K

    2016-01-01

    Blood is a fluid connective tissue which plays a vital role for normal body function. It consist different type of blood cells which is continuously reproduce inside the bone marrow from hematopoietic system. Xenobiotics could be specifically toxic to the hematopoietic system and they can cause hematological disorders by disturbing the normal functions. In vitro hematopoietic colony-forming cell assays play a crucial role to evaluate potential toxic effects of new xenobiotics and also helpful in bridging the gap between preclinical toxicology studies in animal models and clinical investigations. Use of these assays in conjunction with, high-throughput screening reduces the cost and time associated with these assays. This article provides a critical view over in vitro hematopoietic colony-forming cell assays in assessment of hematotoxicity. PMID:25678196

  14. Preclinical profile of cabazitaxel

    PubMed Central

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

    2014-01-01

    First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes. PMID:25378905

  15. Oral-toxicology

    PubMed Central

    Gowda, B. K. Charan; Sundharam, B. Sivapatha; Mahadesh, Jyothi; Mukund

    2014-01-01

    Forensic toxicology deals with the investigation of toxic substances, poisonous products or with the environmental chemicals. This field of science helps to identify poison substance and hazardous chemicals. Forensic toxicology deals with the way that substances are absorbed, distributed or eliminated in the body the metabolism of substances. This paper reviews the manifestations that each poisonous substance presents concentrating toward the commonly used poisonous substance especially in India. It also explains the Indian Penal Code, which is main criminal code intended to cover all substantive aspects of criminal law regarding poison. PMID:24696586

  16. 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.

  17. Studies on the human metabolism and the toxicologic detection of the cough suppressant dropropizine in urine using gas chromatography-mass spectrometry.

    PubMed

    Staack, Roland F; Theobald, Denis S; Maurer, Hans H

    2004-08-01

    Studies are described on the metabolism and the toxicologic analysis of the nonopioid cough suppressant dropropizine [R,S-3-(4-phenyl-1-piperazinyl)1,2-propandiol, DRO] in human urine using gas chromatography-mass spectrometry (GC-MS). The metabolism studies showed that DRO was metabolized in humans mainly by hydroxylation of the aromatic ring, by N-dealkylation of the parent drug and of the hydroxyl-metabolite to the corresponding N-phenylpiperazines, and by degradation of the piperazine moiety. The authors' systematic toxicologic analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction, and microwave-assisted acetylation allowed the unambiguous detection of DRO and its above-mentioned metabolites in human urine up to about 32 hours after intake of a single common therapeutic dose. The target analytes were found to be the parent compound DRO (earlier phase of excretion) and the hydroxylated metabolite para-hydroxy-DRO (later phase of excretion). Both allowed unambiguous detection of an intake of DRO and also differentiation from other phenylpiperazine derivatives. PMID:15257075

  18. Advancing Risk Assessment through the Application of Systems Toxicology

    PubMed Central

    Sauer, John Michael; Kleensang, André; Peitsch, Manuel C.; Hayes, A. Wallace

    2016-01-01

    Risk assessment is the process of quantifying the probability of a harmful effect to individuals or populations from human activities. Mechanistic approaches to risk assessment have been generally referred to as systems toxicology. Systems toxicology makes use of advanced analytical and computational tools to integrate classical toxicology and quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Three presentations including two case studies involving both in vitro and in vivo approaches described the current state of systems toxicology and the potential for its future application in chemical risk assessment. PMID:26977253

  19. Reform in teaching preclinical pathophysiology.

    PubMed

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-12-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools. PMID:26628645

  20. TOXICOLOGY OF METALS. VOLUME II

    EPA Science Inventory

    The report on metal toxicology contains reviews on twenty-three metals. These have been written for inclusion in a Handbook on the Toxicology of Metals: Environmental and Occupational Aspects which is being prepared by the Scientific Committee on the Toxicology of Metals of the P...

  1. Pre-clinical models for oral and periodontal reconstructive therapies.

    PubMed

    Pellegrini, G; Seol, Y J; Gruber, R; Giannobile, W V

    2009-12-01

    The development of new medical formulations (NMF) for reconstructive therapies has considerably improved the available treatment options for individuals requiring periodontal repair or oral implant rehabilitation. Progress in tissue engineering and regenerative medicine modalities strongly depends on validated pre-clinical research. Pre-clinical testing has contributed to the recent approval of NMF such as GEM 21S and INFUSE bone grafts for periodontal and oral regenerative therapies. However, the selection of a suitable pre-clinical model for evaluation of the safety and efficacy of a NMF remains a challenge. This review is designed to serve as a primer to choose the appropriate pre-clinical models for the evaluation of NMF in situations requiring periodontal or oral reconstruction. Here, we summarize commonly used pre-clinical models and provide examples of screening and functional studies of NMF that can be translated into clinical use. PMID:19887682

  2. 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

  3. A 28-day rat inhalation study with an integrated molecular toxicology endpoint demonstrates reduced exposure effects for a prototypic modified risk tobacco product compared with conventional cigarettes.

    PubMed

    Kogel, Ulrike; Schlage, Walter K; Martin, Florian; Xiang, Yang; Ansari, Sam; Leroy, Patrice; Vanscheeuwijck, Patrick; Gebel, Stephan; Buettner, Ansgar; Wyss, Christoph; Esposito, Marco; Hoeng, Julia; Peitsch, Manuel C

    2014-06-01

    Towards a systems toxicology-based risk assessment, we investigated molecular perturbations accompanying histopathological changes in a 28-day rat inhalation study combining transcriptomics with classical histopathology. We demonstrated reduced biological activity of a prototypic modified risk tobacco product (pMRTP) compared with the reference research cigarette 3R4F. Rats were exposed to filtered air or to three concentrations of mainstream smoke (MS) from 3R4F, or to a high concentration of MS from a pMRTP. Histopathology revealed concentration-dependent changes in response to 3R4F that were irritative stress-related in nasal and bronchial epithelium, and inflammation-related in the lung parenchyma. For pMRTP, significant changes were seen in the nasal epithelium only. Transcriptomics data were obtained from nasal and bronchial epithelium and lung parenchyma. Concentration-dependent gene expression changes were observed following 3R4F exposure, with much smaller changes for pMRTP. A computational-modeling approach based on causal models of tissue-specific biological networks identified cell stress, inflammation, proliferation, and senescence as the most perturbed molecular mechanisms. These perturbations correlated with histopathological observations. Only weak perturbations were observed for pMRTP. In conclusion, a correlative evaluation of classical histopathology together with gene expression-based computational network models may facilitate a systems toxicology-based risk assessment, as shown for a pMRTP. PMID:24632068

  4. Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs

    PubMed Central

    Kasai, Kazue; Nakashima, Hiroshi; Liu, Fang; Kerr, Samantha; Wang, Jiang; Phelps, Mitch; Potter, Philip M; Goins, William B; Fernandez, Soledad A; Chiocca, E Antonio

    2013-01-01

    MGH2.1 is a herpes simplex virus type 1 (HSV1) oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA)-activating cytochrome P4502B1 (CYP2B1) and the CPT11-activating secreted human intestinal carboxylesterase (shiCE). Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p.) administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 108 pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 108 pfus in the absence of prodrugs and at 106 pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas. PMID:23922029

  5. Quantitative determination of zolmitriptan in rat blood and cerebrospinal fluid by reversed phase HPLC-ESI-MS/MS analysis: application to in vivo preclinical pharmacokinetic study.

    PubMed

    Dalpiaz, Alessandro; Marchetti, Nicola; Cavazzini, Alberto; Pasti, Luisa; Velaga, Sitaram; Gavini, Elisabetta; Beggiato, Sarah; Ferraro, Luca

    2012-07-15

    A fast HPLC-ESI-MS/MS method has been developed and validated for the quantification of the potent and selective antimigraine zolmitriptan in rat blood and cerebrospinal fluid (CSF). The assay has been then applied for in vivo preclinical studies. The analytical determination has been used to obtain pharmacokinetics of zolmitriptan in the two biological matrices after its intravenous or nasal administration. Liquid-liquid extraction of zolmitriptan was performed from 100 ?L rat blood samples in the presence of N(6)-cyclopentyladenosine (internal standard) with the employment of ethyl acetate. Calibration standards were prepared by using blood matrix and following the same liquid-liquid extraction procedure. CSF samples were analyzed without any pre-treatment steps and by using an external calibration method in pure water matrix. Chromatographic separation was performed under reversed phase and a gradient elution condition on a C18 packed column (100 2.0 mm, 2.5 ?m particles diameter). The mobile phase was a mixture between acetonitrile, water and formic acid (0.1% v/v). The applied HPLC-MS/MS method allowed low limits of detection, as calculated from calibration curves, of 6.6 and 24.4 ng/mL for water matrix and rat blood extracts, respectively. Linearity of the calibration curves was established up to 5 ?M (1.44 ?g/mL), as well as good assay accuracy. The intravenous infusion of 20 ?g zolmitriptan to male Sprague-Dawley rats produced blood concentrations ranging from 9.40.7 to 1.240.07 ?g/mL within 10 h, with a terminal half-life of 3.40.2h. The nasal administration of a water suspension of 20 ?g zolmitriptan produced blood concentrations ranging from 2.920.21 to 0.850.07 ?g/mL within 6h. One hour after zolmitriptan intravenous infusion or nasal administration, its CSF concentrations were 0.05390.0016 and 0.04530.0012 ?g/mL, respectively. This study determined the suitability of the herein proposed method to investigate the pharmacokinetics of zolmitriptan after its administration by means of novel formulations and, hence, to evaluate the efficacy of innovative nose-to-brain drug delivery in preclinical studies. PMID:22743338

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

    SciTech Connect

    Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; Department of Structural Biology, VIB, Brussels ; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Faculté de Médecine de Tunis, Université de Tunis-El Manar ; Lahoutte, Tony

    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.

  7. System Vaccinology for the Evaluation of Influenza Vaccine Safety by Multiplex Gene Detection of Novel Biomarkers in a Preclinical Study and Batch Release Test

    PubMed Central

    Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari

    2014-01-01

    Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, ?2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing. PMID:25010690

  8. In silico toxicology for the pharmaceutical sciences

    SciTech Connect

    Valerio, Luis G.

    2009-12-15

    The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical prediction of human drug metabolism, mechanisms of action for pharmaceuticals, and newer models for predicting human adverse effects. How accurate are these approaches is both a statistical issue and challenge in toxicology. In this review, fundamental concepts and the current capabilities and limitations of this technology will be critically addressed.

  9. In silico toxicology for the pharmaceutical sciences.

    PubMed

    Valerio, Luis G

    2009-12-15

    The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical prediction of human drug metabolism, mechanisms of action for pharmaceuticals, and newer models for predicting human adverse effects. How accurate are these approaches is both a statistical issue and challenge in toxicology. In this review, fundamental concepts and the current capabilities and limitations of this technology will be critically addressed. PMID:19716836

  10. Toxicology and Chemical Safety.

    ERIC Educational Resources Information Center

    Hall, Stephen K.

    1983-01-01

    Topics addressed in this discussion of toxicology and chemical safety include routes of exposure, dose/response relationships, action of toxic substances, and effects of exposure to chemicals. Specific examples are used to illustrate the principles discussed. Suggests prudence in handling any chemicals, whether or not toxicity is known. (JN)

  11. 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 ...

  12. Toxicology Education Foundation

    MedlinePLUS

    ... rats, mice and other animals, ... more 18 Oct Nanotechnology There is a lot of excitement about nanotechnology. “Nano” has become a familiar term in the ... Cosmetics GMOs Green Chemistry History In the Classroom Nanotechnology Occupational Toxicology Pesticides Product Safety Program Reproduction Risk ...

  13. Toxicology, an STS Approach.

    ERIC Educational Resources Information Center

    Wagner, Richard

    1990-01-01

    Presented are activities suggested through Project L.A.B.S. that involve the topic of toxicology. Activities include suggested research, the risk benefit seesaw, human-made compounds, legislation, a historical perspective, and health. A suggested readings list is provided. (KR)

  14. 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; Montreal Heart Institute, Montreal, Quebec H1T 1C8

    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.

  15. Preclinical study of SZ2080 material 3D microstructured scaffolds for cartilage tissue engineering made by femtosecond direct laser writing lithography.

    PubMed

    Mačiulaitis, Justinas; Deveikytė, Milda; Rekštytė, Sima; Bratchikov, Maksim; Darinskas, Adas; Šimbelytė, Agnė; Daunoras, Gintaras; Laurinavičienė, Aida; Laurinavičius, Arvydas; Gudas, Rimtautas; Malinauskas, Mangirdas; Mačiulaitis, Romaldas

    2015-01-01

    Over the last decade DLW employing ultrafast pulsed lasers has become a well-established technique for the creation of custom-made free-form three-dimensional (3D) microscaffolds out of a variety of materials ranging from proteins to biocompatible glasses. Its potential applications for manufacturing a patient's specific scaffold seem unlimited in terms of spatial resolution and geometry complexity. However, despite few exceptions in which live cells or primitive organisms were encapsulated into a polymer matrix, no demonstration of an in vivo study case of scaffolds generated with the use of such a method was performed. Here, we report a preclinical study of 3D artificial microstructured scaffolds out of hybrid organic-inorganic (HOI) material SZ2080 fabricated using the DLW technique. The created 2.1 × 2.1 × 0.21 mm(3) membrane constructs are tested both in vitro by growing isolated allogeneic rabbit chondrocytes (Cho) and in vivo by implanting them into rabbit organisms for one, three and six months. An ex vivo histological examination shows that certain pore geometry and the pre-growing of Cho prior to implantation significantly improves the performance of the created 3D scaffolds. The achieved biocompatibility is comparable to the commercially available collagen membranes. The successful outcome of this study supports the idea that hexagonal-pore-shaped HOI microstructured scaffolds in combination with Cho seeding may be successfully implemented for cartilage tissue engineering. PMID:25797444

  16. Preclinical Cardiorenal Interrelationships in Essential Hypertension

    PubMed Central

    Tsioufis, Costas; Tsiachris, Dimitrios; Kasiakogias, Alexandros; Dimitriadis, Kyriakos; Petras, Dimitris; Goumenos, Dimitris; Siamopoulos, Konstantinos; Stefanadis, Christodoulos

    2013-01-01

    A diseased heart causes numerous adverse effects on kidney function, and vice versa renal disease can significantly impair cardiac function. Beyond these heart-kidney interrelationships at the clinical level, a reciprocal association has been suggested to exist even in the early stages of those organs' dysfunction. The aim of the present review is to provide evidence of the presence of a preclinical cardiorenal syndrome in the particular setting of essential hypertension, focusing on the subsequent hypertensive sequelae on heart and kidneys. In particular, a plethora of studies have demonstrated not only the predictive role of kidney damage, as expressed by either decreased glomerular filtration or increased urine albumin excretion, for adverse left ventricular functional and structural adaptations but also preclinical heart disease, i.e. left ventricular hypertrophy that is associated with deterioration of renal function. Notably, these reciprocal interactions seem to exist even at the level of microcirculation, since both coronary flow reserve and renal hemodynamics are strongly related with clinical and preclinical renal and cardiac damage, respectively. In this preclinical setting, common pathophysiological denominators, including the increased hemodynamic load, sympathetic and renin-angiotensin system overactivity, increased subclinical inflammatory reaction, and endothelial dysfunction, account not only for the reported associations between overt cardiac and renal damage but also for the parallel changes that occur in coronary and renal microcirculation. PMID:23946723

  17. Toxicological characterization of the landfill leachate prior/after chemical and electrochemical treatment: a study on human and plant cells.

    PubMed

    Garaj-Vrhovac, Vera; Ore?anin, Vinja; Gajski, Goran; Geri?, Marko; Ruk, Damir; Kollar, Robert; Radi? Brkanac, Sandra; Cvjetko, Petra

    2013-10-01

    In this research, toxicological safety of two newly developed methods for the treatment of landfill leachate from the Pikornica (Croatia) sanitary landfill was investigated. Chemical treatment procedure combined chemical precipitation with CaO followed by coagulation with ferric chloride and final adsorption by clinoptilolite. Electrochemical treatment approach included pretreatment with ozone followed by electrooxidation/electrocoagulation and final polishing by microwave irradiation. Cell viability of untreated/treated landfill leachate was examined using fluorescence microscopy. Cytotoxic effect of the original leachate was obtained for both exposure periods (4 and 24 h) while treated samples showed no cytotoxic effect even after prolonged exposure time. The potential DNA damage of the untreated/treated landfill leachate was evaluated by the comet assay and cytokinesis-block micronucleus (CBMN) assay using either human or plant cells. The original leachate exhibited significantly higher comet assay parameters compared to negative control after 24 h exposure. On the contrary, there was no significant difference between negative control and chemically/electrochemically treated leachate for any of the parameters tested. There was also no significant increase in either CBMN assay parameter compared to the negative control following the exposure of the lymphocytes to the chemically or electrochemically treated landfill leachate for both exposure periods while the original sample showed significantly higher number of micronuclei, nucleoplasmic bridges and nuclear buds for both exposure times. Results suggest that both methods are suitable for the treatment of such complex waste effluent due to high removal efficiency of all measured parameters and toxicological safety of the treated effluent. PMID:23790829

  18. A rapid and sensitive LC-MS/MS assay for the quantitation of deacetyl mycoepoxydiene in rat plasma with application to preclinical pharmacokinetics studies.

    PubMed

    Gao, Yanhui; Xu, Jiangbo; Xu, Jiaxing; Huang, Yaojian; Shen, Yuemao; Liu, ZhaoPing

    2012-01-01

    The purpose of this study was to develop and validate a high-performance liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for analysis of the deacetyl mycoepoxydiene in rat plasma. The analyte and internal standard (I.S.), benorilate, were extracted from rat plasma by precipitation protein and separated on a C(18) column using acetonitrile-0.5% formic acid as mobile phase. Detection was performed using a turbo-spray ionization source and mass spectrometric positive multi-reaction-monitoring-mode (+MRM) at an ion voltage of +4800 V. The assay was linear over the concentration range 5-5000 ng/mL with the lowest limit of quantification (LLOQ) of 5 ng/mL. The method also afforded satisfactory results in terms of the sensitivity, specificity, precision (intra- and inter-day, RSD<5.8%), accuracy, recovery as well as the stability of the analyte under various conditions. The method was successfully applied to a preclinical pharmacokinetic study in rats after a single intravenous administration of deacetyl mycoepoxydiene 10 mg/kg. PMID:22169059

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

    PubMed

    Davano, Marcelo Gomes; de Campos, Michel Leandro; Peccinini, Rosngela Gonalves

    2015-07-01

    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 25C until injection and the column at 45C for the chromatographic separation. The sample preparation was performed by a rapid protein precipitation with acetonitrile. The linear concentration range was 0.15-20 g/mL. The pharmacokinetic parameters of BNZ in rats were determined and the method was considered sensitive, fast and suitable for application in pharmacokinetic studies. PMID:25424984

  20. Emerging Approaches in Predictive Toxicology

    PubMed Central

    Zhang, Luoping; McHale, Cliona M.; Greene, Nigel; Snyder, Ronald D.; Rich, Ivan N.; Aardema, Marilyn J.; Roy, Shambhu; Pfuhler, Stefan; Venkatactahalam, Sundaresan

    2016-01-01

    Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. PMID:25044351

  1. Preclinical Evaluation of the Immunomodulatory Properties of Cardiac Adipose Tissue Progenitor Cells Using Umbilical Cord Blood Mesenchymal Stem Cells: A Direct Comparative Study

    PubMed Central

    Perea-Gil, Isaac; Mongui-Tortajada, Marta; Glvez-Montn, Carolina; Bayes-Genis, Antoni; Borrs, Francesc E.; Roura, Santiago

    2015-01-01

    Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs) with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed. Thus, in the presented study, we took advantage of the well-established low immunogenicity of umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to comparatively assess the immunomodulatory properties of cardiac ATDPCs in an in vitro allostimulatory assay using allogeneic mature monocyte-derived dendritic cells (MDDCs). Similar to UCBMSCs, increasing amounts of seeded cardiac ATDPCs suppressed the alloproliferation of T cells in a dose-dependent manner. Secretion of proinflammatory cytokines (IL6, TNF?, and IFN?) was also specifically modulated by the different numbers of cardiac ATDPCs cocultured. In summary, we show that cardiac ATDPCs abrogate T cell alloproliferation upon stimulation with allogeneic mature MDDCs, suggesting that they could further regulate a possible harmful immune response in vivo. Additionally, UCBMSCs can be considered as valuable tools to preclinically predict the immunogenicity of prospective regenerative cells. PMID:25861626

  2. Transplantation of umbilical cord-derived mesenchymal stem cells as a novel strategy to protect the central nervous system: technical aspects, preclinical studies, and clinical perspectives.

    PubMed

    Dalous, Jrmie; Larghero, Jrome; Baud, Olivier

    2012-04-01

    The prevention of perinatal neurological disabilities remains a major challenge for public health, and no neuroprotective treatment to date has proven clinically useful in reducing the lesions leading to these disabilities. Efforts are, therefore, urgently needed to test other neuroprotective strategies including cell therapies. Although stem cells have raised great hopes as an inexhaustible source of therapeutic products that could be used for neuroprotection and neuroregeneration in disorders affecting the brain and spinal cord, certain sources of stem cells are associated with potential ethical issues. The human umbilical cord (hUC) is a rich source of stem and progenitor cells including mesenchymal stem cells (MSCs) derived either from the cord or from cord blood. hUC MSCs (hUC-MSCs) have several advantages as compared to other types and sources of stem cells. In this review, we will summarize the most recent findings regarding the technical aspects and the preclinical investigation of these promising cells in neuroprotection and neuroregeneration, and their potential use in the developing human brain. However, extensive studies are needed to optimize the administration protocol, safety parameters, and potential preinjection cell manipulations before designing a controlled trial in human neonates. PMID:22430384

  3. Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV-2/8 Vector in the Mouse Model of Galactosialidosis

    PubMed Central

    Hu, Huimin; Gomero, Elida; Bonten, Erik; Gray, John T; Allay, Jim; Wu, Yanan; Wu, Jianrong; Calabrese, Christopher; Nienhuis, Arthur; d'Azzo, Alessandra

    2012-01-01

    Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients. PMID:22008912

  4. Use of 'dilute-and-shoot' liquid chromatography-high resolution mass spectrometry in preclinical research: application to a DMPK study of perhexiline in mouse plasma.

    PubMed

    Esposito, Simone; Bracacel, Elena; Nibbio, Martina; Speziale, Roberto; Orsatti, Laura; Veneziano, Maria; Monteagudo, Edith; Bonelli, Fabio

    2016-01-25

    This work describes a simple, sensitive and rapid liquid chromatography-high resolution mass spectrometry method for the quantitation of perhexiline and the simultaneous detection of perhexiline metabolites in C57bl/6 mice plasma. Only 5?L of plasma was used for analysis. Pretreatment was limited to a 100-fold dilution ('dilute-and-shoot'). The analyte was detected by high resolution mass spectrometry (Orbitrap technology). Three scan events were performed over the entire chromatogram. Targeted single ion monitoring with data dependent acquisition was employed for perhexiline quantitation and confirmation, while full scan was used to perform untargeted detection of perhexiline phase I and phase II circulating metabolites. The calibration curve was linear (r(2)=0.990) ranging from 0.305ng/mL (LLOQ) to 10000ng/mL. Matrix effect was limited to 6.1%. The method was applied to a pharmacokinetic study of perhexiline in mouse plasma and the results obtained were compared to a standard sample preparation method based on protein precipitation and liquid chromatography-tandem mass spectrometry (MRM mode) detection. The new approach provided comparable results in terms of pharmacokinetics parameters estimate with a high sensitivity, additional information on perhexiline circulating metabolites and a low consumption of biological sample. The combination of the 'dilute-and-shoot' approach together with HRMS targeted and untargeted detection represents a suitable alternative to classic bioanalytical approaches in preclinical research. PMID:26517851

  5. Preclinical evaluation of the immunomodulatory properties of cardiac adipose tissue progenitor cells using umbilical cord blood mesenchymal stem cells: a direct comparative study.

    PubMed

    Perea-Gil, Isaac; Mongui-Tortajada, Marta; Glvez-Montn, Carolina; Bayes-Genis, Antoni; Borrs, Francesc E; Roura, Santiago

    2015-01-01

    Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs) with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed. Thus, in the presented study, we took advantage of the well-established low immunogenicity of umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to comparatively assess the immunomodulatory properties of cardiac ATDPCs in an in vitro allostimulatory assay using allogeneic mature monocyte-derived dendritic cells (MDDCs). Similar to UCBMSCs, increasing amounts of seeded cardiac ATDPCs suppressed the alloproliferation of T cells in a dose-dependent manner. Secretion of proinflammatory cytokines (IL6, TNF?, and IFN?) was also specifically modulated by the different numbers of cardiac ATDPCs cocultured. In summary, we show that cardiac ATDPCs abrogate T cell alloproliferation upon stimulation with allogeneic mature MDDCs, suggesting that they could further regulate a possible harmful immune response in vivo. Additionally, UCBMSCs can be considered as valuable tools to preclinically predict the immunogenicity of prospective regenerative cells. PMID:25861626

  6. 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.

  7. Preclinical Neonatal Rat Studies of Heparin-Binding EGF-Like Growth Factor in Protection of the Intestines From Necrotizing Enterocolitis

    PubMed Central

    RADULESCU, ANDREI; ZORKO, NICHOLAS A.; YU, XIAOYI; BESNER, GAIL E.

    2013-01-01

    We have previously demonstrated that enterally administered heparin-binding EGF-like growth factor (HB-EGF) produced in Escherichia coli decreases the incidence and severity of intestinal injury in a neonatal rat model of necrotizing enterocolitis (NEC). In preparation for upcoming human clinical trials, large-scale production of HB-EGF according to Good Manufacturing Practice (GMP) has been successfully accomplished using a Pichia pastoris yeast system. The current studies used a neonatal rat model of NEC to elucidate several important preclinical characteristics of HB-EGF therapy. We found that enteral administration of HB-EGF (800 ?g/kg/dose) four times a day effectively reduced the incidence and severity of NEC, that Pichia-derived HB-EGF was not significantly different from E. coli-derived HB-EGF in preventing NEC, that EGF was not superior to HB-EGF in preventing NEC, and that prophylactic administration of HB-EGF added to formula starting with the first feed or 12 h later significantly reduced the incidence of NEC, with no change in the incidence of NEC noted if HB-EGF was added to the formula starting 24, 48, or 72 h after birth. Thus, large-scale production of GMP-grade HB-EGF in Pichia pastoris yeast produces a biologically active molecule suitable for human clinical trials. PMID:19127210

  8. Review, discussion, and summary: toxicology

    SciTech Connect

    Graham, J.A.

    1989-02-01

    The research presented in the toxicology session of the Symposium on the Health Effects of Acid Aerosols significantly advances our understanding of the health effects of acid aerosols and clearly illustrates the importance of animal inhalation toxicology to risk assessment. The description of the effects of acid on airway mucus buffering capacity and viscosity helps explain some of the mechanisms responsible for the effects of sulfuric acid on mucociliary clearance and pulmonary function observed in man and animals. Several of the papers illustrate that other pollutants interact with sulfuric acid (H/sub 2/SO/sub 4/), causing concern about exposure risks and helping in elucidating the effects observed in epidemiology studies that have not yet been duplicated in a laboratory. For example, H/sub 2/SO/sub 4/ absorbed in zinc oxide (ZnO) particles appears to be about a log more potent than H/sub 2/SO/sub 4/ alone in causing pulmonary function decrements. Low levels of H/sub 2/SO/sub 4/ and O/sub 3/ were found to be synergistic in increasing collagen synthesis, implying a risk in development of lung fibrosis. More complex mixtures containing H/sub 2/SO/sub 4/ cause a variety of interactions, depending upon the end points examined and the chemistry of the mixture. Other reports indicate that dose rate and length of exposure issues are critical to toxicological outcomes. Animal data on mucociliary clearance, which parallels that of human data, was extended to show that concentration of exposure was more important than time of exposure in eliciting a response, although time played a significant role. A recent chronic study showed that H/sub 2/SO/sub 4/ caused effects that also can occur in the development of chronic bronchitis.

  9. Subsite awareness in neuropathology evaluation of National Toxicology Program (NTP) studies: a review of select neuroanatomical structures with their functional significance in rodents.

    PubMed

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

    2014-01-01

    This review article is designed to serve as an introductory guide in neuroanatomy for toxicologic pathologists evaluating general toxicity studies. The article provides an overview of approximately 50 neuroanatomical subsites and their functional significance across 7 transverse sections of the brain. Also reviewed are 3 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-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

  10. 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

  11. Toxicology research for precautionary decision-making and the role of Human & Experimental Toxicology.

    PubMed

    Grandjean, P

    2015-12-01

    A key aim of toxicology is the prevention of adverse effects due to toxic hazards. Therefore, the dissemination of toxicology research findings must confront two important challenges: one being the lack of information on the vast majority of potentially toxic industrial chemicals and the other being the strict criteria for scientific proof usually required for decision-making in regard to prevention. The present study ascertains the coverage of environmental chemicals in four volumes of Human & Experimental Toxicology and the presentation and interpretation of research findings in published articles. Links in SciFinder showed that the 530 articles published in four selected volumes between 1984 and 2014 primarily dealt with metals (126 links) and other toxicants that have received substantial attention in the past. Thirteen compounds identified by US authorities in 2006 as high-priority substances, for which toxicology documentation is badly needed, were not covered in the journal issues at all. When reviewing published articles, reliance on p values was standard, and non-significant findings were often called 'negative.' This tradition may contribute to the perceived need to extend existing research on toxic hazards that have already been well characterized. Several sources of bias towards the null hypothesis can affect toxicology research, but are generally not considered, thus adding to the current inclination to avoid false positive findings. In this regard, toxicology is particularly prone to bias because of the known paucity of false positives and, in particular, the existence of a vast number of toxic hazards which by default are considered innocuous due to lack of documentation. The Precautionary Principle could inspire decision-making on the basis of incomplete documentation and should stimulate a change in toxicology traditions and in toxicology research publication. PMID:26614810

  12. The Preclinical Alzheimer Cognitive Composite

    PubMed Central

    Donohue, Michael C.; Sperling, Reisa A.; Salmon, David P.; Rentz, Dorene M.; Raman, Rema; Thomas, Ronald G.; Weiner, Michael; Aisen, Paul S.

    2015-01-01

    IMPORTANCE As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. OBJECTIVE To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study). DESIGN, SETTING, AND PARTICIPANTS With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies. MAIN OUTCOMES AND MEASURES For the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD “Aβ-positive” placebo group and compare them with an “Aβ-negative” group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ɛ4 and by clinical progression. RESULTS In ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, −1.239 [0.522] [95% CI, −2.263 to −0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (−1.009 [0.406] [95% CI, −1.805 to −0.213]; P = .01) and 36 months (−1.404 [0.452] [95% CI, −2.290 to −0.519]; P = .002). In the ADCS-PI study, APOE-ɛ4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, −0.742 [0.294] [95% CI, −1.318 to −0.165]; P = .01) and 36 months (−1.531 [0.469] [95% CI, −2.450 to −0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, −4.471 [0.702] [95% CI, −5.848 to −3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% α level, we project 80% power to detect effects in the range of Δ = 0.467 to 0.733 on the ADCS-PACC. CONCLUSIONS AND RELEVANCE Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials. PMID:24886908

  13. TOXICOLOGICAL RESEARCH INVOLVING HUMANS: ETHICAL AND REGULATORY CONSIDERATIONS

    EPA Science I