These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

Preclinical Toxicology and Biodistribution Studies of Recombinant Adeno-Associated Virus 1 Human Acid ?-Glucosidase  

PubMed Central

Abstract A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid ?-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×1012 vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×105 vg/?g genomic DNA (gDNA), while uninjected sites had up to 1.0×104 vg/?g gDNA. Vector DNA was present in blood at 24?hr postinjection at up to 1.0×106 vg/?g gDNA, followed by a decrease to 1.0×103 vg/?g gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections. PMID:24021025

Erger, Kirsten; Porvasnik, Stacy; Cossette, Travis; Roberts, Cheryl; Combee, Lynn; Islam, Saleem; Kelley, Jeffry; Cloutier, Denise; Clément, Nathalie; Abernathy, Corinne R.; Byrne, Barry J.

2013-01-01

2

Metabolomics in Toxicology and Preclinical Research  

PubMed Central

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

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

3

The preclinical toxicology of salmeterol hydroxynaphthoate.  

PubMed

An extensive toxicology programme on salmeterol hydroxynaphthoate (Serevent), a marketed long-acting beta(2)-adrenoceptor agonist, has been carried out. The studies evaluated both the local (respiratory tract) and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential. High acute doses were well tolerated and caused no specific target organ toxicity. In repeat dose studies, animals tolerated salmeterol very well both locally and systemically. No significant effects on the respiratory tract of dogs were seen and only minor laryngeal changes, typical of those occurring with many inhaled medicines, were noted in rats. The high systemic concentrations achieved resulted in a number of changes that are considered to be the result of excessive and prolonged beta( 2)-adrenoceptor stimulation. These included tachycardia, skeletal muscle hypertrophy and minor haematological and blood biochemical changes in general toxicity studies, foetal effects in rabbit organogenesis studies and increased incidences of smooth muscle tumours of the mesovarium in the rat and of the uterus in the mouse oncogenicity studies. Salmeterol showed no evidence of any genotoxic potential. Results of the extensive toxicology programme provide good assurance of the safety for the inhaled use of salmeterol in patients; this has ben confirmed by many years of clinical experience during its development and marketing. PMID:20219844

Owen, K; Beck, S L; Damment, S J P

2010-05-01

4

Recent developments in preclinical toxicological pathology  

SciTech Connect

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.

Finch, John M. [Charles River Laboratories, Preclinical Services, Edinburgh, EH33 2NE (United Kingdom)]. E-mail: john.finch@eur.crl

2005-09-01

5

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

PubMed

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(8), 2.5×10(9), and 1.25×10(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(8), 2.5×10(9), and 1.25×10(10) VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose>5×10(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(10) VP/kg) and beagles (2.5×10(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(10) VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67×10(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. PMID:25151223

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

2014-10-15

6

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide  

Microsoft Academic Search

MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS). Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol “Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple

R M Myers; S M Greiner; M E Harvey; G Griesmann; M J Kuffel; S A Buhrow; J M Reid; M Federspiel; M M Ames; D Dingli; K Schweikart; A Welch; A Dispenzieri; K-W Peng; S J Russell

2007-01-01

7

Respiratory Toxicology Group: Inhalation Studies  

MedlinePLUS

... the font size, or print this page. Respiratory Toxicology Group Inhalation Studies Dan Morgan, Ph.D., D. ... NC 27709 Delivery Instructions Research Summary The Respiratory Toxicology Group conducts studies of chemicals for which inhalation ...

8

Preclinical pharmacology, metabolic stability, pharmacokinetics and toxicology of the peptidic kinin B1 receptor antagonist R-954.  

PubMed

We previously showed that R-954 (AcOrn[Oic(2),(?Me)Phe(5),d?Nal(7),Ile(8)]desArg(9)-bradykinin) is a potent, selective and stable peptide antagonist of the inducible GPCR kinin B1 receptor. This compound shows potential applications for the treatment of several diseases, including cancer and neurological disturbances of diabetes. To enable clinical translation, more information regarding its pharmacological, pharmacokinetics (PK) and toxicological properties at preclinical stage is warranted. This was the principal objective of the present study. Herein, specificity of R-954 was characterized in binding studies on 133 human molecular targets to reveal minor cross-reactivities against the angiotensin AT2 and the bombesin receptors (110- and 330-fold lower affinity than for B1R, respectively). The pharmacokinetic of R-954 was studied in both normal and streptozotocin-diabetic anaesthetized rats providing half-lives of 1.9-2.7h. R-954 does not appear to be metabolized in the rat circulation and in several rat tissue homogenates, as the kidney, lung and liver. It appears to be excreted as parent drug in the bile (21%) and in urine. A preliminary toxicological profile of R-954 was obtained in rats under various administration routes. R-954 appears to be well tolerated. Overall, these results indicate that R-954 exhibits favorable preclinical pharmacological/PK characteristics and encouraging safety profiles, suitable for early studies in humans. PMID:24361511

Gobeil, Fernand; Sirois, Pierre; Regoli, Domenico

2014-02-01

9

Toxicologic studies of SRC materials  

SciTech Connect

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)

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

1980-02-01

10

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

PubMed Central

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

Martin, Pauline L; Bugelski, Peter J

2012-01-01

11

Toxicological study of NTO  

Microsoft Academic Search

The acute oral LDââ values for NTO for mice and rats are greater than 5 g\\/kg. According to classical guidelines, the test material would be considered only slightly toxic or practically non-toxic in both species. Skin application studies in the rabbit with NTO demonstrated that it was mildly irritating cutaneously. With the scoring scheme, the rabbit eye test was considered

J. E. London; D. M. Smith

1985-01-01

12

Toxicological study of NTO  

SciTech Connect

The acute oral LD/sub 50/ values for NTO for mice and rats are greater than 5 g/kg. According to classical guidelines, the test material would be considered only slightly toxic or practically non-toxic in both species. Skin application studies in the rabbit with NTO demonstrated that it was mildly irritating cutaneously. With the scoring scheme, the rabbit eye test was considered negative; however, transient conjunctival and corneal irritation did result from the NTO application in several animals and one developed a chronic anterior uveitis. The material did not induce sensitization in the intradermal guinea pig assay. 6 refs., 1 tab.

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

1985-09-01

13

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide  

PubMed Central

MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS). Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol “Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma.” Dose–response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 × 106 TCID50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 108 and 4 × 108 TCID50/kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1 – 2 × 104 TCID50/kg (106 TCID50 per patient). PMID:17971816

Myers, RM; Greiner, SM; Harvey, ME; Griesmann, G; Kuffel, MJ; Buhrow, SA; Reid, JM; Federspiel, M; Ames, MM; Dingli, D; Schweikart, K; Welch, A; Dispenzieri, A; Peng, K-W; Russell, SJ

2009-01-01

14

Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide.  

PubMed

MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS). Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 x 10(6) TCID50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10(8) and 4 x 10(8) TCID50/kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1-2 x 10(4) TCID50/kg (10(6) TCID50 per patient). PMID:17971816

Myers, R M; Greiner, S M; Harvey, M E; Griesmann, G; Kuffel, M J; Buhrow, S A; Reid, J M; Federspiel, M; Ames, M M; Dingli, D; Schweikart, K; Welch, A; Dispenzieri, A; Peng, K-W; Russell, S J

2007-12-01

15

40 CFR 159.165 - Toxicological and ecological studies.  

Code of Federal Regulations, 2011 CFR

... false Toxicological and ecological studies. 159.165 Section 159.165 Protection...159.165 Toxicological and ecological studies. Adverse effects information must be submitted as follows: (a) Toxicological studies. (1) The results of a study...

2011-07-01

16

40 CFR 159.165 - Toxicological and ecological studies.  

Code of Federal Regulations, 2010 CFR

... false Toxicological and ecological studies. 159.165 Section 159.165 Protection...159.165 Toxicological and ecological studies. Adverse effects information must be submitted as follows: (a) Toxicological studies. (1) The results of a study...

2010-07-01

17

Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic, PAOPA: examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia.  

PubMed

Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia. PMID:23416534

Tan, Mattea L; Basu, Dipannita; Kwiecien, Jacek M; Johnson, Rodney L; Mishra, Ram K

2013-04-01

18

Preclinical Studies of Novel Targeted Therapies  

PubMed Central

Summary The bone marrow (BM) milieu confers drug resistance in multiple myeloma (MM) cells to conventional therapies. Therefore novel biologically-based therapies are needed. Preclinical studies have identified and validated molecular targeted therapeutics in MM. In particular, recognition of the biologic significance of the BM microenvironment both in MM pathogenesis and as a potential target for novel therapeutics has already derived several promising approaches. Thalidomide, lenalidomide (Revlimid®) and bortezomib (Velcade®) are directed not only at MM cells, but also BM milieu, and have rapidly from the bench to the bedside and FDA approval to treat MM. PMID:17996589

Hideshima, Teru; Anderson, Kenneth C.

2008-01-01

19

An Indexing Coverage Study of Toxicological Literature  

ERIC Educational Resources Information Center

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)

Montgomery, Ruth Reinke

1973-01-01

20

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

PubMed Central

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

Bugelski, Peter J; Martin, Pauline L

2012-01-01

21

Endpoints for Prenatal Exposures in Toxicological Studies  

Microsoft Academic Search

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

A. Mantovani; F. Maranghi

22

Love Canal: environmental and toxicological studies  

SciTech Connect

The New York State Department of Health has been involved at the Love Canal since 1978. The State has carried out numerous environmental and toxicological studies. The major purposes for these studies were to define how Love Canal contaminants might be escaping into the environment at large, what paths contaminant migration might take, and what toxicological effects Love Canal chemicals might have individually and together. Although underground contaminant migration was hypothesized along swales and underground utility bedding, these mechanisms have been proven not to be operative except for some migration along the utility bedding under Frontier Avenue. In general no underground migration has occurred outside the confines of the three city blocks that contain the Love Canal referred to as the ''first ring''. Studies have been confused by apparent burial of waste materials in areas proximate but not directly connected to the Love Canal. Migration of Love Canal leachate has occurred through storm sewers. Love Canal contaminants have reached creeks to the north and the Niagara River to the south through storm sewer transport. In spite of finding 2, 3, 7, 8 tetrachlorodibenzoparadioxin (TCDD), toxicological studies in situ and through exposure to volatile components in Love Canal soils do not indicate unusual toxicity. Animal studies continue in an attempt to determine the teratogenic and fetotoxic potential of Love Canal chemicals under different routes of exposure.

Kim, C.S.

1981-01-01

23

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 ...

24

Genetic toxicology studies with glutaraldehyde.  

PubMed

Glutaraldehyde (GA; CAS no. 111-30-8) has a wide spectrum of industrial, scientific and biomedical applications, with a potential for human exposure particularly in its biocidal applications. The likelihood for genotoxic effects was investigated in vitro and in vivo. A Salmonella typhimurium reverse mutation assay showed no evidence for mutagenic activity with strains TA98, TA1535, TA1537 and TA1538, with or without metabolic activation. However, there was a weak mutagenic response (1.9-2.3-fold at the highest non-toxic concentration) with TA100 in the presence of metabolic activation. In a Chinese hamster ovary (CHO) forward gene mutation assay (HGPRT locus) there were no consistent, statistically significant, reproducible or dosage-related increases in the frequency of 6-thioguanine resistant cells. There were no reproducible or dosage-related increases in sister chromatid exchanges in an in vitro test in CHO cells. An in vitro cytogenetics study in CHO cells showed no evidence for an increase in chromosomal aberrations on treatment with GA, either in the presence or absence of metabolic activation. In vivo, a mouse peripheral blood micronucleus test showed no increase in micronucleated polychromatophils at sampling times of 30, 48 and 72 h after acute gavage dosing with GA at 40, 80 and 125 mg kg(-1) (corresponding to 25, 50 and 85% of the LD(50)). The absence of an in vivo clastogenic potential was confirmed by no increase in chromosomal aberrations in a rat bone marrow cytogenetics study with sampling at 12, 24 and 48 h after acute gavage dosing with GA (12.5, 30 or 60 mg kg(-1) with males, and 7.5, 20 or 40 mg kg(-1) with females). Thus, in this series of tests, GA produced genotoxic effects in vitro only in a bacterial reverse mutation assay with no evidence for in vivo genotoxicity. PMID:11807929

Vergnes, Jane S; Ballantyne, Bryan

2002-01-01

25

Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology.  

PubMed

Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30-40% ?-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5-10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the ?-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research. PMID:22028871

Schaaf, Sebastian; Shibamiya, Aya; Mewe, Marco; Eder, Alexandra; Stöhr, Andrea; Hirt, Marc N; Rau, Thomas; Zimmermann, Wolfram-Hubertus; Conradi, Lenard; Eschenhagen, Thomas; Hansen, Arne

2011-01-01

26

Analgesia in Amphibians: Preclinical Studies and Clinical Applications  

PubMed Central

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

Stevens, Craig W.

2010-01-01

27

Forensic Toxicology Certificate  

E-print Network

Forensic Toxicology Certificate What is Forensic Toxicology? Forensic toxicology is a discipline of forensic science that is concerned with the study of toxic substances or poisons. Toxicology encompasses. Students of forensic toxicology obtain knowledge about the absorption, distribution, and elimination

Saldin, Dilano

28

PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer  

E-print Network

PRECLINICAL STUDY Prediction of lymph node involvement in breast cancer from primary tumor tissue- ther lymph node involvement in breast cancer is influenced by gene or miRNA expression of the primary tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix

29

Sequential whole bladder photodynamic therapy treatments: A preclinical study  

Microsoft Academic Search

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

Uniyime O. Nseyo; Henry Kim; Joe DeBord; Karen Tate; Jean DeHaven

1997-01-01

30

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE  

PubMed Central

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

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

31

Eribulin—A review of preclinical and clinical studies  

PubMed Central

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

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

2013-01-01

32

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

PubMed Central

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

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

2010-01-01

33

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

E-print Network

Extracting Respirable Particles from Lunar Regolith for Toxicology Studies B. L. Cooper1 , .D.S. Mc BE SEPARATED PRIOR TO TESTING The equipment that is used for inhalation toxicology studies is designed

Perfect, Ed

34

Summary of Chemically Induced Pulmonary Lesions in the National Toxicology Program (NTP) Toxicology and Carcinogenesis Studies  

PubMed Central

The lung is the second most common target site of neoplasia of chemicals tested by the National Toxicology Program (NTP). Of all peer-reviewed NTP studies to date (N = 545), a total of sixty-four chemicals in sixty-six reports produced significant site-specific neoplasia in the lungs of rats and/or mice. Of the studies associated with lung tumor induction, approximately 35% were inhalation and 35% were gavage studies, with dosed-feed, dosed-water, topical, intraperitoneal, or in utero routes of chemical administration accounting for 18%, 6%, 3%, 1%, and 1% of the studies, respectively. The most commonly induced lung tumors were alveolar/bronchiolar (A/B) adenoma and/or carcinoma for both species. The most frequently observed nonneoplastic lesions included hyperplasia and inflammation in both species. The liver was the most common primary site of origin of metastatic lesions to the lungs of mice; however, skin was most often the primary site of origin of metastatic lesions to the lungs of rats. In summary, A/B adenoma and carcinoma were the most frequently diagnosed chemically induced tumors in the lungs of both rats and mice in the NTP toxicology and carcinogenesis bioassays, and hyperplasia and inflammation were the most common nonneoplastic changes observed. PMID:18441259

Dixon, Darlene; Herbert, Ronald A.; Kissling, Grace E.; Brix, Amy E.; Miller, Rodney A.; Maronpot, Robert R.

2009-01-01

35

DTP | Toxicology and Pharmacology Branch (TPB)  

Cancer.gov

Hendriks, H.R., J. Plowman, D.P. Berger, K.D. Paull, H.H. Fiebig, Ø. Fodstat, H.C. Dreef-van der Meulen, R.E.C. Henrar, H.M. Pinedo and G. Schwartsmann, 1992. Preclinical Antitumor Activity and Animal Toxicology Studies of Rhizoxin, a Novel Tubulin-interacting Agent, Annals of Oncol., 3, 755-763.

36

Resveratrol: A review of preclinical studies for human cancer prevention  

SciTech Connect

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.

Athar, Mohammad; Back, Jung Ho; Tang Xiuwei [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Kwang Ho [Department of Dermatology, Hallym University College of Medicine (Korea, Republic of); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892 (United States); Bickers, David R. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Arianna L. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States)], E-mail: ak309@columbia.edu

2007-11-01

37

A long-term toxicology study on pigs fed a combined genetically modified (GM) soy and  

E-print Network

A long-term toxicology study on pigs fed a combined genetically modified (GM) soy and GM maize diet) in a long- term toxicology study of 22.7 weeks (the normal lifespan of a commercial pig from weaning animal feed, toxicology, stomach inflammation, uterus weight. Introduction Genetically modified (GM

Porter, Warren P.

38

Preclinical and clinical studies of peptide receptor radionuclide therapy.  

PubMed

In the 1980s, the (111)In-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst(2)) overexpressing tumors. On the basis of this success, peptide receptor radionuclide therapy (PRRT) was developed using similar somatostatin analogs with different therapeutic radionuclides. Clinical application of PRRT demonstrated impressive results on tumor response, overall survival, and quality of life in patients with gastroenteropancreatic neuroendocrine tumors. The peptides 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Tyr(3)-octreotate (DOTATATE) and DOTA, Tyr(3)-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst(2), have been granted Orphan Drug status by the European Medicines Agency and the US Food and Drug Administration for application in PRRT. Besides somatostatin receptor-targeting peptides, multiple other radiopeptide analogs were developed targeting several other receptors overexpressed on various tumors. Some of these peptide analogs, including cholecystokinin, gastrin, gastrin-releasing peptide, arginine-glycine-aspartate (RGD)-peptides, and glucagon-like peptide 1 analogs appeared very promising in preclinical and clinical imaging and PRRT studies. Although the success of PRRT with radiolabeled somatostatin analogs has been established, there is still room for improvement. The therapeutic window of PRRT could be enlarged by the use of new and improved targeting compounds, of which new antagonists with excellent tumor to background ratios are very promising. Furthermore, locoregional administration, improved healthy tissue protection, and combination treatment can be applied to increase the effectiveness of PRRT. Combination treatment might include cocktails of different peptide analogs of different therapeutic radionuclides and of radiolabeled peptides with chemotherapeutic or radiosensitizing agents. This review summarizes results of PRRT and describes clinical and preclinical studies regarding PRRT optimizing strategies. PMID:20350630

Pool, Stefan E; Krenning, Eric P; Koning, Gerben A; van Eijck, Casper H J; Teunissen, Jaap J M; Kam, Boen; Valkema, Roelf; Kwekkeboom, Dik J; de Jong, Marion

2010-05-01

39

Characterization of Lunar Dust for Toxicological Studies. I: Particle Size Distribution  

E-print Network

Characterization of Lunar Dust for Toxicological Studies. I: Particle Size Distribution Jaesung of the possible toxicological effects it may have on the human respiratory and pulmonary systems. Utilizing now, the pos- sible toxicology of lunar dust was not an important subject. In addition, techniques

Perfect, Ed

40

Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury  

PubMed Central

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 >10 mg/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

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

2014-01-01

41

Proficiency testing in forensic toxicology: a feasibility study.  

PubMed

This study has shown that a national proficiency testing program in forensic toxicology is feasible. Samples that resemble typical case specimens were prepared and shipped to approximately 100 laboratories. Participation varied between 61 and 73%. Tissue samples obtained from laboratory animals can be used to simulate those encountered by forensic toxicologists. This has been demonstrated using liver homogenates from animals administered pentobarbital and methaqualone and propoxyphene and acetaminophen. There was a large coefficient of variation however, for the quantitation of acetaminophen in liver. The qualitative data obtained during the course of this study showed a very low incidence of false positives. However, there was a disappointingly low percentage of positive responses for (a) low concentrations of secobarbital and (b) the opiate narcotics (morphine and codeine) in blood, despite the fact that sensitive immunoassay procedures are available for detecting these particular compounds in blood samples. The quantitative determination of drugs and metabolites, other than ethanol, shows wide interlaboratory variation. This variation is presumably not a result of the use of different analytical techniques, since gas liquid chromatography was used by the majority of participants to quantitate drugs and metabolites. Forensic toxicologists are willing to participate in a voluntary proficiency testing program conducted by an independent agency. The performance data developed in this study can serve as a baseline for current forensic toxicology laboratory functional capability in the assessment of future changes and improvements in analytical forensic toxicology. PMID:6680733

Peat, M A; Finnigan, J S; Finkle, B S

1983-01-01

42

Developmental toxicology evaluations--issues with including neurotoxicology and immunotoxicology assessments in reproductive toxicology studies.  

PubMed

Developmental and reproductive toxicology (DART) has routinely been a part of safety assessment. Attention is now focused on the effects of chemicals on the developing nervous and immune systems. This focus on developmental neurotoxicology (DNT) and developmental immunotoxicology (DIT) is based on the premise that children differ from adults in some aspects of their biology and, thus, may also differ in their responses to chemicals. This session's objective was to discuss issues common to DNT and DIT as they relate to DART protocols, including high dose selection and maternal toxicity, adequacy of pup exposure during lactation, use of a different dosing paradigm for DART versus DNT or DIT studies, and whether DIT and DNT endpoints can be incorporated into a single DART study for hazard identification purposes. Consensus was achieved on all topics except the adequacy for risk assessment purposes of the use of a limited number of endpoints for DIT and DNT, with the DNT endpoints being the primary focus of disagreement. Panelists indicated that a combination study design for hazard identification was feasible, though flexibility to meet the scientific needs of the project was emphasized. The adequacy of existing triggers for additional developmental studies was also questioned. Panelists iterated the importance of understanding pup exposure during the various life stages and the use of toxicokinetic data in designing these studies. The group agreed to consider the HESI ACSA Life Stages Task Force recommendations as a next step to address some of the issues and challenges raised during this session. PMID:16120748

Ladics, Gregory S; Chapin, Robert E; Hastings, Kenneth L; Holsapple, Michael P; Makris, Susan L; Sheets, Larry P; Woolhiser, Michael R; Burns-Naas, Leigh Ann

2005-11-01

43

A crowdsourcing model for creating preclinical medical education study tools.  

PubMed

During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning. PMID:23619061

Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U

2013-06-01

44

Preclinical safety studies on autologous cultured human skin fibroblast transplantation.  

PubMed

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

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

2014-01-01

45

Toxicological study on pramiverine (author's transl).  

PubMed

4,4-Diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) was investigated alone and in combination (1 + 1000) with N-methyl-N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-aminomethanesulfonate (metamizole) in various species for acute toxicity after oral and intravenous administration, for local tolerance and subacute toxicity. In addition, long-term trials and reproduction toxicity studies were performed with pramiverine. Pramiverine was only slightly toxic and was well tolerated locally as an ampoule solution also in combination with metamizole. The acute trials of the two compounds in mice and rats like the subacute study in rats showed that the toxicity of metamizole was not increased by pramiverine. Rats tolerated in the long-term trial all pramiverine doses examined (0.5; 5.0; 50.0 mg/kg), while cholinolytic concomitant effects were observed in dogs under higher doses (5.0 and 20.0 mg/kg). Pramiverine did not have a foetotoxic and teratogenic effect in mice, rats and rabbits. In the perinatal and postnatal experiment in rats no effect on foetal development, viability and growth of the offspring as well as the course of labour and lactation ability of the dams was observed. PMID:989019

Eberstein, M; Frohberg, H; Hofmann, A; Jochmann, G; Metallinos, A; Schiling, B; Weisse, G

1976-04-01

46

Developmental Toxicology Evaluations--Issues with Including Neurotoxicology and Immunotoxicology Assessments in Reproductive Toxicology Studies  

Microsoft Academic Search

Developmental and reproductive toxicology (DART) has rou- tinely been a part of safety assessment. Attention is now focused on the effects of chemicals on the developing nervous and immune systems. This focus on developmental neurotoxicology (DNT) and developmental immunotoxicology (DIT) is based on the premise that children differ from adults in some aspects of their biology and, thus, may also

Gregory S. Ladics; Robert E. Chapin; Kenneth L. Hastings; Michael P. Holsapple; Susan L. Makris

2005-01-01

47

Need for dietary control by caloric restriction in rodent toxicology and carcinogenicity studies  

Microsoft Academic Search

The conditions under which laboratory animals are maintained can powerfully influence the results of toxicological studies utilized for risk assessment. Nutrition is of importance in toxicological bioassays and research, because diet composition and the conditions under which it is fed can affect the metabolism and activity of xenobiotic test substances and alter the results and reproducibility of long?term studies. It

Kevin P. Keenan; Philippe Laroque; Rakesh Dixit

1998-01-01

48

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...

49

Considerations for Toxicology Studies of Respiratory Drug Products  

Microsoft Academic Search

The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of

Joseph J Degeorge; Chang Ho Ahn; Paul A Andrews; Margaret E Brower; Young S Choi; Misoon Y Chun; Tao Du; Doo Young Lee-Ham; W. David McGuinn; Luqi Pei; Lawrence F Sancilio; Wendelyn Schmidt; Hilary V Sheevers; C. Joseph Sun; Satish Tripathi; W. Mark Vogel; Virgil Whitehurst; Shannon Williams; Alan S Taylor

1997-01-01

50

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...

51

Preclinical studies with synthetic peptides in systemic lupus erythematosus.  

PubMed

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that causes multi-organ damage and significant morbidity and mortality. Various efforts have been made to modulate the imbalanced immune responses in this disease. The manipulation of the immune system through the use of soluble synthetic peptides serving as antigenic epitopes, in repeated doses, has been shown to induce immune tolerance and to reduce the clinical manifestations of the disease in murine models. Although clinical trials in humans with the anti-DNA Ig peptide hCDR1 have failed, recent results from a clinical trial with another peptide, p140, have shown promise. This review provides an overview on the preclinical and translational work with synthetic peptides in SLE. PMID:22201847

Amarilyo, Gil; Hahn, Bevra; La Cava, Antonio

2012-01-01

52

Environmental Toxicology  

NASA Astrophysics Data System (ADS)

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.

Wright, David A.; Welbourn, Pamela

2002-03-01

53

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...

54

Natural substances and Alzheimer's disease: From preclinical studies to evidence based medicine  

Microsoft Academic Search

Over the last 10years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either

Cesare Mancuso; Raffaella Siciliano; Eugenio Barone; Paolo Preziosi

55

Feasibility study of voice-driven data collection in animal drug toxicology studies.  

PubMed

The object of this study was to determine the feasibility of using voice recognition technology to enable hands-free and eyes-free collection of data related to animal drug toxicology studies. Specifically, we developed and tested a prototype voice-driven data collection system for histopathology data using only voice input and computer-generated voice responses. The overall accuracy rate was 97%. Additional work is needed to minimize training requirements and improve audible feedback. We conclude that this architecture could be considered a viable alternative for data collection in animal drug toxicology studies with reasonable recognition accuracy. PMID:7531129

Grasso, M A; Grasso, C T

1994-07-01

56

Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies  

PubMed Central

Kidney toxicity accounts for a significant percentage of morbidity and drug candidate failure. Serum creatinine (SCr) and blood urea nitrogen (BUN) have been used to monitor kidney dysfunction for over a century but these markers are insensitive and non-specific. In multi-site preclinical rat toxicology studies the diagnostic performance of urinary kidney injury molecule-1 (Kim-1) was compared to traditional biomarkers as predictors of kidney tubular histopathologic changes, currently considered the “gold standard” of nephrotoxicity. In multiple models of kidney injury, urinary Kim-1 significantly outperformed SCr and BUN. The area under the receiver operating characteristic curve for Kim-1 was between 0.91 and 0.99 as compared to 0.79 to 0.9 for BUN and 0.73 to 0.85 for SCr. Thus urinary Kim-1 is the first injury biomarker of kidney toxicity qualified by the FDA and EMEA and is expected to significantly improve kidney safety monitoring. PMID:20458318

Vaidya, Vishal S.; Ozer, Josef S.; Frank, Dieterle; Collings, Fitz B.; Ramirez, Victoria; Troth, Sean; Muniappa, Nagaraja; Thudium, Douglas; Gerhold, David; Holder, Daniel J.; Bobadilla, Norma A.; Marrer, Estelle; Perentes, Elias; Cordier, André; Vonderscher, Jacky; Maurer, Gérard; Goering, Peter L.; Sistare, Frank D.; Bonventre, Joseph V.

2010-01-01

57

International Recommendations for Training Future Toxicologic Pathologists Participating in Regulatory-Type, Nonclinical Toxicity Studies*  

PubMed Central

The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a common global framework for training future toxicologic pathologists who will support regulatory-type nonclinical toxicology studies. Trainees optimally should undertake a scientific curriculum of at least 5 years at an accredited institution leading to a clinical degree (veterinary medicine or medicine). Trainees should then obtain 4 or more years of intensive pathology practice during a residency and/or on-the-job “apprenticeship,” at least 2 years of which must be focused on regulatory-type toxicologic pathology topics. Possession of a recognized pathology qualification (i.e., certification) is highly recommended. A non-clinical pathway (e.g., a graduate degree in medical biology or pathology) may be possible if medically trained pathologists are scarce, but this option is not optimal. Regular, lifelong continuing education (peer review of nonclinical studies, professional meetings, reading, short courses) will be necessary to maintain and enhance one’s understanding of current toxicologic pathology knowledge, skills, and tools. This framework should provide a rigorous yet flexible way to reliably train future toxicologic pathologists to generate, interpret, integrate, and communicate data in regulatory-type, nonclinical toxicology studies. PMID:22272030

Bolon, Brad; Barale-Thomas, Erio; Bradley, Alys; Ettlin, Robert A.; Franchi, Carla A.S.; George, Catherine; Giusti, Anna Maria; Hall, Robert; Jacobsen, Matthew; Konishi, Yoichi; Ledieu, David; Morton, Daniel; Park, Jae-Hak; Scudamore, Cheryl L.; Tsuda, Hiroyuki; Vijayasarathi, S.K.; Wijnands, Marcel V.W.

2010-01-01

58

Preclinical pharmacokinetic, toxicological and biomarker evaluation of SR16157, a novel dual-acting steroid sulfatase inhibitor and selective estrogen receptor modulator  

Microsoft Academic Search

Purpose  SR16157 is a novel dual-acting inhibitor of estrogen action that irreversibly inhibits the estrogen biosynthetic enzyme steroid\\u000a sulfatase (STS) and releases the selective estrogen receptor modulator SR16137, which blocks the estrogen receptor. SR16157\\u000a is a promising agent for the endocrine therapy of breast cancer. We conducted preclinical in vivo toxicity evaluations to\\u000a determine the maximum-tolerated dose (MTD), target organ(s) of

Linda Rausch; Carol Green; Karen Steinmetz; Sue LeValley; Paul Catz; Nurulain Zaveri; Karen Schweikart; Joseph Tomaszewski; Jon Mirsalis

2011-01-01

59

PRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion  

E-print Network

PRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion and survival Triple-negative breast cancer (TNBC) is a heterogeneous disease that is usually associated with poor. Keywords GRB7 Á Adapter proteins Á Triple-negative breast cancer Á Tumor cell invasion Á Receptor tyrosine

Kenny, Paraic

60

PRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion  

E-print Network

PRECLINICAL STUDY GRB7 is required for triple-negative breast cancer cell invasion and survival+Business Media, LLC. 2011 Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease targets in this disease. Keywords GRB7 Á Adapter proteins Á Triple-negative breast cancer Á Tumor cell

Kenny, Paraic

61

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

ERIC Educational Resources Information Center

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.…

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

2014-01-01

62

Studies in the behavioral toxicology of environmental contaminants.  

PubMed Central

Behavioral toxicology represents a relatively new research area in the West, and a new source of information pertinent to standard setting. Despite this abbreviated history, however, it can call on a rather advanced technology, largely provided by the rapid and extensive development of behavioral pharmacology during the past two decades. As exemplified by the U.S. contribution to the joint study of carbon disulfide, the approach derived from this background relies on the acquisition of dose--effect data with a preparation yielding stable baseline performance. The first study in this collaborative series employed pigeons trained to peck a response device consisting of a transilluminnated plastic disk. Various relationships between this response and the occasions on which it led to the delivery of food were explored in order to ascertain which behavioral variables were most sensitive to acute exposures. In addition, a central nervous system drug, whose neurochemical mode of action is believed to parallel that of carbon disulfide, was tested in the same preparations. Further research on these questions is being continued with monkeys. Images FIGURE 1. FIGURE 2. PMID:1269505

Weiss, B; Levine, T E

1976-01-01

63

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

SciTech Connect

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.

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

2011-01-15

64

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

ERIC Educational Resources Information Center

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…

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

65

Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons from Pre-clinical Studies  

PubMed Central

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 1970’s. 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 pre-clinical 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. Pre-clinical 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 is 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. PMID:21183290

Medin, Paul M.; Boike, Thomas P.

2010-01-01

66

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

PubMed

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

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

2013-04-01

67

Therapeutic Applications of Incretin Mimetics for Metabolic Diseases: Preclinical Studies  

Technology Transfer Automated Retrieval System (TEKTRAN)

Exenatide (exendin-4) is an incretin mimetic peptide that shares several glucoregulatory actions with the endogenous incretin GLP-1. In addition to its actions on glucose control, exenatide produces effects to reduce food intake and body weight in all species studied. GLP-1 and exenatide have also b...

68

Toxicological screening  

PubMed Central

Toxicity testing of new compounds is essential for drug development process. The preclinical toxicity testing on various biological systems reveals the species-, organ- and dose- specific toxic effects of an investigational product. The toxicity of substances can be observed by (a) studying the accidental exposures to a substance (b) in vitro studies using cells/ cell lines (c) in vivo exposure on experimental animals. This review mainly focuses on the various experimental animal models and methods used for toxicity testing of substances. The pre-clinical toxicity testing helps to calculate “No Observed Adverse Effect Level” which is needed to initiate the clinical evaluation of investigational products. PMID:21772764

Parasuraman, S.

2011-01-01

69

Toxicology Enrichment Materials  

NSDL National Science Digital Library

The series contains fact sheets on toxicology, introductory exercises to familiarize students with the study of toxicology and student assignments addressing specific issues in toxicology. The assignments are designed to enrich typical course curricula and give students practice using information from both library and internet sources.

Suzanne Conklin (Rhode Island College;)

2000-01-01

70

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

SciTech Connect

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.

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

1985-10-01

71

Improving the Quality of NINDS-Supported Preclinical and Clinical Research through Rigorous Study Design and Transparent Reporting  

E-print Network

Improving the Quality of NINDS-Supported Preclinical and Clinical Research through Rigorous Study basic, translational, and clinical research. There is growing recognition that the quality community has developed principles to improve the design, implementation, review, and reporting of clinical

72

Luciferase fragment complementation imaging in preclinical cancer studies  

PubMed Central

The luciferase fragment complementation assay (LFCA) enables molecular events to be non-invasively imaged in live cells in vitro and in vivo in a comparatively cheap and safe manner. It is a development of previous enzyme complementation assays in which reporter genes are split into two, individually enzymatically inactive, fragments that are able to complement one another upon interaction. This complementation can be used to externally visualize cellular activities. In recent years, the number of studies which have used LFCAs to probe questions relevant to cancer have increased, and this review summarizes the most significant and interesting of these. In particular, it focuses on work conducted on the epidermal growth factor, nuclear and chemokine receptor families, and intracellular signaling pathways, including IP3, cAMP, Akt, cMyc, NRF2 and Rho GTPases. LFCAs which have been developed to image DNA methylation and detect RNA transcripts are also discussed. PMID:25594026

Lake, Madryn C.; Aboagye, Eric O.

2014-01-01

73

Nanomaterial synthesis and characterization for toxicological studies: TiO2 case study  

USGS Publications Warehouse

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.

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

2008-01-01

74

Potential antianxiety activity of Fumaria indica: A preclinical study  

PubMed Central

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

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

2013-01-01

75

Analgesic and hypnotic activities of Laghupanchamula: A preclinical study  

PubMed Central

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

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

2014-01-01

76

Why Toxicology?  

NSDL National Science Digital Library

One of the reasons for studying toxicology at the high school level is its relevance to everyday life. On a daily basis we are confronted with news reports about toxic chemicals in our food, water, and environment. How do we decide which of these are worth worrying about? Too often these decisions are based on misconceptions about what is "safe" and what involves too great a risk. In learning about the basic concepts of toxicology, students will become better prepared to make reasoned decisions about issues such as these. This free selection also includes the Table of Contents and Introduction.

Trautmann, Nancy M.; Team, The E.

2001-01-01

77

DTP | Toxicology and Pharmacology Branch (TPB)  

Cancer.gov

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

78

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

PubMed

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

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

2014-01-01

79

Preclinical electrogastrography in experimental pigs.  

PubMed

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

Kv?tina, Jaroslav; Edakkanambeth Varayil, Jithinraj; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopá?ová, Marcela

2010-06-01

80

Preclinical electrogastrography in experimental pigs  

PubMed Central

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

Kv?tina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopá?ová, Marcela

2010-01-01

81

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

PubMed

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

Kwon, Youngjoo

2014-11-01

82

Isolation and characterization of dendritic cells from common marmosets for preclinical cell therapy studies  

PubMed Central

Dendritic cells (DCs) have important functions as modulators of immune responses, and their ability to activate T cells is of great value in cancer immunotherapy. The isolation of DCs from the peripheral blood of rhesus and African green monkeys has been reported, but the immune system in the common marmoset remains poorly characterized, although it offers many potential advantages for preclinical studies. In the present study, we devised methods, based on techniques developed for mouse and human DC preparation, for isolating DCs from three major tissue sources in the common marmoset: bone marrow (BM), spleen and peripheral blood. Each set of separated cells was analysed using the cell surface DC-associated markers CD11c, CD80, CD83, CD86 and human leucocyte antigen (HLA)-DR, all of which are antibodies against human antigens, and the cells were further characterized both functionally and morphologically as antigen-presenting cells. BM proved to be an excellent cell source for the isolation of DCs intended for preclinical studies on cell therapy, for which large quantities of cells are required. In the BM-derived CD11c+ cell population, cells exhibiting the characteristic features of DCs were enriched, with the typical DC morphology and the abilities to undergo endocytosis, to secrete interleukin (IL)-12, and to stimulate Xenogenic T cells. Moreover, BM-derived DCs produced the neurotrophic factor NT-3, which is also found in murine splenic DCs. These results suggest that BM-derived DCs from the common marmoset may be useful for biological analysis and for preclinical studies on cell therapy for central nervous system diseases and cancer. PMID:18005037

Ohta, Shigeki; Ueda, Yoko; Yaguchi, Masae; Matsuzaki, Yumi; Nakamura, Masaya; Toyama, Yoshiaki; Tanioka, Yoshikuni; Tamaoki, Norikazu; Nomura, Tatsuji; Okano, Hideyuki; Kawakami, Yutaka; Toda, Masahiro

2008-01-01

83

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

PubMed

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

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

2013-03-01

84

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

PubMed

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

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

2014-03-01

85

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

PubMed Central

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

Hartung, Thomas

2013-01-01

86

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study  

PubMed Central

Background and objectives: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. Methods: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images. Results: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. Conclusions: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD. PMID:15834021

Kipps, C; Duggins, A; Mahant, N; Gomes, L; Ashburner, J; McCusker, E

2005-01-01

87

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 (...

88

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

NASA Technical Reports Server (NTRS)

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.

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

2010-01-01

89

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

PubMed Central

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

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

2013-01-01

90

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

PubMed Central

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

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

2014-01-01

91

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

PubMed

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

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

2009-01-01

92

Genomic biomarkers for cardiotoxicity in rats as a sensitive tool in preclinical studies.  

PubMed

The development of safer drugs is a high priority for pharmaceutical companies. Among the various toxicities caused by drugs, cardiotoxicity is an important issue because of its lethality. In addition, cardiovascular toxicity leads to the attrition of many drug candidates in both preclinical and clinical phases. Although histopathological and blood chemistry examinations are the current gold standards for detecting cardiotoxicity in preclinical studies, the large number of withdrawals from clinical studies owing to safety problems indicate that a more sensitive tool is required. We recently identified 32 genes that were candidate genomic biomarkers for cardiotoxicity in rats. Based on their functions, the present study focused on 8 of these 32 genes (Spp1, Fhl1, Timp1, Serpine1, Bcat1, Lmcd1, Rnd1 and Tgfb2). Diagnostic accuracy for the genes was determined by a receiver-operating characteristic (ROC) analysis using more cardiotoxic and non-cardiotoxic compounds. In addition, an optimized support vector machine (SVM) model that was composed of Spp1 and Timp1 was newly constructed. This new multi-gene model exhibited a much higher diagnostic accuracy than that observed for plasma cardiac troponin I (cTnI), which is one of the most useful plasma biomarkers for cardiotoxicity detection. Furthermore, we determined that this multi-gene model could predict potential cardiotoxicity in rats in the absence of any cardiac histopathological lesions or elevations of plasma cTnI. Overall, this multi-gene model exhibited advantages over classic tools commonly used for cardiotoxicity evaluations in rats. Our current results suggest that application of the model could potentially lead to the production of safer drugs. PMID:23558518

Nishimura, Yoko; Morikawa, Yuji; Kondo, Chiaki; Tonomura, Yutaka; Fukushima, Ryou; Torii, Mikinori; Uehara, Takeki

2013-10-01

93

Fabry Disease: Preclinical Studies Demonstrate the Effectiveness of ?-Galactosidase A Replacement in Enzyme-Deficient Mice  

PubMed Central

Preclinical studies of enzyme-replacement therapy for Fabry disease (deficient ?-galactosidase A [?-Gal A] activity) were performed in ?-Gal A–deficient mice. The pharmacokinetics and biodistributions were determined for four recombinant human ?-Gal A glycoforms, which differed in sialic acid and mannose-6-phosphate content. The plasma half-lives of the glycoforms were ?2–5 min, with the more sialylated glycoforms circulating longer. After intravenous doses of 1 or 10 mg/kg body weight were administered, each glycoform was primarily recovered in the liver, with detectable activity in other tissues but not in the brain. Normal or greater activity levels were reconstituted in various tissues after repeated doses (10 mg/kg every other day for eight doses) of the highly sialylated AGA-1 glycoform; 4 d later, enzyme activity was retained in the liver and spleen at levels that were, respectively, 30% and 10% of that recovered 1 h postinjection. Importantly, the globotriaosylceramide (GL-3) substrate was depleted in various tissues and plasma in a dose-dependent manner. A single or repeated doses (every 48 h for eight doses) of AGA-1 at 0.3–10.0 mg/kg cleared hepatic GL-3, whereas higher doses were required for depletion of GL-3 in other tissues. After a single dose of 3 mg/kg, hepatic GL-3 was cleared for ?4 wk, whereas cardiac and splenic GL-3 reaccumulated at 3 wk to ?30% and ?10% of pretreatment levels, respectively. Ultrastructural studies demonstrated reduced GL-3 storage posttreatment. These preclinical animal studies demonstrate the dose-dependent clearance of tissue and plasma GL-3 by administered ?-Gal A, thereby providing the in vivo rationale—and the critical pharmacokinetic and pharmacodynamic data—for the design of enzyme-replacement trials in patients with Fabry disease. PMID:11115376

Ioannou, Yiannis A.; Zeidner, Ken M.; Gordon, Ronald E.; Desnick, Robert J.

2001-01-01

94

Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis  

PubMed Central

Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described. PMID:24213461

Tanaka, Takuji

2012-01-01

95

Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model  

PubMed Central

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

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

2011-01-01

96

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

PubMed

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

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

2014-01-01

97

Safety biomarkers in preclinical development: translational potential.  

PubMed

The identification, application, and qualification of safety biomarkers are becoming increasingly critical to successful drug discovery and development as companies are striving to develop drugs for difficult targets and for novel disease indications in a risk-adverse environment. Translational safety biomarkers that are minimally invasive and monitor drug-induced toxicity during human clinical trials are urgently needed to assess whether toxicities observed in preclinical toxicology studies are relevant to humans at therapeutic doses. The interpretation of data during the biomarker qualification phase should include careful consideration of the analytic method used, the biology, pharmacokinetic and pharmacodynamic properties of the biomarker, and the pathophysiology of the process studied. The purpose of this review is to summarize commonly employed technologies in the development of fluid- and tissue-based safety biomarkers in drug discovery and development and to highlight areas of ongoing novel assay development. PMID:24091814

Sasseville, V G; Mansfield, K G; Brees, D J

2014-01-01

98

Toxicology screen  

MedlinePLUS

A toxicology screen refers to various tests to determine the type and approximate amount of legal and illegal drugs ... Toxicology screening is most often done using a blood or urine sample. However, it may be done ...

99

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...

100

Educational Challenges in Toxicology.  

ERIC Educational Resources Information Center

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)

Dixon, Robert L.

1984-01-01

101

Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.  

PubMed

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity. PMID:11261749

Haasio, K; Sopanen, L; Vaalavirta, L; Lindén, I B; Heinonen, E H

2001-01-01

102

Preclinical Study Design for Evaluation of Stem Cell-derived Cellular Therapy Products: A Pathologist's Perspective.  

PubMed

Despite-or perhaps because of-the rapid expansion of interest in stem cell-derived cellular therapy products, relatively few guidelines have been published to assist in the design of scientifically sound preclinical studies. The field is complex and wide ranging, and of necessity regulators tend to treat each project on a case by case basis. One of the core tenets remains the need to retain all tissues from the study, thereby allowing for further analysis of tissues should unexpected effects be seen in clinical studies; attempts to comply with this may result in an unmanageable financial burden. Judicious input from the pathologist at the earliest stages of study design may not only improve the scientific integrity of the study but also help to mitigate some of the cost. Careful animal selection, the development of robust cell markers, and justifiable triage of tissues based on phased tissue examination can all be discussed with the regulatory authorities at pre-pre-investigational new drug (IND) and pre-IND meetings to achieve optimal study design. PMID:25351922

Baker, Julia F M; Assaf, Basel T

2015-01-01

103

Handling of the cotton rat in studies for the pre-clinical evaluation of oncolytic viruses.  

PubMed

Oncolytic viruses are a novel anticancer therapy with the ability to target tumor cells, while leaving healthy cells intact. For this strategy to be successful, recent studies have shown that involvement of the host immune system is essential. Therefore, oncolytic virotherapy should be evaluated within the context of an immunocompetent model. Furthermore, the study of antitumor therapies in tolerized animal models may better recapitulate results seen in clinical trials. Cotton rats, commonly used to study respiratory viruses, are an attractive model to study oncolytic virotherapy as syngeneic models of mammary carcinoma and osteosarcoma are well established. However, there is a lack of published information on the proper handling procedure for these highly excitable rodents. The handling and capture approach outlined minimizes animal stress to facilitate experimentation. This technique hinges upon the ability of the researcher to keep calm during handling and perform procedures in a timely fashion. Finally, we describe how to prepare cotton rat mammary tumor cells for consistent subcutaneous tumor formation, and how to perform intratumoral and intraperitoneal injections. These methods can be applied to a wide range of studies furthering the development of the cotton rat as a relevant pre-clinical model to study antitumor therapy. PMID:25490047

Cuddington, Breanne; Verschoor, Meghan; Mossman, Karen

2014-01-01

104

Examination performances of German and international medical students in the preclinical studying-term – A descriptive study  

PubMed Central

Introduction: Medical students with a migration background face several specific problems during their studies. International surveys show first indications that this group of students performs worse in written, oral or practical exams. However, so far, nothing is known about the performance of international students in written pre-clinical tests as well as in pre-clinical State Examinations for German-speaking countries. Method: A descriptive, retrospective analysis of the exam performances of medical students in the pre-clinical part of their studies was conducted at the Faculty of Medicine of Heidelberg in for the year 2012. Performance in written tests of the final exams in the second (N=276), third (N=292) and fourth semester (N=285) were compared between German students, students from EU countries and students from non-EU countries. Same comparison was drawn for the performance in the oral exam of the First State Examination in the period from 2009 - 2012 (N=1137). Results: German students performed significantly better than students with a non-EU migration background both in all written exams and in the oral State Examination (all p<.05). The performance of students with an EU migration background was significantly better than that of students with a non-EU background in the written exam at the end of the third and fourth semester (p<.05). Furthermore, German students completed the oral exam of the First State Examination significantly earlier than students with a non-EU migration background (<.01). Discussion: Due to its poorer performance in written and oral examinations and its simultaneously longer duration of study, the group of non-German medical students with a country of origin outside of the European Union has to be seen as a high-risk group among students with a migration background. For this group, there is an urgent need for early support to prepare for written and oral examinations. PMID:25228931

Huhn, D.; Resch, F.; Duelli, R.; Möltner, A.; Huber, J.; Karimian Jazi, K.; Amr, A.; Eckart, W.; Herzog, W.; Nikendei, C.

2014-01-01

105

Behavioral toxicology  

SciTech Connect

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.

Needleman, H.L. [Univ. of Pittsburgh, PA (United States)

1995-09-01

106

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

NASA Astrophysics Data System (ADS)

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.

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

2011-02-01

107

Standardization of the Filovirus Plaque Assay for Use in Preclinical Studies  

PubMed Central

The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate virus in samples from animals treated with a potential antiviral therapeutic or vaccine. As these animal studies are required for the development of vaccines and therapeutics under the FDA Animal Rule, it is essential to have a standardized assay to compare their efficacies against the various filoviruses. Here, we present an evaluation of the conditions under which the filovirus plaque assay performs best for the Ebola virus Kikwit variant and the Angola variant of Marburg virus. The indicator cell type and source, inoculum volumes, length of incubation and general features of filovirus biology as visualized in the assay are addressed in terms of the impact on the sample viral titer calculations. These optimization studies have resulted in a plaque assay protocol which can be used for preclinical studies, and as a standardized protocol for use across institutions, to aid in data comparison. This protocol will be validated for use in GLP studies supporting advanced development of filovirus therapeutics and vaccines. PMID:23223188

Shurtleff, Amy C.; Biggins, Julia E.; Keeney, Ashley E.; Zumbrun, Elizabeth E.; Bloomfield, Holly A.; Kuehne, Ana; Audet, Jennifer L.; Alfson, Kendra J.; Griffiths, Anthony; Olinger, Gene G.; Bavari, Sina

2012-01-01

108

Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine.  

PubMed

Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID:21939756

Mancuso, Cesare; Siciliano, Raffaella; Barone, Eugenio; Preziosi, Paolo

2012-05-01

109

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...

110

Preclinical Studies with Umbilical Cord Mesenchymal Stromal Cells in Different Animal Models for Muscular Dystrophy  

PubMed Central

Umbilical cord mesenchymal stromal cells (MSC) have been widely investigated for cell-based therapy studies as an alternative source to bone marrow transplantation. Umbilical cord tissue is a rich source of MSCs with potential to derivate at least muscle, cartilage, fat, and bone cells in vitro. The possibility to replace the defective muscle cells using cell therapy is a promising approach for the treatment of progressive muscular dystrophies (PMDs), independently of the specific gene mutation. Therefore, preclinical studies in different models of muscular dystrophies are of utmost importance. The main objective of the present study is to evaluate if umbilical cord MSCs have the potential to reach and differentiate into muscle cells in vivo in two animal models of PMDs. In order to address this question we injected (1) human umbilical cord tissue (hUCT) MSCs into the caudal vein of SJL mice; (2) hUCT and canine umbilical cord vein (cUCV) MSCs intra-arterially in GRMD dogs. Our results here reported support the safety of the procedure and indicate that the injected cells could engraft in the host muscle in both animal models but could not differentiate into muscle cells. These observations may provide important information aiming future therapy for muscular dystrophies. PMID:21785565

Zucconi, Eder; Vieira, Natassia Moreira; Bueno, Carlos Roberto; Secco, Mariane; Jazedje, Tatiana; Costa Valadares, Marcos; Fussae Suzuki, Miriam; Bartolini, Paolo; Vainzof, Mariz; Zatz, Mayana

2011-01-01

111

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...

112

Scaling Pharmacodynamics from In Vitro and Preclinical Animal Studies to Humans  

PubMed Central

Summary An important feature of mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) models is the identification of drug- and system-specific factors that determine the intensity and time-course of pharmacological effects. This provides an opportunity to integrate information obtained from in vitro bioassays and preclinical pharmacological studies in animals to anticipate the clinical and adverse responses to drugs in humans. The fact that contemporary PK/PD modeling continues to evolve and seeks to emulate systems level properties should provide enhanced capabilities to scale-up pharmacodynamic data. Critical steps in drug discovery and development, such as lead compound and first in human dose selection, may become more efficient with the implementation and further refinement of translational PK/PD modeling. In this review, we highlight fundamental principles in pharmacodynamics and the basic expectations for in vitro bioassays and traditional allometric scaling in PK/PD modeling. Discussion of PK/PD modeling efforts for recombinant human erythropoietin is also included as a case study showing the potential for advanced systems analysis to facilitate extrapolations and improve understanding of inter-species differences in drug responses. PMID:19252333

Mager, Donald E.; Woo, Sukyung; Jusko, William J.

2013-01-01

113

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

PubMed

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

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

2014-10-30

114

[Development and preclinical study of new generation virosomal split influenza vaccine "Grifor"].  

PubMed

New Russian virosomal split vaccine against influenza "Grifor" was developed. The vaccine is represented by mix of highly purified protective external and internal antigens of influenza A (H1N1 and H3N2) and B viruses. Developed technology of manufacture allowed to provide presentation of external antigens of influenza virus in the form of virosomes, and presentation of internal antigens in the form of micelles with maximal preservation of their antigenic activity. Using electron microscopy, electrophoresis in 10% polyacrilamide gel with sodium dodecyl sulfate, and polymerase chain reaction, morphologic and biochemical properties of the vaccine were studied. Preclinical study, including assessment of antigenic characteristics of "Grifor" vaccine compared to vaccine "Vaxigrip" (France), was performed. It was established that administration of the vaccine did not result in death of experimental animals, decrease of body mass, development of pathologic (including inflammatory, dystrophic and necrobiotic) changes in viscera or render adverse effects on blood hematologic and biochemical parameters and on the immune system. The vaccine was not pyrogenic and allergenic, did not have local irritating effects. Obtained results supported the appropriateness of conducting the clinical trials of "Grifor" vaccine on limited number of volunteers. PMID:19338232

Mel'nikov, S Ia; Zverev, V V; Korovkin, S A; Mironov, A N; Dyldina, N V; Mikha?lova, N A; Fa?zuloev, E B; Lotte, V D

2009-01-01

115

Preclinical Systemic Lupus Erythematosus.  

PubMed

Preclinical lupus encompasses a spectrum from enhanced SLE risk without clinical symptoms to individuals with autoantibodies and some SLE clinical features without meeting ACR classification. Studies have identified antibody and serological biomarkers years before disease onset. Incomplete lupus and undifferentiated connective tissue disease may occur during preclinical disease periods, but only 10-20% of these individuals transition to SLE and many have a mild disease course. Further studies are warranted to characterize biomarkers of early disease, identify individuals in need of close monitoring or preventive interventions, and elucidate mechanisms of disease pathogenesis without confounding factors of immunosuppressive medications or organ damage. PMID:25437281

Robertson, Julie M; James, Judith A

2014-11-01

116

Toxicological studies on the organophosphorous insecticide methyl-ISP  

Microsoft Academic Search

Summary  Methyl-ISP, a newly developed organophosphorous insecticide, is used in China to treat and protect plants from pest infestation.\\u000a Our studies demonstrated that methyl-ISP is metabolized rapidly in tat and mouse. Its toxicity was low. no obvious accumulative\\u000a toxicity, chronic toxicity, teratogenicity, mutagenicity, reproductive toxicity or delayed neuirotoxicity could be observed.\\u000a It is therefore concluded that methyl-ISP is relatively safe to

Hui-qiong Wu; Zhi-wei Lai; Han-gong Xu; Rui-kun Song; Tan-geng Ma; Nian Shi; Rui-ming Liu; Yu-gu Liu

1989-01-01

117

Commentary Environmental Fate and Aquatic Toxicology Studies on  

E-print Network

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

Phthalate Esters; Edward F. Group

118

Environmental fate and aquatic toxicology studies on phthalate esters  

SciTech Connect

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.

Group, E.F. Jr.

1986-03-01

119

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

Microsoft Academic Search

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

Martin Kuentz; Peter Egloff; Dieter Röthlisberger

2006-01-01

120

Organotypic human oral tissue models for toxicological studies.  

PubMed

Three-dimensional models of the human oral epithelia have been developed to test the irritation of oral-care products and to provide systems to study the pathology of the oral cavity. The in vitro tissue models, cultured using normal oral epithelial cells and serum free medium, adopt a buccal or gingival phenotype. The buccal tissue (designated ORL-200) is 8-12 cell layers thick and non-cornified; the gingival tissue (designated GIN-100) is 9-13 layers thick and cornified at the apical surface. The tissues express cytokeratins 13 and 14 similar to their corresponding native oral tissues. The MTT viability assay was used to assess inter-lot and intra-lot reproducibility. The MTT average intra-lot coefficient of variation (CV) was less than 10% for both tissues and the time required to reduce tissue viability by 50% (ET-50) following application of 1% Triton-X 100 averaged 1.02+/-0.33 h (n=26) and 7.97+/-0.80 h (n=14) for the buccal and gingival tissues, respectively. The utility of the buccal tissue for irritation studies was examined by testing prototype dentifrice formulations and commercially available products including mouthwashes, toothpastes, and oral cleansers. Use of the MTT ET-50 assay and cytokine release clearly differentiated between the formulations and the oral care products. In conclusion, the oral tissue models represent highly reproducible, non-animal means to screen the irritation potential of newly developed oral care products and should be useful to study the innate immunity, biology, and pathology of the oral mucosa. PMID:17383851

Klausner, Mitchell; Ayehunie, Seyoum; Breyfogle, Bridget A; Wertz, Philip W; Bacca, Lori; Kubilus, Joseph

2007-08-01

121

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

NSDL National Science Digital Library

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

Niedziela, Linda

2007-01-01

122

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

PubMed

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) 39?g/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

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

2014-09-01

123

[Toxicological effects of nitrate: biological study in human and animal].  

PubMed

In order to evaluate the effects of the nitrates toxicity, a study has been carried out on 45 workers of storage and distribution agricultural manures, exposed to nitrate derivatives. Another experimental study has carried out in laboratory on male Albinos wistar rats. These latter were treated with ammonium nitrate (NH(4)NO(3)) introduced by gavage with three increasing concentrations 200, 400 and 600 mg/kg of body weight during three weeks. The biochemical and hematological results on workers showed that no poisoning was announced within this complex, in spite of the observation of kidneys inflammations among about 50% of the population. The chemical treatment of the rats causes a variation in the biochemical and biological parameters: an increase of the hepato-somatic ratio especially in the rats treated by important doses. Moreover, the serum concentration in glucose, cholesterol, creatinin, lactate dehydrogenase and in transaminases (GOT, GPT) was increased significantly compared to the witness in all the treated rats. At the end, the results obtained highlight the detoxifier potential expressed by the reduction in the glutathione level in the deferent organs such as the liver, the kidneys, the spleen, the intestines and the testicles. According to the obtained results, it can be concluded that: (1) living organism can adapt to the lows doses of nitrate for a long time. This is observed in the workers exposed to deferent derivatives of nitrates; (2) high nitrate amounts involve important biological variations even if the exposure time is short. This is proven in the laboratory animals. PMID:17627919

Boukerche, S; Aouacheri, W; Saka, S

2007-01-01

124

Characterization of Activin/BMP2 chimera, AB204, formulated for preclinical studies.  

PubMed

AB204 is an Activin/BMP2 chimera, which has been found to exhibit a higher activity than Bone Morphogenetic Protein 2 (BMP2) in osteogenic activity. To prepare AB204 for its preclinical studies, AB204 has been characterized in various formulation buffers. We observed that AB204 purified by ion-exchange chromatography has low water solubility (2.0 mg/ml), whereas it has high water solubility (higher than 10.0 mg/ml) when purified by reverse-phase chromatography. Analysis of the purification procedures reveals that the buffer composition at the lyophilization step determines the solubility. Lyophilization from sodium acetate buffer at pH 4.5 resulted in formation of sodium hydroxide, which caused low solubility of AB204 by pH increase upon reconstitution in water. However, lyophilization from buffers, containing acetic acid or trifluoroacetic acid (TFA) rendered AB204 to be highly soluble. During the course of these analyses, we found a simple procedure to further reduce residual amount of TFA in the purified AB204. PMID:24555430

Ahn, Chihoon; Maslennikov, Innokentiy; Choi, Jung Youn; Oh, Hyosun; Cheong, Chaejoon; Choe, Senyon

2014-05-01

125

Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies  

PubMed Central

Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry. PMID:16504359

Winstanley, Catharine A.; Eagle, Dawn M.; Robbins, Trevor W.

2006-01-01

126

Computed tomography-based rigidity analysis: a review of the approach in preclinical and clinical studies.  

PubMed

The assessment of fracture risk in patients afflicted with osseous neoplasms has long presented a problem for orthopedic oncologists. These patients are at risk for developing pathologic fractures through lytic defects in the appendicular and axial skeleton with devastating consequences on their quality of life. Lesions with a high risk of fracture may require prophylactic surgical stabilization, whereas low-risk lesions can be treated conservatively. Therefore, effective prevention of pathologic fractures depends on accurate assessment of fracture risk and is a critical step to avoid debilitating complications. Given the complex nature of osseous neoplasms, treatment requires a multidisciplinary approach; yet, little consensus regarding fracture risk assessment exists among physicians involved in the care of these patients. In order to improve the overall standard of care, specific criteria must be adopted to formulate consistent and accurate fracture risk predictions. However, clinicians make subjective assessments about fracture risk on plain radiographs using guidelines now recognized to be inaccurate. Osseous neoplasms alter both the material and geometric properties of bone; failure to account for changes in both of these parameters limits the accuracy of current fracture risk assessments. Rigidity, the capacity to resist deformation upon loading, is a structural property that integrates both the material and geometric properties of bone. Therefore, rigidity can be used as a mechanical assay of the changes induced by lytic lesions to the structural competency of bone. Using this principle, computed tomography (CT)-based structural rigidity analysis (CTRA) was developed and validated in a series of preclinical and clinical studies. PMID:25396051

Villa-Camacho, Juan C; Iyoha-Bello, Otatade; Behrouzi, Shohreh; Snyder, Brian D; Nazarian, Ara

2014-01-01

127

Inhalation developmental toxicology studies: Gallium arsenide in mice and rats  

SciTech Connect

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.

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

1990-12-01

128

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...

129

PRECLINICAL STUDIES A novel synthetic C-1 analogue of 7-deoxypancratistatin  

E-print Network

53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines cells. However, its availability for preclinical and clinical work is limited due to its low

Hudlicky, Tomas

130

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

PubMed Central

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

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

2012-01-01

131

Preclinical phase II study of ifosfamide in human tumour xenografts in vivo.  

PubMed

The in vivo effects of the oxazaphosphorine compound ifosfamide (IFO) on human tumour xenografts were assessed in thymus aplastic nude mice. The human origin of the tumours was confirmed by isoenzymatic and immunohistochemical methods. Tumour models were selected from a panel of 180 regularly growing, well-characterized xenografts. The maximum tolerated dose in tumour-bearing nude mice was determined to be 130 mg/kg per day given on days 1-3 and 15-17. After 21 days, lethality was 14% after i.p. and 6% after s.c. administration. A total of 43 human tumours were tested for antineoplastic activity, 15 of which (36%) showed regression: 4/5 breast cancer xenografts, 1/3 colon, 1/1 gastric, 2/7 non-small-cell lung cancers (NSCLC), 3/4 small-cell lung cancers (SCLC), 1/2 sarcomas and 3/3 testicular cancers. Two ovarian, two uterine and six renal cancer xenografts as well as three melanomas and five tumours of various histologies were resistant. In 30 human tumour xenografts, the antineoplastic efficacy of the two oxazaphosphorine derivatives cyclophosphamide and IFO was compared. The maximum tolerated dose of cyclophosphamide was 200 mg/kg per day given i.p. on days 1 and 15; it led to 17% lethality after 21 days. Cyclophosphamide induced tumour regression or remission in 10/30 xenografts (33%) and IFO in 13/30 (43%). In conclusion, the observed efficacy of IFO parallels the clinical situation. Breast, lung and testicular cancer and sarcomas proved to be responsive. The antitumoural activity of IFO shows similarities to that of cyclophosphamide; however, a higher response rate and lower toxicity were noted for the former. Preclinical phase II studies in nude mice seem to offer an effective way of identifying active drugs as well as sensitive tumour types for further clinical development. PMID:2347054

Berger, D P; Fiebig, H H; Winterhalter, B R; Wallbrecher, E; Henss, H

1990-01-01

132

The toxicological evaluation of realistic emissions of source aerosols study: statistical methods.  

PubMed

The Toxicological Evaluation of Realistic Emissions of Source Aerosols (TERESA) study involved withdrawal, aging, and atmospheric transformation of emissions of three coal-fired power plants. Toxicological evaluations were carried out in rats exposed to different emission scenarios with extensive exposure characterization. Data generated had multiple levels of resolution: exposure, scenario, and constituent chemical composition. Here, we outline a multilayered approach to analyze the associations between exposure and health effects beginning with standard ANOVA models that treat exposure as a categorical variable. The model assessed differences in exposure effects across scenarios (by plant). To assess unadjusted associations between pollutant concentrations and health, univariate analyses were conducted using the difference between the response means under exposed and control conditions and a single constituent concentration as the predictor. Then, a novel multivariate analysis of exposure composition and health was used based on Random Forests(™), a recent extension of classification and regression trees that were applied to the outcome differences. For each exposure constituent, this approach yielded a nonparametric measure of the importance of that constituent in predicting differences in response on a given day, controlling for the other measured constituent concentrations in the model. Finally, an R(2) analysis compared the relative importance of exposure scenario, plant, and constituent concentrations on each outcome. Peak expiratory flow (PEF) is used to demonstrate how the multiple levels of the analysis complement each other to assess constituents most strongly associated with health effects. PMID:21913820

Coull, Brent A; Wellenius, Gregory A; Gonzalez-Flecha, Beatriz; Diaz, Edgar; Koutrakis, Petros; Godleski, John J

2011-08-01

133

Uses of available record systems in epidemiologic studies of reproductive toxicology  

SciTech Connect

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.

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

1983-01-01

134

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

PubMed

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. PMID:6220602

Polednak, A P; Janerich, D T

1983-01-01

135

DTP | Toxicology and Pharmacology Branch (TPB)  

Cancer.gov

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

136

Preclinical, phase I and pharmacokinetic studies with the dimethyl phenyltriazene CB10-277.  

PubMed Central

Decarbazine is an imidazole dimethyltriazene with reproducible activity in patients with metastatic melanoma. CB10-277 is a phenyl dimethyltriazene which, like dacarbazine, requires metabolic activation to its corresponding monomethyl species for antitumour activity. In preclinical models (human melanoma xenografts and transplantable rodent tumours) CB10-277 showed a similar spectrum and level of activity when compared to dacarbazine. Pharmacokinetic studies were performed with CB10-277 in mice treated i.v. at the LD10 (750 mg m-2) and plasma analysed by HPLC. The parent drug area under the plasma concentration vs time curve (AUC) was 142 mM x minutes. Drug metabolism occurred as evidenced by the HPLC identification of the monomethyl species (AUC = 8 mM x minutes) as well as other metabolites. A Phase I trial using a short infusion with doses repeated every 21 days has been performed. Thirty-six patients received 80 courses over a dose range of 80-6,000 mg m-2. The dose limiting toxicity was nausea and vomiting which occurred in 80% of the evaluable courses > or = 900 mg m-2. The only other common side effect was a flushing or warm sensation, which occurred in over 75% of courses at > or = 1,350 mg m-2. There were no hemodynamic consequences. Responses occurred in patients with melanoma (one complete, two partial, one mixed/11), sarcoma (one mixed/6) and carcinoid (one partial/l). Pharmacokinetics were performed in 46 courses. The CB10-277 AUC increased linearly with dose (r = 0.9203, P < 0.001) up to 700 mM x minutes at 6,000 mg m-2). Evidence of CB10-277 metabolism was observed, as in mice, by detection of the monomethyl species and other metabolites. However, the plasma levels of the monomethyl species in patients (1.8 and 3.7 mM x minutes at 6,000 mg m-2) were less than those predicted from studies in mice. Despite this, antitumour activity in dacarbazine sensitive histologies was observed and additional studies with CB10-277 are recommended. PMID:8431367

Foster, B. J.; Newell, D. R.; Carmichael, J.; Harris, A. L.; Gumbrell, L. A.; Jones, M.; Goodard, P. M.; Calvert, A. H.

1993-01-01

137

Radiopaque contrast media. XLIV - Preclinical studies with a new nonionic contrast agent.  

PubMed

L-5-alpha-hydroxypropionylamino-2,4,6-triiodoisophthalic acid di-(1,3-dihydroxy-2-propylamide), abbreviated Iopamidol, a new non-ionic water soluble contrast agent for angiography, myelography, ventriculography and for contrast reinforced computer-assisted axial tomography is described. Extensive preclinical testing showed favorable physico-chemical features of the new compound, low systemic toxicity, excellent cardiovascular and renal tolerability, very mild effects on the blood-brain barrier and on nervous tissue. PMID:923795

Felder, E; Pitrè, D; Tirone, P

1977-11-01

138

Temple study's pre-clinical data shows Angiocidin effective against leukemia  

Cancer.gov

Angiocidin, a novel tumor-inhibiting protein, has been shown to reduce acute myeloid leukemia (AML) cells in mice by almost two-thirds in pre-clinical experiments. A researcher from Temple University’s School of Medicine who discovered Angiocidin, presented the findings during the American Society of Hematology’s national meeting in Atlanta on Dec. 9. Temple University is home to the Fox Chase Cancer Center.

139

The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates.  

PubMed

Toxicity is a leading cause of attrition at all stages of the drug development process. The majority of safety-related attrition occurs preclinically, suggesting that approaches to identify 'predictable' preclinical safety liabilities earlier in the drug development process could lead to the design and/or selection of better drug candidates that have increased probabilities of becoming marketed drugs. In this Review, we discuss how the early application of preclinical safety assessment--both new molecular technologies as well as more established approaches such as standard repeat-dose rodent toxicology studies--can identify predictable safety issues earlier in the testing paradigm. The earlier identification of dose-limiting toxicities will provide chemists and toxicologists the opportunity to characterize the dose-limiting toxicities, determine structure-toxicity relationships and minimize or circumvent adverse safety liabilities. PMID:17643090

Kramer, Jeffrey A; Sagartz, John E; Morris, Dale L

2007-08-01

140

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

NASA Astrophysics Data System (ADS)

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.

Meißner, Tobias; Oelschlägel, Kathrin; Potthoff, Annegret

2014-08-01

141

Ovarian toxicity and carcinogenicity in eight recent national toxicology program studies  

SciTech Connect

Ovarian toxicity and/or carcinogenicity has been documented for at least eight chemicals recently tested in National Toxicity Program prechronic and chronic rodent studies. The chemicals that yielded treatment-related ovarian lesions were 1,3-butadiene, 4-vinylcyclohexene, vinylcylohexene deipoxide, nitrofurantoin, nitrofurazone, benzene, ..delta..-9-tetrahydrocannabinol, and tricresylphosphate. Typical nonneoplastic ovarian changes included hypoplasia, atrophy, follicular necrosis, and tubular hyperplasia. The most commonly observed treatment-related neoplasms were granulosa cell tumors and benign mixed tumors. A relationship between antecedent ovarian hypoplasia, atrophy, and hyperplasia and subsequent ovarian neoplasia is supported by some of these National Toxicology Program studies. Pathologic changes in other tissues such as the adrenal glands and uterus were associated with the treatment-related ovarian changes.

Maronpot, R.R.

1987-08-01

142

Cognition and beta-amyloid in preclinical Alzheimer's disease: data from the AIBL study.  

PubMed

The 'preclinical' phase of Alzheimer's disease is a future target for treatment, but additional research is essential to understand the relationship between ?-amyloid burden and cognition during this time. We investigated this relationship using a large sample of apparently healthy older adults (N=177), which also enabled examination of whether the relationship differed according to age, gender, years of education, apolipoprotein E status, and the presence of subjective memory complaints. In addition to episodic memory, a range of cognitive measures (global cognition, semantic memory, visuospatial performance, and executive function) were examined. Participants were aged over 60 years with no objective cognitive impairment and came from the imaging arm of the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study of ageing. (11)C-PiB PET was used to measure ?-amyloid burden and a PiB 'cut-off' level of 1.5 was used to separate participants with low PiB retention from those with high PiB retention. Thirty-three percent of participants had a PiB positive scan. PiB positive participants were 5 years older, twice as likely to carry an apolipoprotein E ?4 allele, and their composite episodic memory was 0.26 SD worse than PiB negative volunteers. Linear regressions with ?-amyloid burden as a dichotomous predictor, revealed an interaction between ?-amyloid burden and gender, as well as age and education effects, in predicting episodic memory and visuospatial performance. In females, but not in males, increased ?-amyloid was related to worse episodic memory and visuospatial performance. Furthermore, an interaction between ?-amyloid burden and APOE status was found in predicting visuospatial performance, whereby there was a trend for increased ?-amyloid to relate to worse visuospatial performance for those without an APOE ?4 allele. There were no other main or interaction effects of ?-amyloid on any of the other composite cognitive measures. These cross-sectional findings suggest that ?-amyloid burden does not have a large effect on cognition in this subset of apparently healthy older people. The finding of gender differences deserves further research to answer definitively the important question of gender susceptibility to adverse cognitive effects from ?-amyloid. PMID:21529702

Pike, Kerryn E; Ellis, Kathryn A; Villemagne, Victor L; Good, Norm; Chételat, Gael; Ames, David; Szoeke, Cassandra; Laws, Simon M; Verdile, Giuseppe; Martins, Ralph N; Masters, Colin L; Rowe, Christopher C

2011-07-01

143

Cell-Seeded Tubularized Scaffolds for Reconstruction of Long Urethral Defects: A Preclinical Study  

PubMed Central

Background The treatment options for patients requiring repair of a long segment of the urethra are limited by the availability of autologous tissues. We previously reported that acellular collagen-based tubularized constructs seeded with cells are able to repair small urethral defects in a rabbit model. Objective We explored the feasibility of engineering clinically relevant long urethras for surgical reconstruction in a canine preclinical model. Design, setting, and participants Autologous bladder epithelial and smooth muscle cells from 15 male dogs were grown and seeded onto preconfigured collagen-based tubular matrices (6 cm in length). The perineal urethral segment was removed in 21 male dogs. Urethroplasties were performed with tubularized collagen scaffolds seeded with cells in 15 animals. Tubularized constructs without cells were implanted in six animals. Serial urethrography and three-dimensional computed tomography (CT) scans were performed pre- and postoperatively at 1, 3, 6, and 12 mo. The animals were euthanized at their predetermined time points (three animals at 1 mo, and four at 3, 6, and 12 mo) for analyses. Outcome measurements and statistical analysis Statistical analysis of CT imaging and histology was not needed. Results and limitations CT urethrograms showed wide-caliber urethras without strictures in animals implanted with cell-seeded matrices. The urethral segments replaced with acellular scaffolds collapsed. Gross examination of the urethral implants seeded with cells showed normal-appearing tissue without evidence of fibrosis. Histologically, an epithelial cell layer surrounded by muscle fiber bundles was observed on the cell-seeded constructs, and cellular organization increased over time. The epithelial and smooth muscle phenotypes were confirmed using antibodies to pancytokeratins AE1/AE3 and smooth muscle–specific desmin. Formation of an epithelial cell layer occurred in the unseeded constructs, but few muscle fibers formed. Conclusions Cell-seeded tubularized collagen scaffolds can be used to repair long urethral defects, whereas scaffolds without cells lead to poor tissue development and strictures. This study demonstrates that long tissue-engineered tubularized urethral segments may be used for urethroplasty in patients. PMID:22877501

Orabi, Hazem; AbouShwareb, Tamer; Zhang, Yuanyuan; Yoo, James J.; Atala, Anthony

2012-01-01

144

Attempted and Successful Compensation in Preclinical and Early Manifest Neurodegeneration – A Review of Task fMRI Studies  

PubMed Central

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

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

2014-01-01

145

Spaceflight Toxicology  

NASA Technical Reports Server (NTRS)

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.

Meyers, Valerie

2008-01-01

146

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

PubMed

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

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

2009-12-13

147

Toxicological and epidemiological studies on effects of airborne fibers: coherence and pubic health implications.  

PubMed

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

Lippmann, Morton

2014-09-01

148

ToxGuides: Quick Reference Pocket Guide for Toxicological Profiles  

MedlinePLUS

... and Training Case Studies in Environmental Medicine (CSEM) Toxicology Curriculum for Communities Trainer's Manual Toxicological and Health ... ToxGuides™ were developed by the ATSDR Division of Toxicology and and Human Health Sciences. Information is excerpted ...

149

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 ...

150

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...

151

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...

152

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

PubMed Central

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

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

2012-01-01

153

Toxicological studies on Thermomyces lanuginosus xylanase expressed by Fusarium venenatum, intended for use in food.  

PubMed

The xylanase used in this study was produced by a submerged fermentation of Fusarium venenatum and contained a gene code originating from Thermomyces lanuginosus. The enzyme was subject to a 13-week toxicological test in rats and in vitro tests to document its safety in use. The enzyme is to be applied as a processing aid in the baking industry to improve handling and stability of dough. The enzyme was not found to be mutagenic in the Salmonella typhimurium reverse mutation assay, nor did it cause chromosomal aberrations in cultured human lymphocytes. Oral administration to rats of up to 10.0 ml/kg bw/day (equivalent to a Total Organic Solids dosage of 1.12 g/kg bw/day or a xylanase dosage of 89422 FXU (W)/kg bw/day) for 13 weeks did not cause any adverse effect. PMID:11091786

Pedersen, P B; Broadmeadow, A

2000-09-01

154

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

NASA Astrophysics Data System (ADS)

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.

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

2009-06-01

155

The role of the toxicologic pathologist in the biopharmaceutical industry.  

PubMed

Toxicologic pathologists contribute significantly to the development of new biopharmaceuticals, yet there is often a lack of awareness of this specialized role. As the members of multidisciplinary teams, toxicologic pathologists participate in all aspects of the drug development process. This review is part of an initiative by the Society of Toxicologic Pathology to educate scientists about toxicologic pathology and to attract junior scientists, veterinary students, and veterinarians into the field. We describe the role of toxicologic pathologists in identifying candidate agents, elucidating bioactive pathways, and evaluating efficacy and toxicity in preclinical animal models. Educational and specialized training requirements and the challenges of working in a global environment are discussed. The biopharmaceutical industry provides diverse, challenging, and rewarding career opportunities in toxicologic pathology. We hope that this review promotes understanding of the important role the toxicologic pathologist plays in drug development and encourages exploration of an important career option. PMID:21878555

van Tongeren, Susan; Fagerland, Jane A; Conner, Michael W; Diegel, Kelly; Donnelly, Kevin; Grubor, Branka; Lopez-Martinez, Alric; Bolliger, Anne Provencher; Sharma, Alok; Tannehill-Gregg, Sarah; Turner, Patricia V; Wancket, Lyn M

2011-10-01

156

Recent studies in the behavioral toxicology of ELF electric and magnetic fields  

SciTech Connect

Behavioral responses to ELF electric and magnetic fields are reviewed starting with the simple sensory awareness or detection by an animal and moving on through more-complicated behavioral responses such as behavior that averts exposure. The literature selected in this review is taken primarily from the area of behavioral toxicology. As such, it does not review work on specialized response systems to ELF fields. The most notable of these omitted specialized response systems are electroreception, which occurs in a number of fish species, and homing/navigation and communication of the location of food that occurs in several species of birds and in honeybees, respectively. The toxicologic orientation of most researches that evaluate the effects of exposure to ELF electric and magnetic fields has been influenced primarily by the missions of DOE and the power industry programs to determine the health effects of power frequency (50- and 60-Hz) electric and magnetic fields. Because of these large programmatic efforts, most of the recent research has in fact been done at 50 or 60 Hz. In the context of the above limitations, remarkably few robust behavioral effects have been reported. Those that have been reported probably relate to an animal's perception of the electric field, although there are some exceptions to this generalization. The apparent lack of deleterious effects in animals is consistent with recent studies on humans that have been conducted in the UK. With this in mind, it is tempting to conclude that exposure to an ELF field is a rather innocuous event and, other than possible mini-shocks, is without hazard. 43 references.

Lovely, R.H.

1988-01-01

157

Inhalation toxicology.  

PubMed

Inhalation of gases, vapors and aerosols can cause a wide range of adverse health effects, ranging from simple irritation to systemic diseases. The large number of chemicals and complex mixtures present in indoor and outdoor air coupled with the introduction of new materials such as nanoparticles and nanofibers, is an area of growing concern for human health. Animal-based assays have been used to study the toxic effects of chemicals for many years. However, even so, very little is known about the potential toxicity of the vast majority of inhaled chemicals. As well as new or refined OECD test guidelines, continuing scientific developments are needed to improve the process of safety evaluation for the vast number of chemicals and inhaled materials. Although studying the toxic effects of inhaled chemicals is more challenging, promising in vitro exposure techniques have been recently developed that offer new possibilities to test biological activities of inhaled chemicals under biphasic conditions at the air liquid interface. This chapter gives an overview of inhalation toxicology as well as focusing on the potential application of in vitro methods for toxicity testing of airborne pollutants. PMID:20358692

Hayes, Amanda; Bakand, Shahnaz

2010-01-01

158

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

PubMed

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

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

2013-09-26

159

A tumor-mimic model for evaluating the accuracy of HIFU preclinical studies: an in vivo study.  

PubMed

To date, the efficacy of ablative technologies such as HIFU for the treatment of liver tumors in humans has been studied in animal models without tumors or in small animals like rats and rabbits with established tumors. Because of the small size of these animals, the lesion produced by HIFU devices has to be small. Thus, the local and systemic effects of the treatment as encountered in humans cannot be studied. The purpose of this study was to use an in vivo tumor-mimic model to evaluate the accuracy of HIFU ablation in the liver in preclinical studies. Tumor mimics were created in in vivo porcine livers by injecting a 1-cc warm mixture of agarose, cellulose, glycerol and methylene blue, which formed 1-cm hyperechoic discrete lesions on sonograms. Three studies were carried out: (i) in vitro experiments were conducted to study the acoustical proprieties of the tumor mimics; (ii) in vivo experiments were conducted in 10 pigs to evaluate the tolerance of the tumor mimics when injected in the liver; (iii) ultrasound-guided HIFU ablation was performed in 10 pigs to demonstrate that it is possible to treat a predetermined zone accurately. It was shown that the acoustical properties of tumor mimics are visible in sonograms and do not modify the shape and dimensions of HIFU lesions. The local and biological tolerance of tumor mimics was excellent. In addition, it was demonstrated that the average difference between the predetermined location of the HIFU ablation and the actual coagulated area was 32%. Therefore, this tumor mimic can be used to teach HIFU ablation before starting clinical studies, especially if the ultrasound device is to be used manually, as the one presented in this study was. PMID:18002762

N'Djin, W A; Melodelima, D; Parmentier, H; Rivoire, M; Chapelon, J Y

2007-01-01

160

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

PubMed Central

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

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

2010-01-01

161

Regulatory toxicology considerations for the development of inhaled pharmaceuticals.  

PubMed

The preclinical safety studies required to support the development of inhaled drugs are generally the same as for other routes of administration. Repeat-dose toxicology studies should be conducted by inhalation to ensure the characterization of both the local (i.e., respiratory) and systemic toxicity, although some studies (e.g., reproductive) can be performed by utilizing alternative routes, when it is paramount to maximize systemic exposure. Respiratory tract changes in preclinical species can include irritancy of the larynx and nasal cavity, particularly in rodents. Such changes are not necessarily predictive of a risk to humans because of the exquisite sensitivity of the rodent larynx and the lack of exposure to the nasal cavity after oro-inhalation of drugs in the clinical setting. The design of poorly soluble molecules to limit systemic exposure places greater emphasis on the elimination of drugs from the lungs by macrophages. Consequently, an increase in macrophage numbers is often noted, and in the absence of any other changes, this is generally considered to be a nonadverse, physiological response to an inhaled particulate. Other changes in the lung, which can include an inflammatory response and/or epithelial hyperplasia, resulting from irritancy or particulate overload, are a safety concern and are not monitorable in humans. For such changes, safety margins can be calculated in terms of the drug deposited per unit weight of lung. These factors should be taken into account when designing preclinical studies or programs for inhaled drugs. PMID:22273711

Owen, Keith

2013-01-01

162

Advances in reproductive toxicology  

SciTech Connect

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.

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

1992-06-01

163

Toward better research practice-Shortcomings decreasing the significance of epidemiological studies in the toxicological field.  

PubMed

Neurobehavioral studies do not always gain the impact they should have, neither in the scientific nor in the regulatory field of neurotoxicology. Among others, shortcomings and inconsistencies across epidemiological studies may contribute to this situation. Examples were compiled to increase awareness of obstacles for conclusions. Meta-analyses were exploited since they sometimes allow the detection of deficits that are not obvious from individual studies. Exposure assessment, performance measures, and confounding were scrutinized among 98 primary studies included in meta-analyses on mercury, solvents, manganese and pesticides. Inconsistent and hardly comparable markers of exposure were found; figures, units or sampling periods were not always provided. The contribution of test materials to differences in test outcomes across studies could sometimes not be evaluated due to the insufficient description of the employed tests. Hypotheses for the selection of performance variables often remained undisclosed. Matching procedures prevailed with respect to the confounder age; the comparability of groups with respect to intelligence and gender remained more elusive. 8% and 16% of the studies did not even mention confounding from intelligence and gender, respectively. Only one third of the studies provided adjusted means for group comparisons; the proportion was slightly larger for studies published 2000-2010. While 50% of the studies considered confounders for their dose-response assessment, only 29% reported results for the total of test variables. The outlined deficits impede, among others, the assessment of exposure-effect relationships and confounding across studies; thereby they limit the use of the studies for toxicological risk assessment and future prevention. Some shortcomings also impede a deeper insight into the mechanisms of toxicity: tests like the Digit Symbol show that something is affected, but not what is affected. Thorough description of measures employed is among the first consequences from the data. The consideration of mechanistic insights from research on animals and neurobiology may further help to increase the significance of epidemiological studies. PMID:24657405

Meyer-Baron, Monika; Schäper, Michael; van Thriel, Christoph

2014-12-01

164

Toxicological study of pesticides in air and precipitations of Paris by means of a bioluminescence method.  

PubMed

A detailed toxicological study on several pesticides, including chlorothalonil, cyprodynil, dichlobénil, pendimethaline, trifluraline, and alpha-endosulfan, present at trace levels in air and total atmospheric precipitations of Paris is presented. The pesticides contained in the atmospheric samples, collected during sampling campaigns in February-March 2007, are identified and quantified by a high-performance liquid chromatographic (HPLC)-UV detection method. The toxicity measurements are performed by means of the Microtox bioluminescence method, based on the evaluation of the bioluminescence inhibition of the Vibrio fischeri marine bacteria at two exposure times to the pesticide solutions. The specific toxicity, corresponding to the particular toxicity of the compound under study and represented by the EC(50) parameter, is determined for these pesticides. Also, the global toxicity, which is the toxicity of all micro-pollutants present in the sample under study, is estimated for the extracts of air and atmospheric precipitation (rainwater) samples. The specific toxicities strongly vary with the nature of the pesticide, the EC(50) parameter values being comprised between 0.17 and 0.83 mg/mL and 0.15 and 0.66 mg/mL, respectively, for exposure times of 5 and 15 min. The importance of the atmospheric samples' global toxicity and the respective contribution of the toxic potency of the various pesticides contained in these samples are discussed. PMID:19387620

Trajkovska, S; Mbaye, M; Gaye Seye, M D; Aaron, J J; Chevreuil, M; Blanchoud, H

2009-06-01

165

BAYESIAN SEMIPARAMETRIC ANALYSIS OF DEVELOPMENTAL TOXICOLOGY DATA  

E-print Network

BAYESIAN SEMI­PARAMETRIC ANALYSIS OF DEVELOPMENTAL TOXICOLOGY DATA Francesca Dominici Department­response data, with application to developmental toxicology experiments. We model the relationship between dose for developmental toxicology studies. The model combines a parametric form for the dose­response relation

West, Mike

166

Molecular Toxicology Undergraduate Student Learning Goals  

E-print Network

Molecular Toxicology Undergraduate Student Learning Goals Brief Overview of the Intent of the Major Program Molecular toxicology is the mechanism based study of the adverse effects of chemicals on living. This major provides education and training in the field of molecular toxicology and produces graduates

Wildermuth, Mary C

167

A comparative toxicologic and genotoxic study of the herbicide arsenal, its active ingredient imazapyr, and the surfactant nonylphenol ethoxylate.  

PubMed

The herbicide arsenal 250 NA, its technical-grade active ingredient imazapyr, and the surfactant nonylphenol ethoxylate (NP) were evaluated through genotoxicity and toxicity studies in different organisms. A comparative study of these three compounds was carried out to assess how the addition of surfactant components may pose the highest toxicological risk to pesticide formulations. The results showed that arsenal, imazapyr, and NP did not cause chromosome aberration in Allium cepa nor increase the frequency of micronuclei in mice. However, toxicological evaluations showed that NP was the most toxic compound to mice, A. cepa, Drosophila melanogaster, and Biomphalaria tenagophila. In this evaluation, it was observed that the adverse effects were produced by the surfactant additive of the pesticide formulation. PMID:15261733

Grisolia, Cesar Koppe; Bilich, Marina Rolim; Formigli, Lia Menezes

2004-09-01

168

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

PubMed

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

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

2014-03-01

169

Mouse and large-animal toxicology studies of twelve antitumor agents: Relevance to starting dose for Phase I clinical trials  

Microsoft Academic Search

Large-animal toxicology is presently used to establish a starting dose for clinical trials with new cancer chemotherapeutic agents. The relevance of dog, monkey, and mouse data for Phase I clinical trials has been retrospectively analyzed with twelve diverse agents (chlorozotocin, maytansine, anguidine, tritylcysteine, piperazinedione, Baker's antifol, thalicarpine, 3-deazauridine, gallium nitrate, cis-dichlorodiammineplatinum(II) (DDP), 4'-(9-acridinylamino)methanesulfon-manisidide (AMSA), and N-phosphonacetyl-l-aspartic acid (PALA). Schedules studied

J. S. Penta; M. Rozencweig; A. M. Guarino; F. M. Muggia

1979-01-01

170

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

PubMed

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

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

171

Toxicological studies on Polyporus pinsitus laccase expressed by Aspergillus oryzae intended for use in food.  

PubMed

The laccase used in the study was produced by submerged fermentation of Aspergillus oryzae, containing a gene originating from Polyporus pinsitus. Laccase is to be employed as a processing aid in the juice industry to make a clear and stable juice. The enzyme was subject to a series of toxicological tests to document its safety in use. It was not mutagenic in the Salmonella typhimurium reverse mutation assay, and it did not cause chromosomal aberrations in cultured human lymphocytes. No evidence of inhalation toxicity or skin and eye irritation was found. Oral administration to rat of up to 10 ml kg(-1) b.w. day(-1) (equivalent to a total organic solids dosage of 676 mg kg(-1) b.w. day(-1) or a laccase dosage of 2601 LACU kg(-1) b.w. day(-1)) for 13 weeks did not cause any adverse effect. The maximum recommended dosage of laccase used for juice applications is 50 LACU l(-1) juice. PMID:11962689

Brinch, D S; Pedersen, P B

2002-04-01

172

Optimal designs for discriminating between dose-response models in toxicology studies  

E-print Network

We consider design issues for toxicology studies when we have a continuous response and the true mean response is only known to be a member of a class of nested models. This class of non-linear models was proposed by toxicologists who were concerned only with estimation problems. We develop robust and efficient designs for model discrimination and for estimating parameters in the selected model at the same time. In particular, we propose designs that maximize the minimum of $D$- or $D_1$-efficiencies over all models in the given class. We show that our optimal designs are efficient for determining an appropriate model from the postulated class, quite efficient for estimating model parameters in the identified model and also robust with respect to model misspecification. To facilitate the use of optimal design ideas in practice, we have also constructed a website that freely enables practitioners to generate a variety of optimal designs for a range of models and also enables them to evaluate the efficiency of ...

Dette, Holger; Shpilev, Piter; Wong, Weng Kee; 10.3150/10-BEJ257

2010-01-01

173

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

PubMed

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

Manolagas, Stavros C; Kronenberg, Henry M

2014-10-01

174

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

PubMed

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

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

2015-02-01

175

Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice.  

PubMed

Preclinical studies of enzyme-replacement therapy for Fabry disease (deficient alpha-galactosidase A [alpha-Gal A] activity) were performed in alpha-Gal A-deficient mice. The pharmacokinetics and biodistributions were determined for four recombinant human alpha-Gal A glycoforms, which differed in sialic acid and mannose-6-phosphate content. The plasma half-lives of the glycoforms were approximately 2-5 min, with the more sialylated glycoforms circulating longer. After intravenous doses of 1 or 10 mg/kg body weight were administered, each glycoform was primarily recovered in the liver, with detectable activity in other tissues but not in the brain. Normal or greater activity levels were reconstituted in various tissues after repeated doses (10 mg/kg every other day for eight doses) of the highly sialylated AGA-1 glycoform; 4 d later, enzyme activity was retained in the liver and spleen at levels that were, respectively, 30% and 10% of that recovered 1 h postinjection. Importantly, the globotriaosylceramide (GL-3) substrate was depleted in various tissues and plasma in a dose-dependent manner. A single or repeated doses (every 48 h for eight doses) of AGA-1 at 0.3-10.0 mg/kg cleared hepatic GL-3, whereas higher doses were required for depletion of GL-3 in other tissues. After a single dose of 3 mg/kg, hepatic GL-3 was cleared for > or =4 wk, whereas cardiac and splenic GL-3 reaccumulated at 3 wk to approximately 30% and approximately 10% of pretreatment levels, respectively. Ultrastructural studies demonstrated reduced GL-3 storage posttreatment. These preclinical animal studies demonstrate the dose-dependent clearance of tissue and plasma GL-3 by administered alpha-Gal A, thereby providing the in vivo rationale-and the critical pharmacokinetic and pharmacodynamic data-for the design of enzyme-replacement trials in patients with Fabry disease. PMID:11115376

Ioannou, Y A; Zeidner, K M; Gordon, R E; Desnick, R J

2001-01-01

176

Postmortem toxicology of carbamazepine.  

PubMed

The study focuses on a series of 16 fatal cases in which carbamazepine and its two major metabolites (10,11-epoxide and 10,11-dihydroxycarbamazepine) were detected in body fluids and tissues collected at autopsy. The drug may be implicated in a number of deaths; however, most of these are multiple-drug intoxications with a particular contribution of ethanol. The investigations concerning toxicological findings are a source of toxicological postmortem data and show the differences in metabolism rate as depending on the concentration level of carbamazepine and xenobiotics found in the autopsy specimen during the postmortem investigation of a body. PMID:12820747

Klys, Malgorzata; Bystrowska, Beata; Bujak-Gizycka, Beata

2003-01-01

177

A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies.  

PubMed

The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confidence interval. In this way, the new proposed method demonstrates to be as useful as WinNonlin® software when it was applicable. PMID:21268234

Navarro-Fontestad, Carmen; González-Álvarez, Isabel; Fernández-Teruel, Carlos; Bermejo, Marival; Casabó, Vicente Germán

2012-01-01

178

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

PubMed

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

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

2014-01-01

179

Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies  

PubMed Central

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

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

2014-01-01

180

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

SciTech Connect

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.

Bellward, G.D. [Univ. of British Columbia, Vancouver, British Columbia (Canada)

1995-12-31

181

Analytical toxicology  

Microsoft Academic Search

\\u000a This paper reviews procedures for screening, identification and quantification of drugs, poisons and their metabolites in\\u000a biosamples, and the corresponding work-up procedures. Gas chromatography-mass spectrometry and liquid chromatography-mass\\u000a spectrometry are mostly used today in analytical toxicology. Selection of the most appropriate biosample, e.g., ante\\/postmortem\\u000a blood, urine, or tissues or alternative matrices like hair, sweat and oral fluid, nails or meconium,

Hans H. Maurer

182

Forensic toxicology  

Microsoft Academic Search

\\u000a Forensic toxicology has developed as a forensic science in recent years and is now widely used to assist in death investigations,\\u000a in civil and criminal matters involving drug use, in drugs of abuse testing in correctional settings and custodial medicine,\\u000a in road and work-place safety, in matters involving environmental pollution, as well as in sports doping. Drugs most commonly\\u000a targeted

Olaf H. Drummer

183

Toxicology: Statistical perspectives  

Microsoft Academic Search

Toxicity abounds in nature, environment, and in our modern life-style. Toxicology relates to the study of the intake process of such toxins by human being, their mode of propagation, biological reactions, molecular level of penetration, genotoxicity and afte rmaths. Because of the latent nature of a large class of toxic substances, the extreme variability of human metabo- lism as well

Pranab Kumar Sen

2001-01-01

184

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...

185

GRADUATE GROUP MOLECULAR TOXICOLOGY  

E-print Network

GRADUATE GROUP IN MOLECULAR TOXICOLOGY 2013 - 2014 University of California, Berkeley #12;#12;General Information The Interdepartmental Graduate Group in Molecular Toxicology administers the Ph units on the Berkeley campus including Molecular and Cell Biology, Nutritional Sciences and Toxicology

186

Toxicology 1: Toxicology and Living Systems  

NSDL National Science Digital Library

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

American Association for the Advancement of Science (;)

2005-06-13

187

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

PubMed Central

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

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

1999-01-01

188

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

SciTech Connect

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

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

2013-10-15

189

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

PubMed

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

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

2014-11-01

190

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

PubMed Central

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 µg/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

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

2013-01-01

191

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

PubMed

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

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

2014-09-10

192

Genetic toxicology.  

PubMed

Systems for testing genetic toxicology are components of carcinogenic and genetic risk assessment. Present routine genotoxicity-testing is based on at least 20 years of development during which many different test systems have been introduced and used. Today, it is clear that no single test is capable of detecting all genotoxic agents. Therefore, the usual approach is to perform a standard battery of in-vitro and in-vivo tests for genotoxicity. Work-groups of the European Union (EU), the Organization for Economic Co-operation and Development (OECD), and, very recently, the work-group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have defined such standard battery tests. These and some currently used supplementary or confirmatory tests are briefly discussed here. Additional test systems for the assessment of genotoxic and carcinogenic hazard and risk are seriously needed. These tests must be more relevant to man than are current assays and less demanding in respect of cost, time and number of animals. Another aspect for reassessment derives from the actual situation in the pharmaceutical industry. Companies have to prepare for the world economy of the 21st century. Therefore, pharmaceutical research is speeding up tremendously by use of tools such as genomics, combinatorial chemistry, high throughput screening and proteomics. Toxicology and genotoxicology need to re-evaluate their changing environment and must find ways to respond to these needs. In conclusion, genetic toxicology needs to answer questions coming from two major directions: hazard and risk identification and high throughput testing. PMID:9625484

Kramer, P J

1998-04-01

193

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

E-print Network

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

Ullrich, Paul

194

Analytical toxicology.  

PubMed

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

Maurer, Hans H

2010-01-01

195

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. ...

196

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

PubMed Central

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

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

2013-01-01

197

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

PubMed Central

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

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

2014-01-01

198

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

PubMed

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

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

2014-10-01

199

A review of treatment planning for precision image-guided photon beam pre-clinical animal radiation studies.  

PubMed

Recently, precision irradiators integrated with a high-resolution CT imaging device became available for pre-clinical studies. These research platforms offer significant advantages over older generations of animal irradiators in terms of precision and accuracy of image-guided radiation targeting. These platforms are expected to play a significant role in defining experiments that will allow translation of research findings to the human clinical setting. In the field of radiotherapy, but also others such as neurology, the platforms create unique opportunities to explore e.g. the synergy between radiation and drugs or other agents. To fully exploit the advantages of this new technology, accurate methods are needed to plan the irradiation and to calculate the three-dimensional radiation dose distribution in the specimen. To this end, dedicated treatment planning systems are needed. In this review we will discuss specific issues for precision irradiation of small animals, we will describe the workflow of animal treatment planning, and we will examine several dose calculation algorithms (factorization, superposition-convolution, Monte Carlo simulation) used for animal irradiation with kilovolt photon beams. Issues such as dose reporting methods, photon scatter, tissue segmentation and motion will also be discussed briefly. PMID:24629309

Verhaegen, Frank; van Hoof, Stefan; Granton, Patrick V; Trani, Daniela

2014-12-01

200

Space Toxicology  

NASA Technical Reports Server (NTRS)

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.

James, John T.

2011-01-01

201

SPONTANEOUS OCCURRENCE OF A DISTINCTIVE RENAL TUBULE TUMOR PHENOTYPE IN RAT CARCINOGENICITY STUDIES CONDUCTED BY THE NATIONAL TOXICOLOGY PROGRAM (NTP)  

PubMed Central

The Toxicology Data Management System (TDMS) of the National Toxicology Program, NIEHS, NIH, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound. PMID:18441261

Hard, Gordon C; Seely, John Curtis; Kissling, Grace E; Betz, Laura J

2010-01-01

202

Pasteurization of bone for tumour eradication prior to reimplantation – An in vitro & pre-clinical efficacy study  

PubMed Central

Background & objectives: In current era of limb-salvage therapy, pasteurization of bone sarcomas is receiving growing attention as a potential extracorporeal treatment and cost-effective alternative to allografts and radiation before surgical reimplantation. Detailed in vitro and in vivo pre-clinical study to evaluate efficacy of pasteurization to eradicate malignant cells has not been reported yet. The present study was carried out to assess the efficacy of pasteurization to kill tumour cells both in vitro and in vivo. Methods: Surgically resected specimens of osteosarcomas (n=4) were cut into equal halves and one section was pasteurized by heating at 60°C to 65°C for 40 min. Paired samples before and after pasteurization were studied in vitro for DNA ploidy, evaluation of histological change and elimination of mitotic activity. These tissues were transplanted in immune-deficient NOD-SCID mice to evaluate effect on tumour-generating ability, presence of human nuclei, osteopontin and cytokine/chemokines released in tumour-transplanted mice. Results: Non-pasteurized tumour samples had viable tumour cells which exhibited significant growth in culture, increased proliferative ability and clonogenic potential while respective pasteurized tumour tissues did not grow in culture and did not exhibit clonogenicity. Flow cytometry revealed that propidium iodide positive dead cells increased significantly (P< 0.01) post pasteurization. Seven of 12 non-pasteurized tumour transplanted mice demonstrated tumour-forming ability as against 0 of 12 in pasteurized tumour transplanted mice. Solid tumour xenografts exhibited strong expression of anti-human nuclei and osteopontin by immunohistochemistry as well as secretary human interluekin-6 (IL-6) while pasteurized mice failed to express these markers. Interpretation & conclusions: This study has provided a basis to establish pasteurization as being efficacious in ensuring tumour eradication from resected bone tumour specimens. Pasteurized tumour bearing bone can thus safely be used to reconstruct large defects after tumour resection. PMID:24927346

Kode, Jyoti; Taur, Prasad; Gulia, Ashish; Jambhekar, Nirmala; Agarwal, Manish; Puri, Ajay

2014-01-01

203

Preclinical Studies of the Potent and Selective Nicotinic ?4?2 Receptor Ligand VMY-2-95.  

PubMed

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-2-95·2HCl 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 ?g/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

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

204

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

PubMed Central

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

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

2013-01-01

205

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

PubMed Central

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

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

2014-01-01

206

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)

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.

Soler, Luc; Marescaux, Jacques

2006-04-01

207

Molecular Toxicology Major Snapshot Department of Nutritional Science and Toxicology  

E-print Network

Molecular Toxicology Major Snapshot Department of Nutritional Science and Toxicology College of Natural Resources, University of California Berkeley The Department Nutritional Science and Toxicology in the College of Natural Resources at UC Berkeley offers an undergraduate major in Molecular Toxicology

Wildermuth, Mary C

208

Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma.  

PubMed

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm that is resistant to chemotherapy. Bortezomib is an FDA-approved proteasome inhibitor that is currently under clinical investigation in multiple neoplasms but has not been studied extensively in MPM. In this report, we determine the biological and molecular response of cultured MPM cells to bortezomib alone and in combination with cisplatin or pemetrexed. We used four MPM cell lines (MS589, H28, H2052, JMN), a normal mesothelial cell line (HM3), and a lung cancer cell line (H23) in survival studies utilizing bortezomib, cisplatin, and pemetrexed alone and in combination by administering concurrently or by varying the order of administration. We determined the effect of bortezomib on the cell cycle, apoptosis, and on the expression of cell cycle proteins p21/WAF1 and p27/KIP1 and on apoptosis-related proteins IAP-1, IAP-2, survivin, and XIAP. Bortezomib was highly cytotoxic to MPM cells and induced both G(2)/M and G(1)/S cell cycle arrest. Apoptosis increased in a concentration- and time-dependent manner in 3 of 4 MPM cell lines. Bortezomib stabilized or increased protein levels of p21/WAF1 and IAP-1 and to a lesser degree p27/KIP1, IAP-2, XIAP, and survivin. In combination studies with cisplatin, bortezomib was generally synergistic at high concentrations and antagonistic at low concentrations. Bortezomib increased the cytotoxicity of cisplatin and pemetrexed in a concentration-dependent manner when administered prior to either. Bortezomib may improve outcome in MPM patients alone or in combination with standard chemotherapy but the order of administration is likely to be important. This study justifies further evaluation of bortezomib in MPM. PMID:17522864

Gordon, Gavin J; Mani, Madhubalan; Maulik, Gautam; Mukhopadhyay, Lipi; Yeap, Beow Y; Kindler, Hedy L; Salgia, Ravi; Sugarbaker, David J; Bueno, Raphael

2008-04-01

209

Wound healing activity of NOE-aspirin: A pre-clinical study  

Microsoft Academic Search

Aspirin, one of the oldest non-steroidal anti-inflammatory drugs, impedes tissue repair by virtue of retarding inflammation. The present study was undertaken to find out if linking of nitrooxyethyl ester to aspirin reverses its healing-depressant propensity. Nitrooxyethyl ester of aspirin (NOE-Asp) was synthesized in our laboratory through well-established synthetic pathway, starting from aspirin through esterification with ethylene glycol and nitration with

Mandeep Kaushal; N. Gopalan Kutty; C. Mallikarjuna Rao

2007-01-01

210

AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models  

PubMed Central

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM. PMID:23667438

Vasireddy, Vidyullatha; Kohnke, Monika; Black, Aaron D.; Alexandrov, Krill; Zhou, Shangzhen; Maguire, Albert M.; Chung, Daniel C.; Mac, Helen; Sullivan, Lisa; Gadue, Paul; Bennicelli, Jeannette L.; French, Deborah L.; Bennett, Jean

2013-01-01

211

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

PubMed

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

Nesan, Dinushan; Ng, Dominic S

2014-12-01

212

Hydration with Saline Decreases Toxicity of Mice Injected With Calcitriol in Preclinical Studies  

PubMed Central

The effectiveness of saline injection in reducing the toxicity profile of calcitriol when coadministered in mice was evaluated. Mortality was used as an end point to study the toxic effects of calcitriol; the relative risk of mortality in mice injected with saline was evaluated from our previously published animal experiments. We discovered that coadministration with 0.25 mL normal saline solution injected intraperitoneally is associated with a lower mortality rate than calcitriol given alone. The estimated relative risk of mortality was 0.0789 (95% confidence interval, 0.0051–1.22; z = 1.82; P = 0.070) when saline is administered with calcitriol compared to calcitriol alone. There was a reduction in serum calcium levels in mice that received saline (11.4 ± 0.15 mg/dL) compared to mice that did not receive saline (12.42 ± 1.61 mg/dL). Hydration with saline seems to reduce mortality and toxicity in mice receiving calcitriol. Given the decrease in mortality rates, intraperitoneal injections of saline should be considered in studies involving mice receiving injections of calcitriol. PMID:24266410

Azari, Amir A; Kanavi, Mozhgan R.; Darjatmoko, Soesiawati R.; Lee, Vivian; Kim, KyungMann; Potter, Heather D.; Albert, Daniel M.

2014-01-01

213

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

PubMed

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

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

2011-01-01

214

Transoral endoscopic thyroidectomy via the tri-vestibular routes: results of a preclinical cadaver feasibility study.  

PubMed

The concept of natural orifice transluminal endoscopic surgery (NOTES) is an emerging experimental alternative to conventional surgery that eliminates skin incisions using an endoscope passed through a natural orifice (e.g., mouth, urethra, or anus). This study was designed to evaluate the feasibility and safety of thyroid resection via an entirely transoral tri-vestibular route using endoscopy, and to introduce NOTES to the head and neck area of medicine. We performed ten complete endoscopic thyroid lobectomies with central lymph node dissection via a tri-vestibular approach in fresh-frozen cadavers. A 5-mm endoscope with a deflectable tip was used to visualize the surgical field. Three cannulas were inserted through the midline and bilateral incision sites in the vestibule to position the instruments and endoscope. We refined and described the surgical technique in each step using video clips. We identified and preserved neighboring critical structures during surgery. We also confirmed that there were no obvious remnant thyroid tissues and no injury to the neighboring structures after exploration. The transoral tri-vestibular approach seems to provide a good view and surgical field for endoscopic thyroidectomy. However, the transoral approach for thyroidectomy remains experimental, and the detailed surgical technique should be refined via further clinical studies. PMID:24496566

Park, Jun-Ook; Kim, Choung Soo; Song, Jee-Nam; Kim, Ju-Eun; Nam, Inn-Chul; Lee, So-Yoon; Chun, Byung-Joon; Cho, Jung-Hae; Joo, Young-Hoon; Cho, Kwang-Jae; Park, Young Hak; Kim, Min-Sik; Sun, Dong-Il

2014-12-01

215

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

PubMed

Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine ?-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.269. PMID:25174395

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

2014-09-01

216

Application of micro-CT assessment of 3-D bone microstructure in preclinical and clinical studies.  

PubMed

As the mechanical competence of trabecular bone is a function of its apparent density and 3-D distribution, assessment of 3-D trabecular structural characteristics may improve our ability to understand the pathophysiology of osteoporosis, to test the efficacy of pharmaceutical intervention, and to estimate bone biomechanical properties. We have studied ovariectomy-induced osteopenia in rats and its treatment with agents such as estrogen and sodium fluoride. We have demonstrated that 3-D micro-computed tomography (microCT) can directly quantify mouse trabecular and cortical bone structure with an isotropic resolution of 6 microm(3). MicroCT is also useful for studying osteoporosis in mice and phenotypes of mice with gene manipulation, such as SHIP-knockout mice, which are severely osteoporotic due to increased numbers of hyperresorptive osteoclasts, PTHrP heterozygous-null mice, and mice with Zmpste24 deficiency. MicroCT can quantify osteogenesis in mouse Ilizarov leg-lengthening procedures, osteoconduction in a rat cranial defect model, and structural changes in arthritic rabbits, rats, and mice. In clinical studies, we evaluated longitudinal changes in the iliac crests. Paired bone biopsies from the same premenopausal and postmenopausal women showed the changes in 3-D trabecular structure, such as decreased trabecular thickness, shifting of trabecular model from platelike structure to rodlike structure, and decreased degree of anisotropy were remarkable. Treatment with PTH in postmenopausal women with osteoporosis significantly improved trabecular morphology with a shift toward a more platelike structure, increased trabecular connectivity density, and increased cortical thickness. Paired bone biopsy specimens from the iliac crest in postmenopausal women with osteoporosis before and an average of 2 years after beginning of estrogen replacement therapy demonstrated that posttreatment biopsies showed a significant change in the ratio of plates to rods and statistically insignificant changes in other 3-D trabecular parameters. Thus, microCT can characterize 3-D structure of various animal models, and the longitudinal changes in 3-D bone microarchitectural integrity that deteriorates in the transmenopausal period, is preserved with HRT, and is improved with PTH treatment in postmenopausal women. PMID:15984427

Jiang, Yebin; Zhao, Jenny; Liao, Er-Yuan; Dai, Ru-Chun; Wu, Xian-Ping; Genant, Harry K

2005-01-01

217

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

NASA Astrophysics Data System (ADS)

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.

Amara, Francis

218

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

NASA Astrophysics Data System (ADS)

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.

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

2012-11-01

219

Toxicological approaches to complex mixtures.  

PubMed Central

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

Mauderly, J L

1993-01-01

220

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

NASA Astrophysics Data System (ADS)

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.

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

2006-02-01

221

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

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

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

222

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

PubMed Central

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

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

2014-01-01

223

166Ho-microsphere liver radiotherapy: a preclinical SPECT dosimetry study in the pig.  

PubMed

Liver metastases cause the majority of deaths from colorectal cancer and response to chemotherapy is poor. Intrahepatic arterial 90Y-microspheres may induce tumour regression but the beta-radiation dose is variable and cannot be determined in patients. The 81 keV gamma emission of holmium-166 (166Ho) was used to determine, by single photon emission computed tomographic (SPECT) imaging, the beta-radiation absorbed dose to normal liver in pigs following intrahepatic arterial administration of 166Ho-microspheres. The SPECT system was calibrated with anthropomorphic liver phantoms containing known activity concentrations of 166Ho-chloride. The relationship of SPECT counts to phantom activity concentration was linear with a correlation coefficient of r = 0.996. The SPECT pattern of liver distribution following successive administrations of tracer activities of 166Ho-microspheres was similar. The ratio of initial to total SPECT estimates of mean activity concentration in regions of interest, from which anatomically matched biopsy samples were later obtained and counted in an ionization chamber, showed good correlation (r = 0.924). Prospective SPECT dosimetry performed on a tracer activity of 166Ho-microspheres predicted the total administered activity required to deliver a prescribed radiation absorbed dose of 25 Gy to the liver within an error of +/- 8%. This study demonstrates the feasibility of prospective control of the absorbed radiation dose to the critical normal organ by SPECT dosimetry on a tracer dose of 166Ho-microspheres prior to administration of a therapy dose. PMID:7970432

Turner, J H; Claringbold, P G; Klemp, P F; Cameron, P J; Martindale, A A; Glancy, R J; Norman, P E; Hetherington, E L; Najdovski, L; Lambrecht, R M

1994-07-01

224

Preclinical studies on neurobehavioral and neuromuscular effects of cocaine hydrolase gene therapy in mice.  

PubMed

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 hydrolyzing 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 10(13) 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 luciferase 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

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

2014-07-01

225

GABAergic contributions to alcohol responsivity during adolescence: insights from preclinical and clinical studies.  

PubMed

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 ?-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 use disorders. PMID:24631274

Silveri, Marisa M

2014-08-01

226

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

PubMed Central

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 k? 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

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

227

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

NASA Astrophysics Data System (ADS)

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.

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

2014-03-01

228

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

PubMed

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

Wu, J; Polefka, T G

2008-02-01

229

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

NASA Astrophysics Data System (ADS)

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.

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

1990-07-01

230

Capecitabine: Preclinical Pharmacology Studies  

Microsoft Academic Search

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate, which was designed to besequentially converted to 5-fluorouracil (5-FU) by three enzymes located inthe liver and in tumors; the final step is the conversion of5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU by thymidine phosphorylase (dThdPase) in tumors. In human cancer xenograft models, capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma

Hideo Ishitsuka

2000-01-01

231

A tanscriptomics study to elucidate the toxicological mechanism of methylmercury chloride in a human stem cell based in vitro test.  

PubMed

Traditional approaches in evaluating the hazard of drug candidates on the developing offspring are often time-consuming and cost-intensive. Moreover, variations in the toxicological response of different animal species to the tested substance cause severe problems when extrapolating safety dosages for humans. Therefore, more predictive and relevant toxicological systems based on human cell models are required. In the presented study the environmental toxicant methylmercury chloride (MeHgCl), known to cause structural developmental abnormalities in the brain, was used as reference compound to develop a concept contributing to a mechanistic understanding of the toxicity of an investigated substance. Despite the fact, that there are significant data available from animal studies and from poisonings in Japan and Iraq, uncertainties on the mechanism of MeHgCl during human development are still remaining and qualify the substance for further analysis. Transcriptomics analysis in combination with a human cell based in vitro model has been used in order to elucidate the toxicity of MeHgCl at molecular level. Differentiating neural precursor cells that have been exposed continuously to non- and low-cytotoxic concentrations of MeHgCl were investigated. Quantitative change in the mRNA expression profiles of selected genes demonstrated the sensitivity of the cell model and its qualification for a transcriptomics study screening changes in the expression profile of the complete human genome of MeHgCl-treated human neural cells. Potential biomarkers were identified and these candidate marker genes as well as their involvement in a possible toxic mechanism of MeHgCl during the human neurulation process are hereby introduced. The study confirmed the hypothesis that a cellular model based on a human stem cell line can be applied for elucidating unknown mode of actions of developmental toxicants. PMID:23244585

Vojnits, K; Ensenat-Waser, R; Gaspar, J A; Meganathan, K; Jagtap, S; Hescheler, J; Sachinidis, A; Bremer-Hoffmann, S

2012-01-01

232

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

PubMed Central

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

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

2014-01-01

233

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

PubMed

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

Gautam, M K; Goel, R K

2014-01-01

234

National Toxicology Program  

MedlinePLUS

... 00-2:30 p.m. Register to attend Toxicology in the 21st Century (Tox21) The Tox21 Program ... is to develop and apply tools of modern toxicology and molecular biology to identify substances in the ...

235

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...

236

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...

237

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...

238

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

PubMed Central

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

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

2013-01-01

239

Inhalation Toxicology, 2009, 13, Early Online RESEARCH ARTICLE  

E-print Network

Inhalation Toxicology, 2009, 1­3, Early Online RESEARCH ARTICLE Conference summary: International assessment, biomarkers of exposure, toxicology and animal study design, health outcomes measures/study design future research directions. In this issue of Inhalation Toxicology, we present the findings from each

240

Graduate Program Environmental Toxicology  

E-print Network

1 Graduate Program in Environmental Toxicology Graduate Student Guidelines Updated December 7, 2011 for Ph.D. Students 3. ENTOX Form 2 ­ Graduate Research Proposal #12;3 PROGRAM OF ENVIRONMENTAL TOXICOLOGY GRADUATE STUDENT GUIDELINES A. Introduction The Faculty of Environmental Toxicology welcomes you

Duchowski, Andrew T.

241

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...

242

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

SciTech Connect

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.

Mast, T.J.

1987-12-01

243

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

PubMed Central

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

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

244

Toxicological studies on Laccase from Myceliophthora thermophila expressed in Aspergillus oryzae.  

PubMed

The bioindustrially produced enzyme laccase can be used in different technical and food applications to facilitate processes. It can be added to different oral care products such as mouthwash, toothpaste, mints, and gums to prevent halitosis. Laccase, produced by submerged fermentation of Aspergillus oryzae, containing a gene originating from Myceliophthora thermophila, was subject to a series of toxicological tests to document its safety in use. It was not found to be mutagenic in the Salmonella typhimurium reverse mutation assay, nor did it cause chromosomal aberrations in cultured human lymphocytes. No evidence of inhalation toxicity or skin and eye irritation was found. There was no evidence of possible skin sensitization in a human skin sensitization test when Laccase was tested at 10% (w/v): thus Laccase would appear to have a low skin sensitization potential. Oral administration to rats of up to 10.0 mL/kg body wt/day (equivalent to a total organic solids dosage of 1.72 g/kg body wt/day) for 13 weeks did not cause any adverse effect. PMID:12202045

Brinch, D S; Pedersen, P B

2002-06-01

245

September 15, 2000 Applications of Population Approaches in Toxicology  

E-print Network

September 15, 2000 Applications of Population Approaches in Toxicology FREDERIC Y. BOIS a a INERIS, VERNEUIL EN HALATTE, FRANCE ABSTRACT Many experimental or observational studies in toxicology are best. Correspondence: Dr. Frédéric Y. Bois Experimental Toxicology Laboratory INERIS Parc ALATA, BP 2 F-60550 Verneuil

Paris-Sud XI, Université de

246

An Independent Study of the Preclinical Efficacy of C2-8 in the R6/2 Transgenic Mouse Model of Huntington's Disease  

PubMed Central

Background C2-8 is a small molecule inhibitor of polyglutamine aggregation and can reduce photoreceptor neurodegeneration in a Drosophila model of Huntington's disease (HD). Further preclinical studies have shown that oral administration of C2-8 in R6/2 HD transgenic mice can penetrate into the brain, reduce mHTT-exon1 aggregation, improve motor performance and diminish striatal neuron atrophy. Objective In this independent preclinical study, we aimed to evaluate the pharmacokinetic properties and therapeutic efficacy of C2-8 intraperitoneal (IP) delivery in the R6/2 HD mouse. Methods R6/2 mice were IP injected with low dose C2-8 (10 mg/kg), high dose C2-8 (20 mg/kg), or vehicle twice daily from 3 weeks to 3 months old. Longitudinal behavioral tests (accelerating Rotarod and wire-hang) were performed to evaluate the motor deficits, and neuropathology was measured by unbiased stereology. Results We confirmed that the compound has good blood-brain-barrier penetration after acute or sub-chronic intraperitoneal delivery. Chronic treatment with C2-8 in R6/2 mice results in a significant reduction of nuclear mHTT aggregate volume in the brains, replicating a key finding of C2-8 as a polyglutamine aggregation inhibitor in vivo. However, by comparing HD mice with C2-8 treatment to those with vehicle treatment, we were unable to demonstrate significant amelioration of motor deficits using Rotarod and wire-hang tests. Moreover, we did not observe improvement in the striatal neurodegenerative pathology, as measured by brain weight, striatal volume, and striatal neuron volume in the C2-8 treated R6/2 mice. Conclusions Our study supports the practice of independent preclinical studies for novel molecules in HD therapeutic development and suggests that the use of alternative delivery strategies and full-length HD mouse models are likely needed to further assess whether the aggregate-inhibiting properties of C2-8 can be consistently translated into a preclinical benefit in HD mice. PMID:25062731

Wang, Nan; Lu, Xiao-Hong; Sandoval, Susana V.; Yang, X. William

2014-01-01

247

[Actual problems of genetic toxicology].  

PubMed

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

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

2013-03-01

248

Magnesium is not consistently neuroprotective for perinatal hypoxia-ischemia in term-equivalent models in preclinical studies: a systematic review.  

PubMed

There is an important unmet need to further improve the outcome of neonatal encephalopathy in term infants. Meta-analyses of large controlled trials now suggest that maternal magnesium sulfate (MgSO4) therapy is associated with a reduced risk of cerebral palsy and gross motor dysfunction after premature birth, but that it has no effect on death or disability. Because of this inconsistency, it remains controversial whether MgSO4 is clinically neuroprotective and, thus, it is unclear whether it would be appropriate to test MgSO4 for treatment of encephalopathy in term infants. We therefore systematically reviewed the preclinical evidence for neuroprotection with MgSO4 before or after hypoxic-ischemic encephalopathy (HIE) in term-equivalent perinatal and adult animals. The outcomes were highly inconsistent between studies. Although there were differences in dose and timing of administration, there was evidence that beneficial effects of MgSO4 were associated with confounding mild hypothermia and, strikingly, the studies that included rigorous maintenance of environmental temperature or body temperature consistently suggested a lack of effect. On balance, these preclinical studies suggest that peripherally administered MgSO4 is unlikely to be neuroprotective. Rigorous testing in translational animal models of perinatal HIE is needed before MgSO4 should be considered in clinical trials for encephalopathy in term infants. PMID:24854050

Galinsky, Robert; Bennet, Laura; Groenendaal, Floris; Lear, Christopher A; Tan, Sidhartha; van Bel, Frank; Juul, Sandra E; Robertson, Nicola J; Mallard, Carina; Gunn, Alistair J

2014-01-01

249

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

PubMed

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

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

2014-09-10

250

Some pharmacologic and toxicologic studies on Rhazya stricta decne in rats, mice and rabbits.  

PubMed

1. This work examines some in vivo and in vitro pharmacologic and toxicologic effects of extracts of Rhazya stricta, a medicinal plant in the United Arab Emirates. 2. R. stricta extracts at doses of 0.1-10 mg reduced the mean arterial blood pressure (MBP) of anesthetized rats in a dose-dependent manner. The depressor effect was partially sensitive to atropine (5 microM). Although the MBP was reduced by 50% by both doses of extracts, the normal electrocardiogram pattern and the heart rate remained unaltered. 3. Acute treatment of rats with the lyophilized extract at doses of 4 g/kg produced a significant rise in insulin concentration. In streptozotocin-diabetic rats loaded orally with glucose (1 g/kg), R. stricta at doses of 8 g/kg produced significant decreases in plasma glucose concentration at 0.5 and 1 h after treatment. 4. Chronic treatment of rats and mice for 28 days with the lyophilized extract of R. stricta did not affect the plasma glucose or insulin concentration or any of the hematological or biochemical indices measured. 5. The extracts of R. stricta (0.5-4 g/kg) dose-dependently decreased the gastrointestinal transit time in mice by 4-50%. 6. The butanolic extract of R. stricta (1 and 2 g/kg) significantly reduced the carrageenan-induced increase in raw paw edema 3 and 4 h after the extract administration. 7. The rectal temperatures of normothermic and pyrexic rats were reduced significantly 0.5 and 1 h after administration of butanolic R. stricta at doses of 1 and 2 g/kg. 8. The butanolic extract of R. stricta at doses of 1 and 2 g/kg significantly increased the reaction time on the hot plate 30 and 60 min after administration to rats. 9. At concentration < 0.05 mg/ml (bath concentration), lyophilized water and butanol extracts of R. stricta potentiated the twitch responses induced by indirect electrical stimulation in the rat phrenic nerve diaphragm preparation. The responses were inhibited by concentrations > 0.05 mg/ml. Neostigmine (2 x 10(-4)M) did not alter these effects of the extracts. 10. R. stricta extracts dose-dependently decreased the force of contraction and heart rate of the isolated rabbit heart. Atropine (1 x 10(-5)M) had no effect on the inhibitory activity of these extracts. The lyophilized water extract (> 10 mg) and butanol extract (> 5 mg) produced irreversible inhibition and disturbances in the force of contraction and heart rate. PMID:8981078

Tanira, M O; Ali, B H; Bashir, A K; Chandranath, I

1996-10-01

251

75 FR 64311 - National Toxicology Program (NTP); Office of Liaison, Policy and Review Meeting of the NTP Board...  

Federal Register 2010, 2011, 2012, 2013, 2014

...OF HEALTH AND HUMAN SERVICES National Toxicology Program (NTP); Office of Liaison...Comments'' below). The NTP welcomes toxicology study information from completed...larger public health issues or topics in toxicology that could be appropriately...

2010-10-19

252

75 FR 21003 - National Toxicology Program (NTP); Office of Liaison, Policy and Review Meeting of the NTP Board...  

Federal Register 2010, 2011, 2012, 2013, 2014

...OF HEALTH AND HUMAN SERVICES National Toxicology Program (NTP); Office of Liaison...Comments'' below). The NTP welcomes toxicology study information from completed, ongoing...larger public health issues or topics in toxicology that could be appropriately...

2010-04-22

253

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

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

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

2015-01-01

254

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

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

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

2014-11-01

255

Chronic toxicology and carcinogenesis studies of telone ii by Gavage in fischer?344 Rats and B6C3F1 mice  

Microsoft Academic Search

Telone II (technical grade, 1,3?dichloropropene), a soil fumigant, was evaluated in chronic toxicology\\/carcinogenicity studies using Fischer?344 (F344) rats and B6C3F, mice of both sexes. Doses administered were 0, 25, or 50 mg\\/kg to rats and 0, 50, or 100 mg\\/kg to mice. Telone II was given in com oil by gavage 3 times per week for 104 wk. Ancillary studies

Raymond S. H. Yang; J. E. Huff; G. A. Boorman; J. K. Haseman; Mary Kornreich; J. L. Stookey

1986-01-01

256

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

PubMed

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 96h 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 (3?-hydroxysteroid dehydrogenase, Cytochrome P45017A1, Cytochrome P45019), conjugation (UDP-glucuronosyltransferase, sulfotransferase (SULT)), and regeneration (?-glucuronidase, arylsulfatase C (ASC)) enzymes were determined biochemically in tissues with fluorimetric and spectrophotometric assays, and western blot. Explants were viable up to 96h, but progesterone, estrone, and 17?-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 96h, 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 <48h, but not for steroid/endocrine studies. PMID:25283089

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

2015-02-01

257

Toxicology: recommended sequence of required courses www.toxicology.psu.edu Toxicology Program Coordinator  

E-print Network

Toxicology: recommended sequence of required courses www.toxicology.psu.edu Toxicology Program Coordinator: Dr. James Endres Howell 814 867 0194 toxicology@psu.edu Year 1 VB SC 050S(3) First Year Seminar* SPRING AT UNIVERSITY PARK ONLY Year 4 VB SC 430(3) Principles of Toxicology* FALL AT UNIVERSITY PARK ONLY

Omiecinski, Curtis

258

Phase I trials of single agents in adult solid tumours: preclinical and clinical aspects.  

PubMed

Considerable progress has been made in the treatment of cancer. However, there is still a need for new drug development. The preclinical antitumour activity of new anticancer agents is evaluated by sequential testing in murine tumours and human xenografts in mice. More recently, the human tumour stem cell assay has been introduced into the preclinical screen. Toxicology studies are done in animals in order to characterize qualitatively and quantitatively the side effects of the new compounds. These toxicology studies allow an appropriate starting dose to be selected for clinical trials. Most commonly, the starting dose for clinical trials corresponds to 1/10 of the dose that will induce a 10% lethality in the mouse (LD10), if that dose is tolerated by the dog. The escalation scheme for clinical trials must be a compromise between the safety of the patient and quickly reaching biologically active doses. This may be achieved by using the so-called modified Fibonacci scheme. A slightly more rapid alternative is to increase the dose by 100% until the equivalent of the LD10 in the mouse is reached, and then by 50% until toxic effects are observed. Further dose increases depend on the type and severity of these toxic side-effects. Patients included in phase I clinical trials of anticancer agents must have histologically proven malignant disease that cannot be treated by conventional therapeutic modalities. They should have normal haematological, renal and hepatic functions and should be expected to live long enough to evaluate properly the toxic effects of the new compounds.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3732050

Dodion, P; Kenis, Y; Staquet, M

1986-01-01

259

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

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

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

2014-11-01

260

NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in F344/N Rats (Feed Studies).  

PubMed

Oxazepam and related benzodiazepine drugs are used in the treatment of anxiety. All benzodiazepines currently in use share a number of effects, including sedation, hypnosis, decreased anxiety, muscle relaxation, amnesia, and anticonvulsant activity. Oxazepam and four other benzodiazepines (chlordiazepoxide, chlorazepate, diazepam, and flurazepam) were nominated for study by the Food and Drug Administration (FDA) and by the NIEHS based on their widespread use, use by pregnant women, and the lack of adequate rodent carcinogenicity studies. Oxazepam was evaluated in 14-week and 2-year studies by the NTP, and Technical Report No. 443 contains the results of the studies performed with the Swiss-Webster and B6C3F1 strains of mice. Studies with rats were not initiated at the same time as the mouse studies because adequate carcinogenicity studies of oxazepam with the Sprague-Dawley rat strain had been submitted to the FDA. Subsequently, because of the marked neoplastic responses found in the two mouse strains, the NTP initiated 2-year studies of oxazepam with the F344/N rat. Groups of male and female F344/N rats were exposed to oxazepam (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells, and mouse peripheral blood samples were analyzed for the frequency of micronucleated normochromatic erythrocytes. 2-YEAR STUDY: Groups of 50 male and 50 female F344/N rats were fed diets containing 0, 625, 2,500, or 5,000 ppm oxazepam for up to 105 weeks. A stop-exposure group of 50 males and 50 females received 10,000 ppm oxazepam in feed for 26 weeks, after which animals received undosed feed for the remainder of the 2-year study. The continuous-exposure concentrations resulted in average daily doses of 25, 100, or 250 mg oxazepam/kg body weight to males and 25, 110, or 220 mg/kg to females. Stop- exposure males and females received an average daily dose of 630 mg/kg during the exposure period. Survival, Body Weights, and Clinical Findings: All 5,000 ppm continuous-exposure and 10,000 ppm stop-exposure males died before the end of the study. Survival of 2,500 ppm continuous-exposure males and females was significantly less than that of the controls. The mean body weight gains of 2,500 and 5,000 ppm males and females were less than those of the controls throughout the study. The mean body weights of 10,000 ppm stop-exposure males were generally less than those of the controls throughout the study; those of 10,000 ppm stop-exposure females were less than those of the controls during the exposure portion of the study but increased steadily after the cessation of dosing at week 27. Feed consumption by exposed groups was similar to that by the controls after week 1 of the study. Treatment-related eye/nasal discharge, hyperactivity when handled, and/or ataxia were observed in exposed male and female rats on or about day 2 of exposure but were no longer apparent after day 7. Plasma Oxazepam Determinations: Plasma oxazepam concentrations were measured at the end of the study. The concentrations ranged from approximately 0.5 (625 ppm males) to 2.8 &mgr;g/mL (5,000 ppm females). Pathology Findings: In the standard histopathologic evaluation, the incidence of renal tubule adenoma was slightly increased in male rats exposed to 2,500 ppm and was at the upper limit of the historical control range for this neoplasm in 2-year NTP feed studies. In an extended evaluation (step section) of the kidneys of male rats, the incidences of renal tubule adenoma occurred with a positive trend in exposed groups. In standard and step sections (combined), male rats exposed to 2,500 or 5,000 ppm showed a significant increase in the incidences of renal tubule adenoma and hyperplasia. In addition, the incidences of renal tubule adenoma and hyperplasia were significantly increased in the 10,000 ppm stop-exposure group. The incidences of nephropathy in continuously exposed female rats were significantly greater than in the controls, and the severity of nephropathy increased wis

1998-10-01

261

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...

262

Preclinical pharmacokinetics: an approach towards safer and efficacious drugs.  

PubMed

Lack of efficacy and toxicity are considered to be major reasons for drug failures and pharmacokinetics governs them to a large extent. Compound with favorable pharmacokinetics is more likely to be efficacious and safe. Therefore, the preclinical pharmacokinetic evaluation should be comprehensive enough to ensure that compounds do not fail in the clinic. Preclinical ADME screening facilitates early elimination of weak candidates and directs the entire focus of the drug development program towards fewer potential lead candidates. Hence, it is mandatory that the pre-clinical candidates are subjected to as many possible reality checks. Reliance on in-vitro tests should be minimized because they do not represent the real physiological environment but rather slow down the pace of a drug discovery program. Compounds can be straight away subjected to in-vivo high throughput screens such as cassette dosing, cassette analysis or rapid rat screen etc. Candidates with the desired in-vivo pharmacokinetic profile may be further profiled in-vitro, using assays such as metabolic stability, reaction phenotyping, CYP-450 inhibition and induction, plasma protein binding etc. in human microsomes, human recombinant CYP-450 enzymes and human plasma. This also provides an early indication of whether the compound which worked in animals would work in human as well. In-vitro metabolic stability profile is a qualitative as well as quantitative comparison of metabolism of a compound in human and animal models. It helps in identifying the right model for toxicity studies. Extensive metabolism is generally considered a liability as it limits the systemic exposure and shortens the half-life of a compound. Several strategies such as reduction of lipophilicity, modification and / or blocking of metabolically soft spots and use of enzyme inhibitors; have been developed to combat metabolism. In spite of several concerns, the fact that active metabolites of several marketed drugs have been developed as drugs with better efficacy, safety and pharmacokinetics profile; cannot be denied. Therefore, instead of considering metabolic instability a liability it can be exploited as a tool for discovering better drugs. It is equally important to identify the metabolic pathways of the drug candidates by conducting in-vitro CYP450 reaction phenotyping assays. The identification of drug metabolizing enzymes involved in the major metabolic pathways of a compound helps in predicting the probable drug-drug interactions in human. Compounds with more than one metabolic pathway have less likelihood of clinically significant drug interactions. In-vitro CYP450 inhibition and induction screens are used to evaluate the potential of compound towards drug - drug interactions and the most prone candidates may either be discarded or taken ahead with a caution. It is known that only unbound drug is pharmacologically active and therefore the assessment of bound fraction by the estimation of plasma protein binding of a compound is another important parameter to be explored in-vitro. In addition to the process of 'weeding out' weak candidates early in the drug discovery process, it is equally important to identify the probable causes of poor ADME exhibited by some compounds as this information is useful to medicinal chemists for improving upon backbones that exhibit un favorable pharmacokinetic profile. Toxicity study is the foundation of an INDA (Investigational new drug application) and therefore, the final selection of a compound can be performed only after proper toxicological evaluation in animal models. Toxicokinetics forms an integral part of toxicity study and is used to assess the exposure of candidates in toxicity models and correlate the drug levels in blood and various tissues with the toxicological findings. Although in-vivo screening of compounds in animal models and in-vitro assays in human recombinant CYP-450 enzymes help in drug candidate selection, both approaches have their own limitations. There is no certainty that the selected candidates will exhibit the desired

Singh, Sonu Sundd

2006-02-01

263

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

PubMed

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

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

2001-01-01

264

[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

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.

DeNardo, S.J.

1995-12-31

265

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

PubMed

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

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

2013-01-01

266

Preclinical safety of a nucleic acid-targeted Helinx compound: a clinical perspective.  

PubMed

Helinx technology (Cerus Corp, Concord, CA) uses amotosalen HCl (S-59) and ultraviolet A (UVA) light in an ex vivo photochemical treatment (PCT) to inactivate viruses, bacteria, and leukocytes in platelet concentrates while preserving therapeutic function. A comprehensive preclinical safety program was conducted, which included carcinogenicity, single-dose and multiple-dose (up to 13 weeks' duration) toxicity, safety pharmacology (central nervous system [CNS], renal, and cardiovascular), reproductive toxicity, genotoxicity, vein irritation, phototoxicity, and toxicokinetic testing. The results of the toxicokinetic analyses indicated that the test articles provided large multiples of the clinical exposure to S-59, whether the comparison was based on dose, maximum plasma concentration, or area under the concentration-time curve. No specific target organ toxicity, reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS toxicity, electrocardiographic (ECG) effects, and phototoxicity at supraclinical doses. On the basis of the extremely large safety margins, the CNS and ECG observations (at >30,000-fold the expected clinical exposure) as well as the results of genotoxicity and phototoxicity studies are not considered to be of toxicological relevance. The results of an extensive series of studies have thus demonstrated no toxicologically relevant effects of platelets treated with Helinx technology. PMID:11727281

Ciaravino, V

2001-10-01

267

Preclinical assessment of abuse liability of drugs  

Microsoft Academic Search

Studies that are used in preclinical assessment of the liability of a drug to become an abuse problem are reviewed. These studies examine the capacity of a drug to produce physiological dependence or to function as a reinforcer. Studies that examine physiological dependence by assessing whether a drug reverses signs of withdrawal from a standard drug are rapid, reliable and

J. L. Katz; S. R. Goldberg

1988-01-01

268

L-Histidinol: Preclinical Therapeutic Studies in Combination with Antitumor Agents and Pharmacokinetic Studies in Mice1  

Microsoft Academic Search

Therapeutic studies were conducted with L-histidinol, in combination with cyclophosphamide, bischloroethylnitrosourea, 5-fluorouracil, phen- ylalanine mustard, or m-platinum(H)diammine dichloride, in several transplantable tumors in mice. These tumor types included murine LI 210 P388 leukemias, M5076 sarcoma, mammary 16\\/C adenocarcinoma, hu man LOX melanoma, and colon III-29 adenocarcinoma. Therapeutic benefits of adding i.-histidinol to a regimen, compared to the regimen alone, were

Daniel Zaharko; Jacqueline Plowman; William VVaud; Donald Dykes; Louis Malspeis

269

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...

270

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 ...

271

Pre-clinical diastolic dysfunction.  

PubMed

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

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

2014-02-11

272

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

PubMed

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

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

2014-01-01

273

Behavioral pharmacology of cannabinoids with a focus on preclinical models for studying reinforcing and dependence-producing properties.  

PubMed

Cannabis preparations as recreational drugs are the most widely used illicit drugs in the world. Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behavior and in a specific proportion in repeated drug use, the reinforcing/rewarding attributes of these subjective effects are difficult to define in experimental animals. This led to the notion of cannabinoids being considered as "atypical" or "anomalous" drugs of abuse. To this end, our knowledge and understanding of the way cannabis and its main psychoactive constituent, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), act in the central nervous system to exert their reinforcing/rewarding effects is far from complete. The aim of the present article is to review from a preclinical perspective the current status of what is known about the behavioral pharmacology of cannabinoids including the recently identified cannabinoid neurotransmission modifiers with a particular emphasis on their motivational/reinforcing and dependence-producing properties. We conclude that cannabinoids exhibit reinforcing/rewarding properties in experimental animals mostly under particular experimental conditions, which is not the case for other drugs of abuse, such as opiates, psychostimulants, alcohol and nicotine. The paper will discuss these findings critically and also point to open questions that should be addressed in the future in order to improve our understanding of these specific actions of cannabinoids that will also impact drug discovery and development efforts of related compounds as therapeutics in the clinic. PMID:19630731

Panagis, George; Vlachou, Styliani; Nomikos, George G

2008-11-01

274

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

PubMed Central

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

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

2014-01-01

275

Novel liquid chromatographic method for simultaneous estimation of pioglitazone and glimepiride in rat plasma by solid phase extraction: application to preclinical pharmacokinetic studies.  

PubMed

The need for a reliable bioanalytical method is of primary importance during preclinical studies. The aim of the present study was simultaneous determination of pioglitazone (CAS 111025-46-8) (PIO) and glimepiride (CAS 93479-97-1) (GLM) in plasma of rats. A high-performance liquid chromatographic method has been developed and validated using C18 column and UV detector. A mobile phase composed of acetonitrile and ammonium acetate buffer pH 4.5 in the ratio of 55:45%. The plasma samples clean-up was carried out using solid phase cartridges. The method was in the linear range of 50-8000 ng/mL for PIO and 50-2000 ng/mL for GLM. The coefficient of regression was found to be > or = 0.99. Precision and accuracy were within the acceptable limits, as indicated by relative standard deviation varying from 1.5 to 6.1% for PIO and 3.1 to 7.0% for GLM whereas the accuracy ranged from 97.0 to 106.4% for PIO and 96.5 to 106.4% for GLM. The mean extraction recovery was found to be 90.2 +/- 4.5, 76.8 +/- 2.8 and 85.2 +/- 5.2% for PIO, GLM and internal standard, respectively. Moreover, PIO and GLM were stable in plasma, up to 30 days of storage at -70 degrees C and after being subjected to bench top, auto-sampler, and three freeze-thaw cycles. The developed method was applied for preclinical pharmacokinetic studies. PMID:21355443

Musmade, Prashant B; Talole, Kranti B; Deshpande, Praful B; Karthik, Arumugam; Pathak, Shriram M; Pandey, Sureshwar; Udupa, Nayanabhirama

2011-01-01

276

The chemical, toxicological and ecological studies in assessing the heavy metal pollution in Le An River, China  

Microsoft Academic Search

By integrating the chemical, toxicological and ecological data, the impact of heavy metal pollution on the Le An River was assessed. The results showed that the water and sediment pollution has affected the aquatic ecosystem due to discharges from Dexing copper mines and mines along the Jishui River. The ecological deterioration between the Dexing copper mine and the converges with

Mengchang He; Zijian Wang; Hongxiao Tang

1998-01-01

277

Porcine adipose-derived stem cells from buccal fat pad and subcutaneous adipose tissue for future preclinical studies in oral surgery  

PubMed Central

Introduction Adipose-derived stem cells (ASCs) are progenitor cells used in bone tissue engineering and regenerative medicine. Despite subcutaneous adipose tissue being more abundant, the buccal fat pad (BFP) is easily accessible for dentists and maxillofacial surgeons. For this reason, considering the need for preclinical study and the swine as an optimal animal model in tissue engineering applications, we compared the features of porcine ASCs (pASCs) from both tissue-harvesting sites. Methods ASCs were isolated from interscapular subcutaneous adipose tissue (ScI) and buccal fat pads of six swine. Cells were characterized for their stemness and multipotent features. Moreover, their osteogenic ability when cultured on titanium disks and silicon carbide-plasma-enhanced chemical vapor-deposition fragments, and their growth in the presence of autologous and heterologous serum were also assessed. Results Independent of the harvesting site, no differences in proliferation, viability, and clonogenicity were observed among all the pASC populations. Furthermore, when induced toward osteogenic differentiation, both ScI- and BFP-pASCs showed an increase of collagen and calcified extracellular matrix (ECM) production, alkaline phosphatase activity, and osteonectin expression, indicating their ability to differentiate toward osteoblast-like cells. In addition, they differentiated toward adipocyte-like cells, and chondrogenic induced pASCs were able to increase glycosaminoglycans (GAGs) production over time. When cells were osteoinduced on synthetic biomaterials, they significantly increased the amount of calcified ECM compared with control cells; moreover, titanium showed the osteoinductive effect on pASCs, also without chemical stimuli. Finally, these cells grew nicely in 10% FBS, and no benefits were produced by substitution with swine serum. Conclusions Swine buccal fat pad contains progenitor cells with mesenchymal features, and they also osteo-differentiate nicely in association with synthetic supports. We suggest that porcine BFP-ASCs may be applied in preclinical studies of periodontal and bone-defect regeneration. PMID:24330736

2013-01-01

278

[Toxicological studies on pepleomycin sulfate (NK 631). I. Acute toxicity of pepleomycin in mice, rats and dogs (author's transl)].  

PubMed

Studies on acute toxicities of pepleomycin sulfate were carried out in both sexes of mice and rats, comparing with bleomycin, and male dogs. Pepleomycin was administered subcutaneously, intravenously and intraperitoneally in both sexes of mice and rats, and intravenously in male dogs respectively. Mice and rats, and intravenously in male dogs respectively. Mice and rats were observed respectively for 10 and 14 days after the administration. LD50 values were calculated by the method of Litchifield & Wilcoxon. LD50 values of pepleomycin were 4 approximately 6 times smaller than those of bleomycin in all routes of mice, but difference between them was not significant in all routes of rats. Additionally sex-difference of LD50 values was scacely recognized in all routes of both species. Toxicological findings observed in common to all routes of both species were ataxia, depression, tremor and epiphora, and only in all routes of mice, head-twitch, running-round and rolling were especially recognized as toxic behavior, which were not observed in bleomycin. Hepatic and renal lesions were recognized in biochemically and histopathologically in the survived rats. The dogs treated with pepleomycin 50 and 30 mg/kg had the decrease in food intake and the loss of body weight. They became moribund in 9 approximately 36 days after administration. In these dogs the lesions of liver and kidney were severely recognized in biochemical and histopathological findings. One of them which received 50 mg/kg recovered biochemically and histopathologically in 209 days after administration by the supplemental nutrition in early stage. PMID:83404

Ito, K; Irie, Y; Miyamoto, K; Yamashita, T; Tsubosaki, M; Matsuda, A; Konoha, N

1978-12-01

279

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

PubMed Central

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

Schoeny, R

1996-01-01

280

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

SciTech Connect

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.

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

2009-02-01

281

Preclinical and clinical research on inflammation after intracerebral hemorrhage  

PubMed Central

Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models, microglial activation has been shown to occur within 1 h, much earlier than neutrophil infiltration. Recent advances in our understanding of neuroinflammatory pathways have revealed several new molecular targets, and related therapeutic strategies have been tested in preclinical ICH models. This review summarizes recent progress made in preclinical models of ICH, surveys preclinical and clinical studies of inflammatory cells (leukocytes, macrophages, microglia, and astrocytes) and inflammatory mediators (matrix metalloproteinases, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron), and highlights the emerging areas of therapeutic promise. PMID:20713126

Wang, Jian

2010-01-01

282

Safety pharmacology, toxicology and pharmacokinetic assessment of human Gc globulin (vitamin D binding protein).  

PubMed

Gc globulin is an important protein of the plasma actin-scavenger system. As such, it has been shown to bind free actin and prevent hypercoagulation and shock in patients with massive actin release resulting from severe tissue injuries. Treatment of such patients with Gc globulin could therefore potentially be life-saving. This article presents pre-clinical toxicology experiments conducted on purified plasma-derived human Gc globulin. The Gc globulin formulation was shown to be stable for at least 4 years with full retention of actin-binding capacity. In vitro studies did not reveal activation of the kallikrein system or the complement system and cellular studies showed no toxic effects on a variety of human cell lines. In vivo studies showed no acute toxic effects in mice, rats or guinea pigs upon intravenous infusion. A 14-day local tolerance study in rabbits showed no adverse effects, and 14-day toxicity studies in rats and horses did not show any unwanted reactions. In a 14-day toxicology study in beagle dogs, formation of antibodies was seen and in the end of the study period, three out of four dogs showed clinical immunological reactions, which could be ascribed to the formation of antibodies. The half-life, T, for human Gc globulin was 12 hr in rats, 16 hr in horses and 30 hr in dogs. The safety profile of plasma-derived Gc globulin is concluded to be consistent to that required for use in man. PMID:20560927

Pihl, Tina Holberg; Jørgensen, Charlotte Svaerke; Santoni-Rugiu, Eric; Leifsson, Páll Skúli; Hansen, Erik Wind; Laursen, Inga; Houen, Gunnar

2010-11-01

283

Preclinical Studies to Predict Efficacy of Vascular Changes Induced by Combretastatin A-4 Disodium Phosphate in Patients  

SciTech Connect

Purpose: To determine how combretastatin A-4 disodium phosphate (CA4DP) dose-dependent changes in radiation response of a C3H mouse mammary carcinoma relate to measurements of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and how those mouse DCE-MRI results compare with published clinical DCE-MRI data. Methods and Materials: C3H mammary carcinomas grown in female CDF{sub 1} mice were treated when at 200 mm{sup 3} in size. Groups of mice were given graded radiation doses, either alone or followed 30 min later by an intraperitoneal injection of CA4DP, administered at doses of 10-250 mg/kg. The radiation dose producing local tumor control in 50% of treated animals at 90 days (TCD{sub 50}) was calculated for each CA4DP dose. DCE-MRI was performed before and 3 h after CA4DP administration, and parameters describing vascularity and interstitial volume were estimated. Results: TCD{sub 50} showed a dose-dependent decrease reaching significance at 25 mg/kg. At greater doses of 50 and 100 mg/kg, the TCD{sub 50} increased slightly and was not significantly different from that of controls. TCD{sub 50} significantly decreased again at 250 mg/kg. The drug dose-response curves for all post-treatment vascular DCE-MRI parameters showed a shape similar to that of the TCD{sub 50} curve. A similar dose dependency was seen with previously published clinical data. Conclusion: Our preclinical DCE-MRI data could predict the CA4DP enhancement of the tumor radiation response and suggest the clinical CA4DP doses necessary to improve the radiation response in patients.

Nielsen, Thomas [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Department of Neuroradiology, Aarhus University Hospital, Aarhus (Denmark)], E-mail: thomas@oncology.dk; Murata, Rumi [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Maxwell, Ross J. [University of Newcastle Upon Tyne, Northern Institute for Cancer Research, Newcastle Upon Tyne (United Kingdom); Stodkilde-Jorgensen, Hans [MR Research Centre, Aarhus University Hospital, Aarhus (Denmark); Ostergaard, Leif [Department of Neuroradiology, Aarhus University Hospital, Aarhus (Denmark); Horsman, Michael R. [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark)

2008-03-01

284

Toxicology 3: Toxicology and Human Health  

NSDL National Science Digital Library

In this lesson, students apply their knowledge about pollutants and human anatomy towards understanding ways in which normal body functioning is impaired by environmental toxicants. Students first review concepts in toxicology and lung anatomy using online problem sets. They then conduct an online investigation and analyze scientific data to examine the effect of environmental tobacco smoke on human lung development.

American Association for the Advancement of Science (;)

2005-06-14

285

Comparative Effectiveness of 3-Dimensional vs 2-Dimensional and High-Definition vs Standard-Definition Neuroendoscopy: A Preclinical Randomized Crossover Study  

PubMed Central

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

Hughes-Hallett, Archie; Cundy, Thomas P.; Di Marco, Aimee; Pratt, Philip; Nandi, Dipankar; Darzi, Ara; Yang, Guang-Zhong

2013-01-01

286

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

NASA Astrophysics Data System (ADS)

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.

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

2014-02-01

287

Toxicology and carcinogenesis studies of microencapsulated trans-cinnamaldehyde in rats and mice  

Microsoft Academic Search

trans-Cinnamaldehyde is a widely used natural ingredient that is added to foods and cosmetics as a flavoring and fragrance agent. Male and female F344\\/N rats and B6C3F1 mice were exposed to microencapsulated trans-cinnamaldehyde in the feed for three months or two years. All studies included untreated and vehicle control groups. In the three-month studies, rats and mice were given diets

M. J. Hooth; R. C. Sills; L. T. Burka; J. K. Haseman; K. L. Witt; D. P. Orzech; A. F. Fuciarelli; S. W. Graves; J. D. Johnson; J. R. Bucher

2004-01-01

288

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...

289

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...

290

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...

291

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...

292

Particulate matter properties and health effects: consistency of epidemiological and toxicological studies.  

PubMed

Identifying the ambient particulate matter (PM) fractions or constituents, critically involved in eliciting adverse health effects, is crucial to the implementation of more cost-efficient abatement strategies to improve air quality. This review focuses on the importance of different particle properties for PM-induced effects, and whether there is consistency in the results from epidemiological and experimental studies. An evident problem for such comparisons is that epidemiological and experimental data on the effects of specific components of ambient PM are limited. Despite this, some conclusions can be drawn. With respect to the importance of the PM size-fractions, experimental and epidemiological studies are somewhat conflicting, but there seems to be a certain consistency in that the coarse fraction (PM10-2.5) has an effect that should not be neglected. Better exposure characterization may improve the consistency between the results from experimental and epidemiological studies, in particular for ultrafine particles. Experimental data indicate that surface area is an important metric, but composition may play an even greater role in eliciting effects. The consistency between epidemiological and experimental findings for specific PM-components appears most convincing for metals, which seem to be important for the development of both pulmonary and cardiovascular disease. Metals may also be involved in PM-induced allergic sensitization, but the epidemiological evidence for this is scarce. Soluble organic compounds appear to be implicated in PM-induced allergy and cancer, but the data from epidemiological studies are insufficient for any conclusions. The present review suggests that there may be a need for improvements in research designs. In particular, there is a need for better exposure assessments in epidemiological investigations, whereas experimental data would benefit from an improved comparability of studies. Combined experimental and epidemiological investigations may also help answer some of the unresolved issues. PMID:17165623

Schwarze, P E; Ovrevik, J; Låg, M; Refsnes, M; Nafstad, P; Hetland, R B; Dybing, E

2006-10-01

293

Nano-based antileishmanial agents: a toxicological study on nanoparticles for future treatment of cutaneous leishmaniasis.  

PubMed

Cutaneous leishmaniasis (CL) is endemic in the tropical and subtropical countries. Antileishmanial drugs that are traditionally used for treatment of CL are mainly toxic, ineffective for some parasite isolates, and mostly expensive. Previous studies showed that some metal and metal oxide nanoparticles have antimicrobial activity. Moreover, the use of nanoparticles together with ultra violet (UV) and infra red (IR) light increases toxic effects of nanoparticles by generation of reactive oxygen species (ROSs) and heat, respectively. There is little information on antileishmanial activity of nanoparticles, alone or together with UV/IR. Thus, the purpose of this research was to study antileishmanial effects of some nanoparticles including silver nanoparticles (Ag NPs), gold nanoparticles (Au NPs), titanium dioxide nanoparticles (TiO2 NPs), zinc oxide nanoparticles (ZnO NPs), and magnesium oxide nanoparticles (MgO NPs) on Leishmania major parasites under UV, IR, and dark conditions. After 24h exposure to nanoparticles, different biological parameters such as cell viability, proliferation, infectivity, and infection index were investigated under UV/IR/dark conditions. In this study, the highest antileishmanial activity was seen for Ag NPs, followed by Au NPs, TiO2 NPs, ZnO NPs, and MgO NPs. Both UV and IR light increased antileishmanial properties of all nanoparticles. In spite of antileishmanial activity of nanoparticles under UV, IR, and dark conditions, these nanoparticles had high cytotoxicity on macrophages, which must be considered in future studies. The authors declare that the use of nanoparticles for treatment of CL may have both positive and negative consequences. PMID:23806227

Jebali, Ali; Kazemi, Bahram

2013-09-01

294

[Determination of 2-metoxy-4-allylhydroxybenzene during chemico-toxicological studies of the biological materials].  

PubMed

This study was designed to evaluate the extraction of 2-metoxy-4-allylhydroxybenzene with hydrophobic organic solvents for its analysis by thin layer chromatography and chromatography on a L 40/100 mcm silica gel column. It is proposed to identify and quantitatively determine2-metoxy-4-allylhydroxybenzene in the extracts from cadaveric liver tissue by means of thin layer chromatography, reverse-phase high performance liquid chromatography with a diode matrix detector and chromatography-mass spectrometry. PMID:23405469

Astashkina, A P; Shormanov, V K; Kirichek, A V; Simonov, E A; Sukhomlinova, E A; Grishechko, O I

2012-01-01

295

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

PubMed Central

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

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

296

Preclinical safety of anecortave acetate.  

PubMed

A number of preclinical safety pharmacology and toxicity studies have been performed on the angiostatic cortisene anecortave acetate in various species and using different routes of administration (oral, intravenous, subcutaneous, topical ocular, intraocular injection, posterior juxtascleral) and a wide range of doses (0-1,000 mg/kg). Anecortave acetate did not interact with a broad panel of pharmacological receptors and had no apparent pharmacological effects on major organ systems including the central nervous, gastrointestinal, renal, cardiovascular, and respiratory systems. Oral, topical ocular, and posterior juxtascleral administration of anecortave acetate had no significant ocular or systemic side effects or toxicity. In addition, there was no significant carcinogenic or reproductive/developmental toxicity associated with anecortave acetate in genotoxicity, carcinogenicity, and reproductive toxicity studies. PMID:17240255

Heaton, Jim; Kastner, Philip; Hackett, Robert

2007-01-01

297

Toxicological significance of dihydrodiol metabolites  

SciTech Connect

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.

Hsia, M.T.

1982-01-01

298

Multilateral in vivo and in vitro protective effects of the novel heat shock protein coinducer, bimoclomol: results of preclinical studies.  

PubMed

Bimoclomol, the recently developed non-toxic heat shock protein (HSP) coinducer, was shown to display multilateral protective activities against various forms of stress or injuries at the level of the cell, tissue or organism. The compound enhanced the transcription, translation and expression of the 70 kD heat shock protein (HSP-70) in myogenic and HeLa cell lines exposed to heat stress, and increased cell survival on exposure to otherwise lethal thermal injury. Bimoclomol increased contractility of the working mammalian heart, this effect was associated with the increased intracellular calcium transients due to increased probability of opening of ryanodine receptors in the sarcoplasmic reticulum (SR). In healthy tissues these cardiac effects were evident only at relatively high concentrations of the drug, while in the ischemic myocardium bimoclomol exerted significant cardioprotective and antiarrhythmic effects at submicromolar concentrations. It decreased ischemia-induced reduction of contractility and of cardiac output, and dramatically decreased the elevation of the ST-segment during ischemia as well as the occurrence of ventricular fibrillation upon reperfusion. Bimoclomol was also active in various pathological animal models subjected to acute or chronic stress. In the spontaneously hypertensive rats chronic pretreatment with bimoclomol restored sensitivity of aortic rings to acetylcholine; this effect was accompanied by accumulation of HSP-70 in the tissues. Bimoclomol pretreatment significantly diminished the consequences of vascular disorders associated with diabetes mellitus. Diabetic neuropathy, retinopathy, and nephropathy were prevented or diminished, while wound healing was enhanced by bimoclomol. Enhancement of wound healing by bimoclomol was observed after thermal injury as well as following ultraviolet (UV) irradiation. In addition to the beneficial effects on peripheral angiopathies, bimoclomol antagonized the increase in permeability of blood-brain barrier induced by subarachnoid hemorrhager or arachidonic acid. A general and very important feature of the above effects of bimoclomol was that the drug failed to cause alterations under physiological conditions (except the enhanced calcium release from cardiac sarcoplasmic reticulum). Bimoclomol was effective only under conditions of stress. Consistent with its HSP-coinducer property, bimoclomol alone had very little effect on HSP production. Its protective activity became apparent only in the presence of cell damage. Currently, bimoclomol reached the end of the Phase II clinical trial in a group of 410 patients with diabetic complications. Results of this trial will answer the question, whether a compound with promising in vitro and in vivo preclinical findings will produce the anticipated beneficial effects in humans. In the event of a positive outcome of this trial, the indications for bimoclomol will be substantially extended. PMID:11484067

Nánási, P P; Jednákovits, A

2001-01-01

299

Toxicological study and oxidative stress evaluation for safety assessment of xylanase preparations in Wistar rats.  

PubMed

Acute and 90-day subchronic oral toxicity studies were conducted to establish the safety evaluation of xylanases preparations. A potential oxidative stress evaluation was also performed through testing the generation of oxidative radicals, depletion of antioxidants via oxidative modification of lipids, proteins and DNA of organ cells. During the subchronic oral toxicity study, no mortality was observed, obvious treatment-related clinical signs and urinalysis parameters were in normal range. Differences in some hematological parameters, biochemistry, relative organ weight, and histopathology examinations between the treated group and the control group were not judged to be adverse. Our results indicated that the no-observed-adverse-effect level for xylanases was 1,500 TXU/kg/day and the plasma antioxidant assays showed that these xylanases did not produce free-radicals nor oxidative injuries. On the basis of the bacterial reverse mutation assay data, it is concluded that the expressed xylanase in Pichia pastoris do not present any mutagenic potential when tested in relevant genotoxicological assays. PMID:25044497

Driss, Dorra; Soudani, Najla; Boudawara, Tahia; Zeghal, Najiba; Chaabouni, Semia Ellouze

2014-11-01

300

TOXNET: Toxicology Data Network  

MedlinePLUS

... Schedule Welcome to TOXNET Your resource for searching databases on toxicology, hazardous chemicals, environmental health, and toxic ... Household Products TOXMAP TRI Search Please select a database for ADVANCED SEARCH Search Term Records with Include ...

301

Toxicological Sciences Online  

NSDL National Science Digital Library

The journal Toxicological Sciences is now available online, thanks to a combined effort of the Society for Toxicology and Stanford University's HighWire Press. Toxicological Sciences publishes "research articles that are broadly relevant to assessing the potential adverse health effects resulting from exposure of human or animals to chemicals, drugs, natural products, or synthetic materials." Manuscripts are published in "all areas of toxicology" including descriptive, mechanistic, interpretive, theoretical, experimental, and observational investigations. The full text (.pdf format) of all articles is available online starting 1999, with abstracts from 1998. The Society has yet to announce when the free trial period will end, but at present, the site allows free access to all online materials, as well as a free sample issue.

2001-01-01

302

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

SciTech Connect

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

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

1988-02-01

303

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

PubMed Central

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

2014-01-01

304

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

PubMed

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

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

2011-01-01

305

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

PubMed

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

Ballantyne, B; Vergnes, J S

2001-01-01

306

Preclinical development of monoclonal antibodies  

PubMed Central

The development of mAbs remains high on the therapeutic agenda for the majority of pharmaceutical and biotechnology companies. Often, the only relevant species for preclinical safety assessment of mAbs are non-human primates (NHPs), and this raises important scientific, ethical and economic issues. To investigate evidence-based opportunities to minimize the use of NHPs, an expert working group with representatives from leading pharmaceutical and biotechnology companies, contract research organizations and institutes from Europe and the USA, has shared and analyzed data on mAbs for a range of therapeutic areas. This information has been applied to hypothetical examples to recommend scientifically appropriate development pathways and study designs for a variety of potential mAbs. The addendum of ICHS6 provides a timely opportunity for the scientific and regulatory community to embrace strategies which minimize primate use and increase efficiency of mAb development. PMID:20065651

Pullen, Nick; Coney, Lee; Dempster, Maggie; Andrews, Laura; Bajramovic, Jeffrey; Baldrick, Paul; Buckley, Lorrene; Jacobs, Abby; Hale, Geoff; Green, Colin; Ragan, Ian; Robinson, Vicky

2009-01-01

307

Preclinical molecular imaging of tumor angiogenesis.  

PubMed

Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging technologies accelerate the translation of preclinical research to the clinic. In oncology, various imaging modalities are widely applied to drug development, tumor early detection and therapy response monitoring. So far, several angiogenesis related imaging agents are promising in cancer diagnosis. However, more effective imaging agents with less side-effect still need to be pursued to visualize angiogenesis process non-invasively. The main purpose of this review is to summarize the recent progresses in preclinical molecular imaging of angiogenesis and to discuss the potential of the current preclinical probes specific to various angiogenesis targets including vascular endothelial growth factor and its receptors (VEGF/VEGFRs), integrin avb3 and matrix metalloproteinases (MMPs). It is predictable that related investigations in the field will benefit cancer research and quicken the anti-angiogenic drug development. PMID:20639815

Zhu, L; Niu, G; Fang, X; Chen, X

2010-06-01

308

Preclinical Cardiorenal Interrelationships in Essential Hypertension  

PubMed Central

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

Tsioufis, Costas; Tsiachris, Dimitrios; Kasiakogias, Alexandros; Dimitriadis, Kyriakos; Petras, Dimitris; Goumenos, Dimitris; Siamopoulos, Konstantinos; Stefanadis, Christodoulos

2013-01-01

309

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

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

Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari

2014-01-01

310

[Clinical toxicology of the Academy: yesterday, today and tomorrow].  

PubMed

National toxicology school of the Kirov Military Medical Academy, demonstrates the unity of clinical and experimental approaches related to one purpose throughout its history--saving human life and health from exposure to toxic substances of chemical nature. For more than three centuries the russian science of toxicology has been steadily developing, often ahead of the world science. It helped to create the means of protection and develop methods of treatment for chemical lesions. Currently, toxicology departments of military field therapy and military toxicology and medical protection are actively involved in the current study of military medicine, restructuring policy to provide toxicological aid in the Armed Forces, the development and introduction of Innovative methods of diagnosis and treatment of victims of toxicological etiology. PMID:24738280

Sofronov, G A; Khalimov, Iu Sh; Matveev, S Iu; Kuz'mich, V G; Fomichev, A V

2013-12-01

311

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

SciTech Connect

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.

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

2014-05-15

312

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

NASA Astrophysics Data System (ADS)

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.

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

2014-05-01

313

Interdisciplinary 2007 Toxicology External Review i  

E-print Network

TEXAS A&M UNIVERSITY Interdisciplinary Faculty of May 2007 Toxicology #12;#12;2007 Toxicology of Toxicology Chair . . . . . . . . . . 1 B. Charge to the Review Team. Development of the IFT and Related Centers and Programs . . . . . . . . . . . 3 1. Toxicology Training Grant

314

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

PubMed

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

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

2014-11-26

315

Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.  

PubMed

The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study. PMID:12485205

McCall, R B; Huff, R; Chio, C L; TenBrink, R; Bergh, C L; Ennis, M D; Ghazal, N B; Hoffman, R L; Meisheri, K; Higdon, N R; Hall, E

2002-12-01

316

Biodegradation of Rubine GFL by Galactomyces geotrichum MTCC 1360 and subsequent toxicological analysis by using cytotoxicity, genotoxicity and oxidative stress studies.  

PubMed

Galactomyces geotrichum MTCC 1360 showed 87?% decolorization of the azo dye Rubine GFL (50 mg l(-1)) within 96 h at 30 °C and pH 7.0 under static conditions, with significant reduction of chemical oxygen demand (67?%) and total organic carbon (59?%). Examination of oxidoreductive enzymes, namely laccase, tyrosinase and azo reductase, confirmed their role in decolorization and degradation of Rubine GFL. Biodegradation of Rubine GFL into different metabolites was confirmed using high-performance TLC, HPLC, Fourier transform IR spectroscopy and GC-MS analysis. During toxicological studies, cell death was observed in Rubine GFL-treated Allium cepa root cells. Toxicological studies before and after microbial treatment were done with respect to cytotoxicity, genotoxicity, oxidative stress, antioxidant enzyme status, protein oxidation and lipid peroxidation using root cells of A. cepa. The analysis with A. cepa showed that the dye exerts oxidative stress and subsequently has a toxic effect on the root cells, whereas its metabolites are less toxic. Phytotoxicity studies revealed the less toxic nature of the metabolites as compared with Rubine GFL. PMID:22723285

Waghmode, Tatoba R; Kurade, Mayur B; Kabra, Akhil N; Govindwar, Sanjay P

2012-09-01

317

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

PubMed Central

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

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

2013-01-01

318

Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human-Mouse Chimeric and Glycoengineered Antibody.  

PubMed

Metuzumab is an affinity-optimized and nonfucosylated anti-CD147 human-mouse chimeric IgG1 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC). The purpose of this study was to characterize the pharmacokinetics, safety, and antitumor activities of metuzumab in mouse, rat, and monkey. The ADCC activity was assessed by a lactate dehydrogenase release assay. The pharmacokinetics of metuzumab were determined in Sprague-Dawley rats and in cynomolgus monkeys. Single- and repeat-dose toxicology studies of the i.v. administration of high-dose metuzumab were conducted in cynomolgus monkeys. Mice bearing human tumor xenografts were used to evaluate the antitumor efficacy of metuzumab. The ADCC potency of metuzumab was enhanced compared with the nonglycoengineered parental antibody. Metuzumab also effectively inhibited tumor growth in A549 and NCI-H520 xenograft models. In the monkey model, the total clearance of metuzumab decreased with increasing dose. The nonspecific clearance in monkeys was estimated to be 0.53 to 0.92 mL/h/kg. In single- and repeat-dose toxicology studies in cynomolgus monkeys, metuzumab did not induce any distinct or novel adverse findings and was well tolerated at all tested doses. These preclinical safety data facilitated the initiation of an ongoing clinical trial of metuzumab for the treatment of non-small cell lung cancer (NSCLC) in China. Mol Cancer Ther; 14(1); 162-73. ©2014 AACR. PMID:25376611

Zhang, Zheng; Zhang, Yang; Sun, Qian; Feng, Fei; Huhe, Muren; Mi, Li; Chen, Zhinan

2015-01-01

319

Robotic System for Handling Infectious Clinical and PreClinical Serum Samples  

Microsoft Academic Search

The Bioanalytical Laboratory at the Schering-Plough Research Institute is a service laboratory which performs drug level measurements in serum in support of pre-clinical toxicological tests, as well as human clinical trials for anti-viral compounds. A new robot system for the laboratory had two external constraints put on it, besides those typical for a robotic system: since it handled infectious serum

David Pechter; Eugene Lockhart; Robert Firman; Jun Chen; Rick Johnstone; Eric Chaplin

1999-01-01

320

Studies on the human metabolism and the toxicologic detection of the cough suppressant dropropizine in urine using gas chromatography-mass spectrometry.  

PubMed

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

Staack, Roland F; Theobald, Denis S; Maurer, Hans H

2004-08-01

321

American College of Medical Toxicology  

NSDL National Science Digital Library

The American College of Medical Toxicology (ACMT) is a professional, nonprofit association of physicians with recognized expertise in medical toxicology, whose mission is to ensure that patients exposed to poisons and toxic substances receive optimal care.

2007-05-06

322

Non-precautionary aspects of toxicology  

SciTech Connect

Empirical studies in toxicology aim at deciphering complex causal relationships, especially in regard to human disease etiologies. Several scientific traditions limit the usefulness of documentation from current toxicological research, in regard to decision-making based on the precautionary principle. Among non-precautionary aspects of toxicology are the focus on simplified model systems and the effects of single hazards, one by one. Thus, less attention is paid to sources of variability and uncertainty, including individual susceptibility, impacts of mixed and variable exposures, susceptible life-stages, and vulnerable communities. In emphasizing the need for confirmatory evidence, toxicology tends to penalize false positives more than false negatives. An important source of uncertainty is measurement error that results in misclassification, especially in regard to exposure assessment. Standard statistical analysis assumes that the exposure is measured without error, and imprecisions will usually result in an underestimation of the dose-effect relationship. In testing whether an effect could be considered a possible result of natural variability, a 5% limit for 'statistical significance' is usually applied, even though it may rule out many findings of causal associations, simply because the study was too small (and thus lacked statistical power) or because some imprecision or limited sensitivity of the parameters precluded a more definitive observation. These limitations may be aggravated when toxicology is influenced by vested interests. Because current toxicology overlooks the important goal of achieving a better characterization of uncertainties and their implications, research approaches should be revised and strengthened to counteract the innate ideological biases, thereby supporting our confidence in using toxicology as a main source of documentation and in using the precautionary principle as a decision procedure in the public policy arena.

Grandjean, Philippe [Institute of Public Health, University of Southern Denmark, Winslowparken 17, DK-5000 Odense C (Denmark) and Department of Environmental Health, Harvard School of Public Health, Landmark Center 3-110 East, 401 Park Drive, Boston, MA 02215 (United States)]. E-mail: pgrand@health.sdu.dk

2005-09-01

323

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

PubMed

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

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

2014-01-01

324

The ?2?1 binding domain of chondroadherin inhibits breast cancer-induced bone metastases and impairs primary tumour growth: A preclinical study.  

PubMed

cyclicCHAD is a peptide representing the ?2?1 integrin binding sequence of the matrix protein chondroadherin (CHAD), which in our hands proved effective at counteracting bone loss in ovariectomised mice by inhibiting osteoclastogenesis. Given that bone metastases are characterised by exacerbated osteoclast activity as well, we tested this therapy in mice intracardiacally injected with the osteotropic human breast cancer cell line MDA-MB-231. Treatment with cyclicCHAD significantly decreased cachexia and incidence of bone metastases, and induced a trend of reduction of visceral metastasis volume, while in orthotopically injected mice cyclicCHAD reduced tumour volume. In vitro studies showed its ability to impair tumour cell motility and invasion, suggesting a direct effect not only on osteoclasts but also on the tumour cell phenotype. Interestingly, when administered together with a suboptimal, poorly effective, dose of doxorubicin (DXR), cyclicCHAD improved survival and reduced visceral metastases volume to a level similar to that of the optimal dose of DXR alone. Taken together, these preclinical data suggest that cyclicCHAD is a new inhibitor of bone metastases, with an appreciable direct effect also on tumour growth and a synergistic activity in combination with low dose chemotherapy, underscoring an important translational impact. PMID:25529009

Rucci, Nadia; Capulli, Mattia; Olstad, Ole K; Önnerfjord, Patrik; Tillgren, Viveka; Gautvik, Kaare M; Heinegård, Dick; Teti, Anna

2015-03-01

325

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)

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.

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

2014-08-01

326

Preclinical studies with the anti-CD19-saporin immunotoxin BU12-SAPORIN for the treatment of human-B-cell tumours.  

PubMed Central

The immunotoxin BU12-SAPORIN was constructed by covalently coupling the single-chain ribosome-inactivating protein saporin to the anti-CD19 monoclonal antibody BU12 via a disulphide linker using the heterobifunctional reagent SPDP. The immunoreactivity and specificity of BU12-SAPORIN was identical to that of unmodified native BU12 antibody. BU12-SAPORIN was selectively cytotoxic in vitro in a dose-dependent manner for the CD19+ human common acute lymphoblastic leukaemia (cALL) cell line NALM-6 but exhibited no toxicity for the CD19- T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2. The survival of severe combined immunodeficient (SCID) mice with disseminated NALM-6 leukaemia was significantly prolonged compared with sham-treated control animals by a course of therapy with BU12-SAPORIN but not with the irrelevant anti-CD7 immunotoxin HB2-SAPORIN. BU12-SAPORIN had no therapeutic effect in SCID mice with disseminated CD19- HSB-2 leukaemia. These preclinical studies have clearly demonstrated the selective cytotoxicity of BU12-SAPORIN for CD19+ target cells both in vitro and in vivo. This, taken together with the lack of expression of the CD19 molecule by any normal life-sustaining tissue and its ubiquitous and homogeneous expression by the majority of cALL and B-NHL cells, provides the rationale for undertaking a phase I trial of systemic therapy with BU12-SAPORIN. Images Figure 1 PMID:8519647

Flavell, D. J.; Flavell, S. U.; Boehm, D. A.; Emery, L.; Noss, A.; Ling, N. R.; Richardson, P. R.; Hardie, D.; Wright, D. H.

1995-01-01

327

Preclinical evaluation of HIV eradication strategies in the simian immunodeficiency virus-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenase.  

PubMed

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

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

2013-02-01

328

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

PubMed Central

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

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

2013-01-01

329

Rigor or mortis: best practices for preclinical research in neuroscience.  

PubMed

Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. PMID:25442936

Steward, Oswald; Balice-Gordon, Rita

2014-11-01

330

Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs  

PubMed Central

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

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

331

The antispasmodic drug mebeverine leads to positive amphetamine results by fluorescence polarization immunoassay (FPIA)--studies on the toxicological analysis of urine by FPIA and GC-MS.  

PubMed

Mebeverine (Duspatal, MB), an antispasmodic drug, is the veratric acid ester of 4-[ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino]butan-1-ol (MB-OH), which is a N-substituted ethylamphetamine derivative. MB is metabolized via ester hydrolysis to MB alcohol (MB-OH) and veratric acid. N-Dehydroxybutylation leads to methoxyethylamphetamine (MO-EA) and, after O-demethylation, to hydroxy EA (HO-EA). N-Bisdealkylation leads to p-methoxyamphetamine (PMA). MO-EA and PMA are also known as designer drugs. Fluorescence polarization immunoassay (FPIA) and gas chromatographic-mass spectrometric studies on the toxicological analysis of MB after ingestion of a single 405-mg oral dose of MB were performed. We could show that intake of MB leads to positive FPIA results for amphetamine. The N-dehydroxybutyl metabolites of MB, MO-EA, HO-EA, and the bis-dealkyl metabolite PMA should be responsible for the positive immunoassay results. Using our systematic toxicological analysis procedure, every positive amphetamine immunoassay could be explained by detection of MO-EA, HO-EA, and/or PMA. Misinterpretation of the origin of MO-EA, HO-EA, or PMA can be avoided by detecting the specific (non-dehydroxybutylated) metabolites of MB, which are excreted for a much longer time after ingestion. PMID:11499887

Kraemer, T; Wennig, R; Maurer, H H

2001-01-01

332

Inhalation Toxicology, 20:981993, 2008 Copyright c Informa UK Ltd.  

E-print Network

Inhalation Toxicology, 20:981­993, 2008 Copyright c Informa UK Ltd. ISSN: 0895-8378 print / 1091 Materials used in 28-Day and 90-Day Intratracheal Instillation Toxicology Studies in Rats W. Miles Miles., Billings, Montana, USA Two recent intratracheal instillation toxicology studies in rats clearly show

Ahmad, Sajjad

333

The Graduate School TOX Toxicology  

E-print Network

The Graduate School TOX Toxicology KEY: # = new course * = course changed = course dropped University of Kentucky 2013-2014 Undergraduate Bulletin 1 TOX 508 RESEARCH METHODS IN TOXICOLOGY. (1-3) The course provides students with `hands on' experience in research methods used to solve toxicological

MacAdam, Keith

334

ESD Toxicology Laboratory Representative References  

E-print Network

1 ESD Toxicology Laboratory Representative References Application Category Literature citation.2: 205-230. #12;ESD Toxicology Laboratory Representative References cont'd 2 Pure-chemical testing: 6th ASTM Symp. on Aquatic Toxicology. Amer. Soc. Testing and Materials. pp 445-459. Milleman, R. E

335

Oral-toxicology  

PubMed Central

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

Gowda, B. K. Charan; Sundharam, B. Sivapatha; Mahadesh, Jyothi; Mukund

2014-01-01

336

Shuttle Lesson Learned - Toxicology  

NASA Technical Reports Server (NTRS)

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.

James, John T.

2010-01-01

337

Enivronmental Health and Toxicology  

NSDL National Science Digital Library

This site is packed with information related to the topic of environmental health and toxicology. There is an excellent tutorial section specifically targeted toward educators and students. The site has a wealth of information about chemicals used in industry and in the average household. This site would be beneficial to students working on environmental problems or trying to understand the chemicals they encounter on a day-to-day basis. The variety of toxicology and environmental health databases assembled and the links provides on this site provide a valuable resource for students to gather information.

2011-04-25

338

Evaluation of diethylnitrosamine- or hepatitis B virus X gene-induced hepatocellular carcinoma with 18F-FDG PET/CT: A preclinical study.  

PubMed

The aim of this study was to evaluate whether the development of hepatocellular carcinoma (HCC) in murine models resembles tumor progression in humans, using non?invasive molecular imaging methods. Murine HCC models were generated by treating mice with diethylnitrosamine (DEN) or by the transgenic expression of hepatitis B virus X (HBx) protein (HBx-Tg model). Tumor development was detected using 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological changes and expression of glucose transporter 1 (Glut1) and hexokinase 2 (HK2) were evaluated using hematoxylin and eosin and immunohistochemical staining, respectively. Tumor lesions as small as 1 mm in diameter were detected by MRI. Tumor development was monitored using 18F-FDG PET/CT at 6.5?10 months after DEN treatment or 11?20 months after birth of the HBx-Tg model mice. A correlation study between the 18F-FDG uptake levels and expression levels of HK2 and Glut1 in developed HCC showed a high 18F-FDG uptake in poorly differentiated HCCs that expressed high levels of HK2, in contrast to that in well-differentiated tumors. The progression of primary HCCs resembling human HCC in murine models was detected and monitored by 18F-FDG PET/CT. The correlation between tumor size and SUVmax was verified in the two HCC models. To the best of our knowledge, this is the first study to demonstrate that in vivo 18F-FDG uptake varies in HCCs according to differentiation grade in a preclinical study. PMID:25371060

Park, Ju Hui; Kang, Joo Hyun; Lee, Yong Jin; Kim, Kwang Il; Lee, Tae Sup; Kim, Kyeong Min; Park, Ji Ae; Ko, Yin Ohk; Yu, Dae-Yeul; Nahm, Sang-Soep; Jeon, Tae Joo; Park, Young-Seo; Lim, Sang Moo

2015-01-01

339

TOXICOLOGICAL RESEARCH INVOLVING HUMANS: ETHICAL AND REGULATORY CONSIDERATIONS  

EPA Science Inventory

This paper discusses the need for the Society of Toxicology (SOT) to develop a policy for ethical research in humans, and a review for publication of these studies. Observations on human beings have been the foundation upon which toxicologic knowledge has been built since the in...

340

Regulatory considerations for preclinical development of anticancer drugs  

Microsoft Academic Search

The entry of new anticancer treatments into phase I clinical trials is ordinarily based on relatively modest preclinical\\u000a data. This report defines the battery of preclinical tests important for assessing safety under an Investigational New Drug\\u000a application (IND) and outlines a basis for extrapolating starting doses of investigational anticancer drugs in phase I clinical\\u000a trials from animal toxicity studies. Types

Joseph J. DeGeorge; Chang-Ho Ahn; Paul A. Andrews; Margaret E. Brower; Diana W. Giorgio; M. Anwar Goheer; Doo Y. Lee-Ham; W. David McGuinn; Wendelyn Schmidt; C. Joseph Sun; Satish C. Tripathi

1997-01-01

341

Toxicology, an STS Approach.  

ERIC Educational Resources Information Center

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)

Wagner, Richard

1990-01-01

342

Toxicology and Chemical Safety.  

ERIC Educational Resources Information Center

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)

Hall, Stephen K.

1983-01-01

343

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 ...

344

Fibrillar Amyloid Correlates of Preclinical Cognitive Decline  

PubMed Central

Background It is not known whether preclinical cognitive decline is associated with fibrillar ?-amyloid (A?) deposition irrespective of Apolipoprotein E (APOE) ?4 status. Methods From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ?4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVR), reflecting fibrillar A? burden. Results At P<.005 (uncorrected), decliners had significantly greater DVR’s in comparison to nondecliners. Conclusions Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ?4 genotype. PMID:23583233

Stonnington, Cynthia M.; Chen, Kewei; Lee, Wendy; Locke, Dona E.C.; Dueck, Amylou C.; Liu, Xiaofen; Roontiva, Auttawut; Fleisher, Adam S.; Caselli, Richard J.; Reiman, Eric M.

2013-01-01

345

A rapid and sensitive LC-MS/MS assay for the determination of berbamine in rat plasma with application to preclinical pharmacokinetic study.  

PubMed

Berbamine (BBM), a natural compound from Chinese herb Berberis amurensis, has recently received a great deal of attention due to its anti-leukemia activity. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of BBM in rat plasma was developed for the first time. Caffeine was used as an internal standard. Chromatographic separation was performed on an ODS column with gradient elution using methanol-1% formic acid as mobile phase at a flow rate of 0.3mL/min. Quantification was through tandem mass spectrometry with positive electrospray ionization (ESI) and multiple reaction monitoring (MRM) at m/z 305.2?566.3 and 195.1?138.0 for BBM and IS, respectively. The lower limit of quantification was 1ng/mL with a linear range of 1-1000ng/mL. The intra- and inter-day assay precision (RSD) ranged from 2.0-6.4% to 2.5-5.5%, respectively, and the intra- and inter-day assay accuracy (RE) was between -5.8-6.0% and -6.5-1.4%, respectively. The validated method was successfully applied to the preclinical pharmacokinetic studies of BBM in rats. The elimination half-lives (t1/2) were (472.4±66.1), (509.6±97.0) and (486.2±94.6) min after single intravenous administration of 2, 4 and 8mg/kg BBM, respectively. The area under the plasma concentration versus time curve (AUC0-24h) and initial plasma concentration (C0) were linearly related to dose. PMID:23660248

Liu, Qingwang; Wang, Junsong; Yang, Lei; Jia, Yuanwei; Kong, Lingyi

2013-06-15

346

In situ study of the impact of inter- and intra-reader variability on region of interest (ROI) analysis in preclinical molecular imaging  

PubMed Central

We estimated reader-dependent variability of region of interest (ROI) analysis and evaluated its impact on preclinical quantitative molecular imaging. To estimate reader variability, we used five independent image datasets acquired each using microPET and multispectral fluorescence imaging (MSFI). We also selected ten experienced researchers who utilize molecular imaging in the same environment that they typically perform their own studies. Nine investigators blinded to the data type completed the ROI analysis by drawing ROIs manually that delineate the tumor regions to the best of their knowledge and repeated the measurements three times, non-consecutively. Extracted mean intensities of voxels within each ROI are used to compute the coefficient of variation (CV) and characterize the inter- and intra-reader variability. The impact of variability was assessed through random samples iterated from normal distributions for control and experimental groups on hypothesis testing and computing statistical power by varying subject size, measured difference between groups and CV. The results indicate that inter-reader variability was 22.5% for microPET and 72.2% for MSFI. Additionally, mean intra-reader variability was 10.1% for microPET and 26.4% for MSFI. Repeated statistical testing showed that a total variability of CV < 50% may be needed to detect differences < 50% between experimental and control groups when six subjects (n = 6) or more are used and statistical power is adequate (80%). Surprisingly high variability has been observed mainly due to differences in the ROI placement and geometry drawn between readers, which may adversely affect statistical power and erroneously lead to negative study outcomes. PMID:23526701

Habte, Frezghi; Budhiraja, Shradha; Keren, Shay; Doyle, Timothy C; Levin, Craig S; Paik, David S

2013-01-01

347

Toxicological evaluation of pidotimod.  

PubMed

This paper reports the toxicological evaluation of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6). Its acute toxicity in mice, rats and dogs was very low after oral, i.v., i.m. and i.p. administration. The repeated administration studies in rats were performed for 4 months via the i.p. route and for 12 months via the oral route. Pidotimod did not show toxic effects at dosages up to 200 mg/kg i.p. and 800 mg/kg p.o. These dosages correspond to 32.5 times the maximum dosage intended for clinical use. The repeated administration studies in dogs were performed for 26 weeks via the i.m. route and for 52 weeks via the oral route. Pidotimod did not show toxic effects at dosages up to 300 mg/kg i.m. and 600 mg/kg p.o.. It did not affect male or female rat fertility at dosages up to 600 mg/kg by oral and 500 mg/kg by i.v. route. The compound was not teratogenic in rats (600 mg/kg p.o. and 1000 mg/kg i.v.), with no effects on subsequent embryofoetal development at dosages up to 1000 mg/kg/day, and in rabbits (300 mg/kg p.o. and 500 mg/kg. i.v.). There were no peri- and postnatal toxic effects in rats (600 mg/kg p.o. and 500 mg/kg i.v.). Local tolerability of pidotimod after i.m. administration was very good. In conclusion pidotimod is characterized by a high safety margin in all animal species. PMID:7857340

Coppi, G; Amico-Roxas, M; Bertè, F; Bussi, R; Gnemi, P; Harling, R J; Mailland, F; Manzardo, S; Massey, J E; Spencer-Briggs, D J

1994-12-01

348

Toxicological characterization of the landfill leachate prior/after chemical and electrochemical treatment: a study on human and plant cells.  

PubMed

In this research, toxicological safety of two newly developed methods for the treatment of landfill leachate from the Piškornica (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

Garaj-Vrhovac, Vera; Oreš?anin, Višnja; Gajski, Goran; Geri?, Marko; Ruk, Damir; Kollar, Robert; Radi? Brkanac, Sandra; Cvjetko, Petra

2013-10-01

349

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

E-print Network

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

Kelly, Shawn K.

350

Environmental Toxicology and Chemistry, Vol. 19, No. 10, pp. 23912393, 2000 Printed in the USA  

E-print Network

2391 Environmental Toxicology and Chemistry, Vol. 19, No. 10, pp. 2391­2393, 2000 2000 SETAC Printed in the USA 0730-7268/00 $9.00 .00 Letter to the Editor REPTILE TOXICOLOGY: CHALLENGES in reptile toxicology. Reptiles are the least studied group of vertebrates (mam- mals, birds, fish

Hopkins, William A.

351

Environmental Toxicology and Chemistry, Vol. 27, No. 9, pp. 18251851, 2008 Printed in the USA  

E-print Network

1825 Environmental Toxicology and Chemistry, Vol. 27, No. 9, pp. 1825­1851, 2008 2008 SETAC Printed of Environmental Toxicology, Department of Biology, Clemson University, P.O. Box 709 Pendleton, South Carolina studies on colloidal behavior and toxicology. The need for standard reference and testing materials

Alvarez, Pedro J.

352

Environmental Toxicology and Chemistry, Vol. 27, No. 9, pp. 18881894, 2008 Printed in the USA  

E-print Network

1888 Environmental Toxicology and Chemistry, Vol. 27, No. 9, pp. 1888­1894, 2008 2008 SETAC Printed there is a spill of C60 powder or C60 solution in a solvent [8], several toxicological studies have focused on nC60 to obtain representative results of potential environmental impacts. In addition to toxicological tests

Alvarez, Pedro J.

353

D.M. Whitacre (ed) Reviews of Environmental Contamination and Toxicology 214, 87-124  

E-print Network

D.M. Whitacre (ed) Reviews of Environmental Contamination and Toxicology 214, 87-124 DOI 10 and Toxicology 214 (2011) p. 87 - p. 124" DOI : 10.1007/978-1-4614-0668-6_5 #12;physiological characteristics the importance of reinforcing the ecological relevance of toxicological studies to improve ecotoxicological risk

Paris-Sud XI, Université de

354

Evaluation of Wound-Healing Potential of Pisonia grandis R.Br: A Preclinical Study in Wistar Rats  

Microsoft Academic Search

Pisonia grandis R.Br (family: Nyctaginaceae) is a herb claimed to be used for treatment of inflammation, wound healing, algesia, and ulcer. The present study was done to evaluate the wound-healing potential of methanolic extract of its leaves. Following preliminary photochemical evaluation, the extract was incorporated in simple ointment base and evaluated using 2 types of wound models in Wistar rats—excision

D. Prabu; M. Nappinnai; K. Ponnudurai; K. Prabhu

2008-01-01

355

[Preclinical studies for the use of the platelet function analyser PFA-100 with the collagen/ADP cartridge in dogs].  

PubMed

In this study, the following three aspects of platelet function analyser were investigated in dogs, using a collagen/ADP cartridge: precision, influence of the cartridge batch and of the sample storage time. Closure time and total volume of blood flow until closure of the capillary were measured. Based on several series of 5 repeated measurements mean coefficients of variation were 5% (3-6%; closure time) or 3% (1-5%; total volume). Neither closure time, nor total volume showed significant differences (p > 0.05) when comparing the results of 6 different batches of the collagen/ADP cartridge. Closure time (p = 0.0211, analysis of variance) and total volume (p = 0.0310) were significantly influenced by storage time, based on the sample material of 6 healthy dogs which was stored for 24 hours. Shortening of the closure time and decrease of the total volume observed in the time interval 1-2 hours after blood collection was followed by a significant prolongation of closure time and increase of the total volume (p < 0.05) starting 8 hours after blood collection. This study shows sufficient reproducibility which is not affected by reagent batch number. The results of the studies on storage indicated nearly identical recommendations for storage time before measurement of canine (0.5-2 hours) and human (0.5-3 hours) sample material. PMID:12073497

Mischke, R; Keidel, A

2002-05-01

356

Adjuvant anticholinesterase therapy for the management of epilepsy-induced memory deficit: a critical pre-clinical study.  

PubMed

Epilepsy is one of the major neurological disorders still awaiting safer drugs with improved antiepileptic effect and lesser side effects. Apart from epilepsy itself, AEDs also have been shown to induce cognitive impairment in patients with epilepsy. There are limited data for the treatment of this menace. As cholinergic approach has widely been practiced for the restoration of memory in various neurodegenerative disorders, this study was envisaged to evaluate add on effect of acetylcholinesterase inhibitor (tacrine) with phenytoin in pentylenetetrazole-kindling-induced learning and memory deficit in mice. In this study, mice were kindled using subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.; at interval of 48 ± 2 hr) and successfully kindled animals were divided into different groups and treated with vehicle, phenytoin and phenytoinin in combination with tacrine (0.3 mg/kg), atropine (1 mg/kg) and tacrine + atropine. Effect of different interventions on learning and memory was evaluated using elevated plus maze and passive shock avoidance on days 5, 10, 15 and 20. Phenytoin-treated kindled animals were associated with learning and memory deficit, while tacrine supplementation improved memory deficit with increased seizure severity score. Atropine treatment significantly reversed the protective effect of tacrine. Neurochemical findings also support the behavioural finding of the study. Our results suggest the use of anticholinesterases, with better seizure tolerance, for the management of cognitive impairment of epilepsy, as adjunct therapy. PMID:24890882

Mishra, Awanish; Goel, Rajesh Kumar

2014-12-01

357

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

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

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

2013-01-01

358

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

PubMed Central

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

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

2011-01-01

359

Bias analyses of preclinical and clinical d2 dopamine ligands: studies with immediate and complex signaling pathways.  

PubMed

G protein-coupled receptors (GPCRs) often activate multiple signaling pathways, and ligands may evoke functional responses through individual pathways. These unique responses provide opportunities for biased or functionally selective ligands to preferentially modulate one signaling pathway over another. Studies with several GPCRs have suggested that selective activation of signaling pathways downstream of a GPCR may lead to safer and more effective drug therapies. The dopamine D2 receptor (D2R) is one of the main drug targets in the therapies for Parkinson's disease and schizophrenia. Recent studies suggest that selective modulation of individual signaling pathways downstream of the D2R may lead to safer antipsychotic drugs. In the present study, immediate effectors of the D2R (i.e., G?i/o, G??, ?-arrestin recruitment) and more complex signaling pathways (i.e., extracellular signal-regulated kinase phosphorylation, heterologous sensitization, and dynamic mass redistribution) were examined in response to a series of D2R ligands. This was accomplished using Chinese hamster ovary cells stably expressing the human D2L dopamine receptor in the PathHunter ?-Arrestin GPCR Assay Platform. The use of a uniform cellular background was designed to eliminate potential confounds associated with cell-to-cell variability, including expression levels of receptor as well as other components of signal transduction, including G protein subunits. Several well characterized and clinically relevant D2R ligands were evaluated across each signaling pathway in this cellular model. The most commonly used methods to measure ligand bias were compared. Functional selectivity analyses were also used as tools to explore the relative contribution of immediate D2R effectors for the activation of more complex signaling pathways. PMID:25539635

Brust, Tarsis F; Hayes, Michael P; Roman, David L; Burris, Kevin D; Watts, Val J

2015-03-01

360

Toxicologic methods: controlled human exposures.  

PubMed Central

The assessment of risk from exposure to environmental air pollutants is complex, and involves the disciplines of epidemiology, animal toxicology, and human inhalation studies. Controlled, quantitative studies of exposed humans help determine health-related effects that result from breathing the atmosphere. The major unique feature of the clinical study is the ability to select, control, and quantify pollutant exposures of subjects of known clinical status, and determine their effects under ideal experimental conditions. The choice of outcomes to be assessed in human clinical studies can be guided by both scientific and practical considerations, but the diversity of human responses and responsiveness must be considered. Subjects considered to be among the most susceptible include those with asthma, chronic obstructive lung disease, and cardiovascular disease. New experimental approaches include exposures to concentrated ambient air particles, diesel engine exhaust, combustion products from smoking machines, and experimental model particles. Future investigations of the health effects of air pollution will benefit from collaborative efforts among the disciplines of epidemiology, animal toxicology, and human clinical studies. PMID:10931779

Utell, M J; Frampton, M W

2000-01-01

361

Development of Allogeneic NK Cell Adoptive Transfer Therapy in Metastatic Melanoma Patients: In Vitro Preclinical Optimization Studies  

PubMed Central

Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy. PMID:23483943

Besser, Michal J.; Shoham, Tsipi; Harari-Steinberg, Orit; Zabari, Naama; Ortenberg, Rona; Yakirevitch, Arkadi; Nagler, Arnon; Loewenthal, Ron; Schachter, Jacob; Markel, Gal

2013-01-01

362

Development of allogeneic NK cell adoptive transfer therapy in metastatic melanoma patients: in vitro preclinical optimization studies.  

PubMed

Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy. PMID:23483943

Besser, Michal J; Shoham, Tsipi; Harari-Steinberg, Orit; Zabari, Naama; Ortenberg, Rona; Yakirevitch, Arkadi; Nagler, Arnon; Loewenthal, Ron; Schachter, Jacob; Markel, Gal

2013-01-01

363

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

SciTech Connect

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

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

2012-06-15

364

Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: A preclinical study in a novel rat model  

SciTech Connect

Purpose: Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator. Methods and Materials: Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the 'scrotal hernia' was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation. Results: Orazipone significantly ameliorated histologic injury and transforming growth factor-{beta} immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation. Conclusions: This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens.

Boerma, Marjan [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Wang, Junru [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Richter, Konrad K. [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Hauer-Jensen, Martin [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States) and Department of Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States)]. E-mail: mhjensen@life.uams.edu

2006-10-01

365

Validated LC-MS/MS assay for the determination of felbinac: Application to a preclinical pharmacokinetics study of felbinac trometamol injection in rat.  

PubMed

A rapid and sensitive analytical method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of felbinac in rat plasma, bile, urine, feces and tissue. Sample preparation involved liquid-liquid extraction with ethyl ether-dichloromethane (60:40, v/v). Chromatography of felbinac and the internal standard probenecid was performed within 2min on a Venusil MP C(18) column (100mmx4.6mm i.d., 5microm) with a mobile phase consisting of acetonitrile-5mM ammonium acetate containing 0.1% formic acid (pH 3.0) (80:20, v/v) at a flow rate of 1.2ml/min. Detection by electrospray negative ionization mass spectrometry and multiple-reaction monitoring of the transitions of felbinac at m/z 211.1-->167.0 and of probenecid at m/z 283.9-->239.9 was linear over the concentration range 5-5000ng/ml with a lower limit of quantitation of 5ng/ml using a sample volume of only 50microl. Intra- and inter-day precisions (as relative standard deviation, R.S.D.) were < or =7.3% and < or =6.4%, respectively, and accuracy (as relative error, R.E.) was in the range -2.1 to 7.4%. Recoveries and matrix effects were satisfactory in all the biological matrices examined. The method was applied to a preclinical pharmacokinetic study in rat involving a single intravenous injection of felbinac trometamol. PMID:19376665

Zhang, Chao; Wang, Lu; Yang, Wei; Wang, Xisha; Fawcett, J Paul; Sun, Yantong; Gu, Jingkai

2009-08-15

366

Quantification of pinosylvin in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pre-clinical pharmacokinetic study.  

PubMed

Pinosylvin (trans-3,5-dihydroxystilbene), a naturally occurring analogue of resveratrol (trans-3,5,4'-trihydoxystilbene), exhibited various beneficial pharmacological activities in pre-clinical studies. To further probe its potential medicinal application, a sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was developed and validated for the quantification of pinosylvin in rat plasma. A simple protein precipitation procedure was used for plasma cleanup before analysis by LC-MS/MS with electrospray ionisation and multiple reaction monitoring in its negative ion mode. This LC-MS/MS method demonstrated good selectivity, accuracy (intra- and inter-day analytical recovery within 100±7.7%), precision (intra- and inter-day coefficient of variation<12.0%) and sensitivity (lower limit of detection=1.0ng/mL), with excellent linearity (R(2)>0.99) over the range of 1-1000ng/mL. The pharmacokinetic profiles of pinosylvin were subsequently assessed in Sprague-Dawley rats. Following intravenous administration (5 or 10mg/kg), plasma levels of pinosylvin declined rapidly with a short half-life (t1/2<10min). Upon oral administration at 15mg/kg, pinosylvin could not be quantified in plasma (<1ng/mL) while dose-escalation to 50mg/kg led to a low and erratic plasma exposure with very poor estimated oral bioavailability (F<1%). The short half-life and limited systemic exposure of pinosylvin prompt caution in its therapeutic application and it warrants exploration in developing pinosylvin pro-drug. PMID:23777612

Yeo, Samuel Chao Ming; Luo, Wenxia; Wu, Jinzhu; Ho, Paul C; Lin, Hai-Shu

2013-07-15

367

Function and redox state of peritoneal leukocytes as preclinical and prodromic markers in a longitudinal study of triple-transgenic mice for Alzheimer's disease.  

PubMed

The aging process involves the impairment of the immune system (immunosenescence), based on the imbalance of the redox status, as occurs in neurodegenerative diseases such as Alzheimer's disease (AD). Since in AD there is a systemic disorder, we aimed to assess longitudinally, from before the onset until the complete establishment of AD, cell populations, several functions, and oxidative stress parameters in peritoneal leukocytes of triple transgenic mice for AD (3xTgAD). These animals mimic the human AD pathophysiology. The results indicate a premature immunosenescence in 3xTgAD at 4 months of age, when the immunoreactivity against intracellular amyloid-? fibrils appears. Thus, decreases in functions such as chemotaxis, phagocytosis, and lymphoproliferation, as well as a lower reduced glutathione content and higher xanthine oxidase activity, appear in leukocytes. Moreover, NK percentage and cytotoxic activity, CD25+ B and naïve CD8 T cells percentage, GSSG/GSH ratio, and GSH content were already changed before the onset of AD, at the age of 2 months. Furthermore, the changes in some parameters such as CD5+ B1 cells, phagocytosis, lymphoproliferation, and xanthine oxidase activity continue at 15 months of age, when AD pathophysiology is completely established. Because the immune system parameters studied are markers of health and longevity, the premature immunosenescence could explain the shorter life span shown by 3xTgAD observed in the present work. These results suggest that peripheral immune cell functions and their oxidative stress status could be good early peripheral markers of the preclinical and prodromal stages and progression of AD. PMID:25079793

Maté, Ianire; Cruces, Julia; Giménez-Llort, Lydia; De la Fuente, Mónica

2015-01-01

368

In-Vivo Efficacy of Compliant 3D Nano-Composite in Critical-Size Bone Defect Repair: a Six Month Preclinical Study in Rabbit  

PubMed Central

Bone defects above critical size do not heal completely by itself and thus represent major clinical challenge to reconstructive surgery. Numerous bone substitutes have already been used to promote bone regeneration, however their use, particularly for critical-sized bone defects along with their long term in vivo safety and efficacy remains a concern. The present study was designed to obtain a complete healing of critical-size defect made in the proximal tibia of New Zealand White rabbit, using nano-hydroxyapatite/gelatin and chemically carboxymethylated chitin (n-HA/gel/CMC) scaffold construct. The bone-implant interfaces and defect site healing was evaluated for a period up to 25 weeks using radiography, micro-computed tomography, fluorescence labeling, and histology and compared with respective SHAM (empty contra lateral control). The viscoelastic porous scaffold construct allows easy surgical insertion and post-operatively facilitate oxygenation and angiogenesis. Radiography of defect treated with scaffold construct suggested expedited healing at defect edges and within the defect site, unlike confined healing at edges of the SHAM sites. The architecture indices analyzed by micro-computed tomography showed a significant increase in percentage of bone volume fraction, resulted in reconciled cortico-trabecular bone formation at n-HA/gel/CMC constructs treated site (15.2% to 52.7%) when compared with respective SHAM (10.2% to 31.8%). Histological examination and fluorescence labeling revealed that the uniformly interconnected porous surface of scaffold construct enhanced osteoblasts’ activity and mineralization. These preclinical data suggest that, n-HA/gel/CMC construct exhibit stimulation of bone's innate regenerative capacity, thus underscoring their use in guided bone regeneration. PMID:24204879

Sagar, Nitin; Pandey, Alok K.; Gurbani, Deepak; Khan, Kainat; Singh, Dhirendra; Chaudhari, Bhushan P.; Soni, Vivek P.; Chattopadhyay, Naibedya; Dhawan, Alok; Bellare, Jayesh R.

2013-01-01

369

[111In-DOTA]Somatostatin-14 analogs as potential pansomatostatin-like radiotracers - first results of a preclinical study  

PubMed Central

Background In this study, we report on the synthesis, radiolabeling, and biological evaluation of two new somatostatin-14 (SS14) analogs, modified with the universal chelator DOTA. We were interested to investigate if and to what extent such radiotracer prototypes may be useful for targeting sst1-5-expressing tumors in man but, most importantly, to outline potential drawbacks and benefits associated with their use. Methods AT1S and AT2S (DOTA-Ala1-Gly2-c[Cys3-Lys4-Asn5-Phe6-Phe7-Trp8/DTrp8-Lys9-Thr10-Phe11-Thr12-Ser13-Cys14-OH], respectively) were synthesized on the solid support and labeled with 111In. The sst1-5 affinity profile of AT1S/AT2S was determined by receptor autoradiography using [Leu8,dTrp22,125I-Tyr25]SS28 as radioligand. The ability of AT2S to stimulate sst2 or sst3 internalization was qualitatively analyzed by an immunofluorescence-based internalization assay using hsst2- or hsst3-expressing HEK293 cells. Furthermore, the internalization of the radioligands [111In]AT1S and [111In]AT2S was studied at 37?°C in AR4-2J cells endogenously expressing sst2. The in vivo stability of [111In]AT1S and [111In]AT2S was tested by high-performance liquid chromatography analysis of mouse blood collected 5?min after radioligand injection, and biodistribution was studied in normal mice. Selectively for [111In]AT2S, biodistribution was further studied in SCID mice bearing AR4-2J, HEK293-hsst2A+, -hsst3+ or -hsst5+ tumors. Results The new SS14-derived analogs were obtained by solid phase peptide synthesis and were easily labeled with 111In. Both SS14 conjugates, AT1S, and its DTrp8 counterpart, AT2S, showed a pansomatostatin affinity profile with the respective hsst1-5 IC50 values in the lower nanomolar range. In addition, AT2S behaved as an agonist for sst2 and sst3 since it stimulated receptor internalization. The 111In radioligands effectively and specifically internalized into rsst2A-expressing AR4-2J cells with [111In]AT2S internalizing faster than [111In]AT1S. Ex vivo mouse blood analysis revealed a rapid degradation of both radiopeptides in the bloodstream with the DTrp8 analog showing higher stability. Biodistribution results in healthy mice were consistent with these findings with only [111In]AT2S showing specific uptake in the sst2-rich pancreas. Biodistribution of [111In]AT2S in tumor-bearing mice revealed receptor-mediated uptake in the AR4-2J (1.82?±?0.36 %ID/g - block 0.21?±?0.17 %ID/g at 4?h post injection (pi)), the HEK293-hsst2A+ (1.49?±?0.2 %ID/g - block 0.27?±?0.20 %ID/g at 4?h pi), the HEK293-hsst3+ (1.24?±?0.27 %ID/g - block 0.32?±?0.06 %ID/g at 4?h pi), and the HEK293-hsst5+ tumors (0.41?±?0.12 %ID/g - block 0.22?±?0.006 %ID/g at 4?h pi). Radioactivity washed out from blood and background tissues via the kidneys. Conclusions This study has revealed that the native SS14 structure can indeed serve as a motif for the development of promising pansomatostatin-like radiotracers. Further peptide stabilization is required to increase in vivo stability and, consequently, to enhance in vivo delivery and tumor targeting. PMID:22682002

2012-01-01

370

Pleiotropic effects of the rho-kinase inhibitor fasudil after subarachnoid hemorrhage: a review of preclinical and clinical studies.  

PubMed

There is growing evidence that Rho-kinase contributes to cardiovascular disease, which has made Rho-kinase a target for the treatment of human diseases. To date, the only Rho-kinase inhibitor employed clinically in humans is fasudil, which has been used for the prevention of cerebral vasospasm and subsequent ischemic injury after surgery for subarachnoid hemorrhage (SAH). A number of pathological processes, in particular hemodynamic dysfunctions and inflammatory reactions, are thought to be related in the pathogenesis of delayed cerebral vasospasm and subsequent ischemic injury after SAH. This review focuses on fasudil's pleiotropic therapeutic effects: amelioration of hemodynamic dysfunction and inflammation, and discusses in detail the clinical studies on fasudil administered after the occurrence of SAH. PMID:24923440

Satoh, Shin-ichi; Ikegaki, Ichiro; Kawasaki, Koh; Asano, Toshio; Shibuya, Masato

2014-01-01

371

177Lu-EC0800 combined with the antifolate pemetrexed: preclinical pilot study of folate receptor targeted radionuclide tumor therapy.  

PubMed

Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate (177)Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of (177)Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with (177)Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of (177)Lu-EC0800 with PMXther resulted in a two- to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMXsubther or untreated control mice. PMXsubther protected the kidneys from undesired side effects of (177)Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using (99m)Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity. PMID:24030631

Reber, Josefine; Haller, Stephanie; Leamon, Christopher P; Müller, Cristina

2013-11-01

372

Preclinical assessment of infant formula.  

PubMed

Infant formulas are the sole or predominant source of nutrition for many infants and are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. Preclinical safety assessment therefore needs to include both short-term and long-term studies in animals. It is recommended that procedures are instituted by which experts may serve as independent scientists for companies developing novel products, without having their integrity compromised, and later serve the legislative institutions. A two-level assessment approach to determine the potential toxicity of a novel ingredient, its metabolites, and their effects in the matrix on developing organ systems has been suggested by IOM. This appears reasonable, as novel ingredients can be of different levels of concern. The use of modern methods in genomics and proteomics should be considered in these evaluation processes as well as novel methods to evaluate outcomes, including metabolomics and molecular techniques to assess the microbiome. PMID:22699767

Lönnerdal, Bo

2012-01-01

373

Association of Inhalation Toxicologists (AIT) working party recommendation for standard delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals.  

PubMed

There are many ways in which the dose can be expressed in inhalation toxicology studies. This can lead to confusion when comparing results from studies performed in different laboratories. A working party of the Association of Inhalation Toxicologists has reviewed this subject in detail and has collected data from 10 inhalation laboratories and used these data to determine a new algorithm for the calculation of Respiratory Minute Volume (RMV), one of the most important factors in the calculation of delivered dose. The recommendations of the working party for regulatory inhalation toxicology studies with pharmaceuticals are as follows: 1. The dose should be reported as the delivered dose calculated according to the formula: DD = C x RMV x D(xIF)/BW, where DD = delivered dose (mg/Kg); C = concentration of substance in air (mg/L); RMV =respiratory minute volume or the volume of air inhaled in one minute (L/min); D = duration of exposure (min); IF = proportion by weight of particles that are inhalable by the test species, the inhalable fraction (inclusion of this parameter is not essential provided that the aerosol has reasonable respirability for the intended species. If it is included, the way in which it is determined should be clearly stated); BW = bodyweight (Kg). 2. The RMV for mice, rats, dogs and cynomolgus monkeys should be calculated according to the formula:RMV(L/min) = 0.608 x BW(Kg)(0.852). 3. If deposited dose or the amount of material actually retained inthe respiratory tract is presented as supplementary information,the way in which it is calculated should be clearly stated.4. Dose should always be presented in mg/Kg but may also bepresented in other ways, such as mg/unit body surface area, as supplementary information. PMID:18802802

Alexander, David J; Collins, Christopher J; Coombs, Derek W; Gilkison, Ian S; Hardy, Colin J; Healey, Graham; Karantabias, George; Johnson, Neil; Karlsson, Anna; Kilgour, Joanne D; McDonald, Paddy

2008-10-01

374

Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study.  

PubMed

Cytokine-induced killer (CIK) cells are ex vivo activated and expanded CD8+ natural killer T cells that have been shown to have antitumor activity. This is the first study exploring cell killing of primary ovarian carcinoma cells with and without bispecific antibodies. Primary cancer cells and autologous CIK cells were collected from women with epithelial ovarian cancer. Bispecific antibodies against cancer antigen-125 (BSAbxCA125) and Her2 (BSAbxHer2) were developed using chemical heteroconjugation. On fluorescence-activated cell sorting analysis, the expansion of CIK cells resulted in a significant increase of CD3+CD8+ and CD3+CD56+ T cells. With enhancement by bispecific antibodies, the mean percent lysis in a 51Cr release assay of fresh ovarian cancer cells exposed to autologous CIK cells increased from 21.7 +/- 0.3% to 89.4 +/- 2.1% at an E:T ratio of 100:1 (P < 0.001). Anti-NKG2D antibodies attenuated the CIK activity by 56.8% on primary cells (P < 0.001). In a xenograft severe combined immunodeficient mouse model, real-time tumor regression and progression was visualized using a noninvasive in vivo bioluminescence imaging system. Four hours after CIK cell injection, we were able to visualize CD8+NKG2D+ CIK cells infiltrating Her2-expressing cancer cells on fluorescence microscopy. Mice that underwent adoptive transfer of CIK cells redirected with BSAbxCA125 and BSAbxHer2 had significant reduction in tumor burden (P < 0.001 and P < 0.001) and improvement in survival (P = 0.05 and P = 0.006) versus those treated with CIK cells alone. Bispecific antibodies significantly enhanced the cytotoxicity of CIK cells in primary ovarian cancer cells and in our in vivo mouse model. The mechanism of cytolysis seems to be mediated in part by the NKG2D receptor. PMID:16551871

Chan, John K; Hamilton, Chad A; Cheung, Michael K; Karimi, Mobin; Baker, Jeanette; Gall, Jonathan M; Schulz, Stephan; Thorne, Steve H; Teng, Nelson N; Contag, Christopher H; Lum, Lawrence G; Negrin, Robert S

2006-03-15

375

Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.  

PubMed

Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists. PMID:15347732

Melichar, Jan K; Hume, Susan P; Williams, Tim M; Daglish, Mark R C; Taylor, Lindsay G; Ahmad, Rabia; Malizia, Andrea L; Brooks, David J; Myles, Judith S; Lingford-Hughes, Anne; Nutt, David J

2005-01-01

376

A longitudinal study assessing lens thickness changes in the eye of the growing beagle using ultrasound scanning: relevance to age of dogs in regulatory toxicology studies.  

PubMed

The lens is formed in utero with new secondary lens fibres added as outer layers throughout life in a growth pattern characteristic of the species. This study examined the time course of beagle lens growth to better understand the optimal starting age of dogs for safety studies to support adult versus paediatric indications, and to assess the feasibility of non-invasively monitoring lens growth with high frequency ultrasound. Ultrasound scanning was performed in six female beagle dogs using the Vevo770. All dogs were imaged in B-mode using local anaesthetic but without sedation. Imaging was carried out every 2 weeks from 8 to 22 weeks of age and then monthly until 62 weeks of age. The dogs tolerated the procedure well. The lens was visible in all dogs and measuring the lens thickness with high frequency ultrasound demonstrated good analytical reproducibility [Root Mean Square (RMS)?=?3.13%]. No differences between the left and right eye existed and lens thickness correlated with body weight. The highest weekly growth rate was before 12 weeks of age. A statistically significant difference between monthly thickness was detected until 42 weeks of age at which point growth reached a plateau. During the experiment, lenses grew by 29.7% reaching an average thickness of 6.4 mm?±?0.03. By 10 months of age (the typical age used for routine toxicological evaluation), beagles have reached a plateau in lens growth that is analogous to human adults. Where lens is a target organ of concern it is suggested that beagles under 6 months old may be a better model for determining paediatric safety. PMID:24436247

Maynard, Juliana; Sykes, Angela; Powell, Helen; Healing, Guy; Scott, Marietta; Holmes, Andrew; Ricketts, Sally-Ann; Stewart, Jane; Davis, Stewart

2014-12-01

377

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Two-Generation Reproduction Study of Lewisite in Rats Final Report  

SciTech Connect

Occupational health standards have not been established for Lewisite [bis(2-chlorethyl)arsine], a potent toxic vesicant which reacts with the sulfhydryl groups of proteins through its arsenic group. The purposes of this study were to determine the reproductive consequences and dose~response of continuing Lewisite exposure of parental males and females and their offspring in a 42-week two-generation study. Solutions of Lewisite were prepared for administration by diluting the neat agent with sesame oil. Rats were administered Lewisite (0, 0.10, 0.25 or 0.60 mg/kg/day for 5 days a week) via intragastric intubation prior to mating, during mating and after mating until the birth of their offspring. The dams continued to receive Lewisite during lactation. At weaning, male and female offspring of each group were selected to continue on the study; rece1v1ng Lewisite during adolescence, mating and throughout gestation. Again, the dams continued to receive Lewisite until weaning of the offspring. Lewisite had no adverse effect on reproduction performance, fertility or reproductive organ weights of male or female rats through two consecutive generations. No adverse effect to offspring were attributed to Lewisite exposure. Minor changes in growth was the only maternal effect observed. Lewisite exposure of parental rats caused no gross or microscopic lesions in testes, epididymis, prostrate, seminal vesicles, ovaries, uterus or vagina. Severe inflammation of the lung was observed at necropsy in cases in which Lewisite gained access to the respiratory system from accidental dosing or reflux and aspiration; this usually caused early death of the animal. The NOEL for reproductive effects in this study was greater than 0.60 mg/kg/day.

Sasser, L. B.; Cushing, J. A.; Kalkwarf, D. R.; Mellick, P. W.; Buschbom, R. L.

1989-07-15

378

Toxicological Benchmarks for Wildlife  

Microsoft Academic Search

Ecological risks of environmental contaminants are evaluated by using a two-tiered process. In the first tier, a screening assessment is performed where concentrations of contaminants in the environment are compared to no observed adverse effects level (NOAEL)-based toxicological benchmarks. These benchmarks represent concentrations of chemicals (i.e., concentrations presumed to be nonhazardous to the biota) in environmental media (water, sediment, soil,

B. E. Opresko; D. M. Suter

1993-01-01

379

Toxicological Profile Information Sheet  

NSDL National Science Digital Library

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

2008-08-28

380

History of wildlife toxicology  

Microsoft Academic Search

The field of wildlife toxicology can be traced to the late nineteenth and early twentieth centuries. Initial reports included\\u000a unintentional poisoning of birds from ingestion of spent lead shot and predator control agents, alkali poisoning of waterbirds,\\u000a and die-offs from maritime oil spills. With the advent of synthetic pesticides in the 1930s and 1940s, effects of DDT and\\u000a other pesticides

Barnett A. Rattner

2009-01-01

381

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

SciTech Connect

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

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

1988-08-01

382

Research Models in Developmental Behavioral Toxicology.  

ERIC Educational Resources Information Center

Developmental models currently used by child behavioral toxicologists and teratologists are inadequate to address current issues in these fields. Both child behavioral teratology and toxicology scientifically study the impact of exposure to toxic agents on behavior development: teratology focuses on prenatal exposure and postnatal behavior…

Dietrich, Kim N.; Pearson, Douglas T.

383

Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans  

PubMed Central

3,4-Methylenedioxymethamphetamine (MDMA) induces both acute adverse effects and long-term neurotoxic loss of brain 5-HT neurones in laboratory animals. However, when choosing doses, most preclinical studies have paid little attention to the pharmacokinetics of the drug in humans or animals. The recreational use of MDMA and current clinical investigations of the drug for therapeutic purposes demand better translational pharmacology to allow accurate risk assessment of its ability to induce adverse events. Recent pharmacokinetic studies on MDMA in animals and humans are reviewed and indicate that the risks following MDMA ingestion should be re-evaluated. Acute behavioural and body temperature changes result from rapid MDMA-induced monoamine release, whereas long-term neurotoxicity is primarily caused by metabolites of the drug. Therefore acute physiological changes in humans are fairly accurately mimicked in animals by appropriate dosing, although allometric dosing calculations have little value. Long-term changes require MDMA to be metabolized in a similar manner in experimental animals and humans. However, the rate of metabolism of MDMA and its major metabolites is slower in humans than rats or monkeys, potentially allowing endogenous neuroprotective mechanisms to function in a species specific manner. Furthermore acute hyperthermia in humans probably limits the chance of recreational users ingesting sufficient MDMA to produce neurotoxicity, unlike in the rat. MDMA also inhibits the major enzyme responsible for its metabolism in humans thereby also assisting in preventing neurotoxicity. These observations question whether MDMA alone produces long-term 5-HT neurotoxicity in human brain, although when taken in combination with other recreational drugs it may induce neurotoxicity. LINKED ARTICLES This article is commented on by Parrott, pp. 1518–1520 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.x and to view the the rebuttal by the authors (Green et al., pp. 1521–1522 of this issue) visit http://dx.doi.org/10.1111/j.1476-5381.2012.01940.x PMID:22188379

Green, AR; King, MV; Shortall, SE; Fone, KCF

2012-01-01

384

Advances in Preclinical SPECT Instrumentation  

PubMed Central

Preclinical SPECT imaging of rodents is both in demand and very demanding. The need for high spatial resolution in combination with good sensitivity has given rise to considerable innovation in the areas of detectors, collimation, acquisition geometry, and image reconstruction. Some of the developments described herein are beginning to carry over into clinical imaging as well. PMID:22586145

Peterson, Todd E.; Shokouhi, Sepideh

2012-01-01

385

42 CFR 493.937 - Toxicology.  

Code of Federal Regulations, 2011 CFR

...2011-10-01 2011-10-01 false Toxicology. 493.937 Section 493.937 ...Specialty and Subspecialty § 493.937 Toxicology. (a) Program content and frequency...approved for proficiency testing for toxicology, the annual program must...

2011-10-01

386

42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2011 CFR

...2011-10-01 false Condition: Toxicology. 493.1213 Section 493.1213...Testing § 493.1213 Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...

2011-10-01

387

42 CFR 493.937 - Toxicology.  

Code of Federal Regulations, 2014 CFR

...2014-10-01 2014-10-01 false Toxicology. 493.937 Section 493.937 ...Specialty and Subspecialty § 493.937 Toxicology. (a) Program content and frequency...approved for proficiency testing for toxicology, the annual program must...

2014-10-01

388

42 CFR 493.937 - Toxicology.  

Code of Federal Regulations, 2010 CFR

...2010-10-01 2010-10-01 false Toxicology. 493.937 Section 493.937 ...Specialty and Subspecialty § 493.937 Toxicology. (a) Program content and frequency...approved for proficiency testing for toxicology, the annual program must...

2010-10-01

389

42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2012 CFR

...2012-10-01 false Condition: Toxicology. 493.1213 Section 493.1213...Testing § 493.1213 Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...

2012-10-01

390

42 CFR 493.937 - Toxicology.  

Code of Federal Regulations, 2012 CFR

...2012-10-01 2012-10-01 false Toxicology. 493.937 Section 493.937 ...Specialty and Subspecialty § 493.937 Toxicology. (a) Program content and frequency...approved for proficiency testing for toxicology, the annual program must...

2012-10-01

391

42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2014 CFR

...2014-10-01 false Condition: Toxicology. 493.1213 Section 493.1213...Testing § 493.1213 Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...

2014-10-01

392

42 CFR 493.937 - Toxicology.  

Code of Federal Regulations, 2013 CFR

...2013-10-01 2013-10-01 false Toxicology. 493.937 Section 493.937 ...Specialty and Subspecialty § 493.937 Toxicology. (a) Program content and frequency...approved for proficiency testing for toxicology, the annual program must...

2013-10-01

393

42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2010 CFR

...2010-10-01 false Condition: Toxicology. 493.1213 Section 493.1213...Testing § 493.1213 Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...

2010-10-01

394

Fish Physiology, Toxicology, and Water Quality  

E-print Network

Fish Physiology, Toxicology, and Water Quality Proceedings of the Ninth International/010 February 2007 Fish Physiology, Toxicology, and Water Quality Proceedings of the Ninth International International Symposium on Fish Physiology, Toxicology, and Water Quality. The subject of the meeting

DeWitt, Thomas J.

395

42 CFR 493.1213 - Condition: Toxicology.  

Code of Federal Regulations, 2013 CFR

...2013-10-01 false Condition: Toxicology. 493.1213 Section 493.1213...Testing § 493.1213 Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology, the laboratory must meet the...

2013-10-01

396

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

PubMed Central

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

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

2014-01-01

397

Locust bean gum safety in neonates and young infants: an integrated review of the toxicological database and clinical evidence.  

PubMed

Locust bean gum (LBG) is a galactomannan polysaccharide used as thickener in infant formulas with the therapeutic aim to treat uncomplicated gastroesophageal reflux (GER). Since its use in young infants below 12weeks of age is not explicitly covered by the current scientific concept of the derivation of health based guidance values, the present integrated safety review aimed to compile all the relevant preclinical toxicological studies and to combine them with substantial evidence gathered from the clinical paediatric use as part of the weight of evidence supporting the safety in young infants below 12weeks of age. LBG was demonstrated to have very low toxicity in preclinical studies mainly resulting from its indigestible nature leading to negligible systemic bioavailability and only possibly influencing tolerance. A standard therapeutic level of 0.5g/100mL in thickened infant formula is shown to confer a sufficiently protective Margin of Safety. LBG was not associated with any adverse toxic or nutritional effects in healthy term infants, while there are limited case-reports of possible adverse effects in preterms receiving the thickener inappropriately. Altogether, it can be concluded that LBG is safe for its intended therapeutic use in term-born infants to treat uncomplicated regurgitation from birth onwards. PMID:24997231

Meunier, Leo; Garthoff, Jossie A; Schaafsma, Anne; Krul, Lisette; Schrijver, Jaap; van Goudoever, Johannes B; Speijers, Gerrit; Vandenplas, Yvan

2014-10-01

398

Microbiological and toxicological effects of Perla black bean (Phaseolus vulgaris L.) extracts: in vitro and in vivo studies.  

PubMed

We investigated the microbiological and toxicological effects of three Perla black bean extracts on the growth and culture of selected pathogenic microorganisms, the toxicity over Vero cell lines and an in vivo rat model. Three different solvents were used to obtain Perla black bean extracts. All three Perla black bean extracts were tested for antibacterial and antiparasitic activity and further analysed for intrinsic cytotoxicity (IC(50)). Methanol Perla black bean extract was used for acute toxicity test in rats, with the up-and-down doping method. All Perla black bean extracts inhibited bacterial growth. Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella oxytoca, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis and Listeria monocytogenes showed inhibition, while Escherichia coli and Enterobacter aerogenes did not. Acidified water and acetic acid Perla black bean extract were tested in parasites. The best IC(50) was observed for Giardia lamblia, while higher concentrations were active against Entamoeba histolytica and Trichomonas vaginalis. The Vero cells toxicity levels (IC(50)) for methanol, acidified water and acetic acid Perla black bean extract were [mean +/- S.D. (95% CI)]: 275 +/- 6.2 (267.9-282.0), 390 +/- 4.6 (384.8-395.2) and 209 +/- 3.39 (205.6-212.4) microg/ml, respectively. In vivo acute toxicity assays did not show changes in absolute organ weights, gross and histological examinations of selected tissues or functional tests. The acetic acid and methanol Perla black bean extract proved to exhibit strong antibacterial activity and the acidified water Perla black bean extract exerted parasiticidal effects against Giardia lamblia, Entamoeba hystolitica and Trichomonas vaginalis. The three Perla black bean extracts assayed over Vero cells showed very low toxicity and the methanol Perla black bean extract in vivo did not cause toxicity. PMID:19053992

Lara-Díaz, Víctor Javier; Gaytán-Ramos, Angel A; Dávalos-Balderas, Alfredo José; Santos-Guzmán, Jesús; Mata-Cárdenas, Benito David; Vargas-Villarreal, Javier; Barbosa-Quintana, Alvaro; Sanson, Misu; López-Reyes, Alberto Gabriel; Moreno-Cuevas, Jorge E

2009-02-01

399

Evaluation Of Microdosing Strategies For Studies In Preclinical Drug Development: Demonstration Of Linear Pharmacokinetics In Dogs Of A Nucleoside Analogue Over A 50-Fold Dose Range  

SciTech Connect

The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Thus, Compound A displayed multiphasic kinetics and possessed low plasma clearance (4.4 mL/min/kg), a long terminal elimination half-life (19.4 hr) and high oral bioavailability (82%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the pharmacokinetics of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the kinetics of absorption, distribution and elimination in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques. The applications of accelerator mass spectrometry (AMS) are broad ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil and water (Hughen et al., 2000; Beck et al., 2001; Keith-Roach et al., 2001; Mironov et al., 2002), to archaeology and volcanology (Stafford et al., 1984; Vogel et al., 1990; Smith et al., 1999) to its use as a bioanalytical tool for nutritional research (Buchholz et al., 1999; Deuker et al., 2000; Weaver and Liebman, 2002). Biomedical applications of AMS and its use in the arena of pharmaceutical research also have been detailed in review articles (Barker and Garner, 1999; Garner, 2000; Turteltaub and Vogel, 2000). To date, most studies on the metabolism and disposition of xenobiotics by AMS have focused on how carcinogens bind to DNA and proteins to form adducts (Turteltaub et al., 1990, 1997; Frantz et al., 1995; Dingley et al., 1999; Li et al., 2003). Its application to the field of pharmaceutical sciences has been limited to a few studies (Kaye et al., 1997; Young et al., 2001; Garner et al., 2002). However, the pharmaceutical industry is becoming increasingly aware of the potential benefits that may accrue from the ultra high sensitivity afforded by AMS in terms of evaluating the pharmacokinetics of lead drug candidates in early development. Specifically, AMS allows administration of sub-pharmacological doses (microdoses) of carbon-14 or tritium-labeled investigational drugs to animals or humans at radiologically insignificant levels with the goal of obtaining preliminary information regarding the absorption, distribution, metabolism, and excretion of test compounds (Turteltaub and Vogel, 2000). An unresolved issue, however, is whether the pharmacokinetics determined following a microdose are representative of those following a conventional (pharmacological) dose (Lappin and Garner, 2003). This paper examines the linearity of kinetics of an antiviral nucleoside analogue, Compound A, across sub-pharmacological and pharmacological dose ranges in the dog prior to initiation of a human microdose study. The specific objectives of this study, therefore, were (1) to assess the pharmacokinetics of Compound A in dogs by a conventional dosing approach utilizing LC-MS/MS for sample analysis, (2) to assess the pharmacokinetics of Compound A in dogs by the microdose approach utilizing AMS for sample ana

Sandhu, P; Vogel, J S; Rose, M J; Ubick, E A; Brunner, J E; Wallace, M A; Adelsberger, J K; Baker, M P; Henderson, P T; Pearson, P G; Baillie, T A

2004-04-22

400

Synthetic toxicology: where engineering meets biology and toxicology.  

PubMed

This article examines the implications of synthetic biology (SB) for toxicological sciences. Starting with a working definition of SB, we describe its current subfields, namely, DNA synthesis, the engineering of DNA-based biological circuits, minimal genome research, attempts to construct protocells and synthetic cells, and efforts to diversify the biochemistry of life through xenobiology. Based on the most important techniques, tools, and expected applications in SB, we describe the ramifications of SB for toxicology under the label of synthetic toxicology. We differentiate between cases where SB offers opportunities for toxicology and where SB poses challenges for toxicology. Among the opportunities, we identified the assistance of SB to construct novel toxicity testing platforms, define new toxicity-pathway assays, explore the potential of SB to improve in vivo biotransformation of toxins, present novel biosensors developed by SB for environmental toxicology, discuss cell-free protein synthesis of toxins, reflect on the contribution to toxic use reduction, and the democratization of toxicology through do-it-yourself biology. Among the identified challenges for toxicology, we identify synthetic toxins and novel xenobiotics, biosecurity and dual-use considerations, the potential bridging of toxic substances and infectious agents, and do-it-yourself toxin production. PMID:21068213

Schmidt, Markus; Pei, Lei

2011-03-01

401

Global Recognition of Qualified Toxicologic Pathologists: Credential Review as a Potential Route for Recognizing the Proficiency of Pathologists Involved in Regulatory-type Nonclinical Studies*  

PubMed Central

Recent international summits of the International Federation of Societies of Toxicologic Pathologists (IFSTP) have debated the desirability and potential means by which the proficiency of an individual toxicologic pathologist might be recognized and communicated throughout the world. The present document describes the advantages and disadvantages of implementing such a global recognition system by any means, and provides a proposal whereby recognition might be accorded via rigorous credential review of a practitioner’s education and experience. PMID:22271988

Ettlin, Robert A.; Bolon, Brad; Pyrah, Ian; Konishi, Yoichi; Black, Hugh E.

2009-01-01

402

Reprint Library for Toxicology Data Bank  

ERIC Educational Resources Information Center

The Industrial Toxicology Research Center, Lucknow, India, maintains a register of toxicology and provides its research workers with current information mainly through its collection of reprints. (Author)

Agarwal, S. N.; Khan, R. R.

1975-01-01

403

NTP Toxicology and Carcinogenesis Studies of Glutaraldehyde (CAS NO. 111-30-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).  

PubMed

Glutaraldehyde is used in large volume in a variety of industries as a disinfectant, preservative, fixative and cross-linking agent, and as a chemical intermediate in the synthesis of pharmaceuticals and pesticides. Glutaraldehyde was nominated by the National Cancer Institute, the Occupational Safety and Health Administration, and the National Institute of Environmental Health Sciences for carcinogenicity studies because of potential occupational exposure. Male and female F344/N rats and B6C3F1 mice were exposed to glutaraldehyde (25% aqueous solution) (approximately 93% pure) by inhalation for 2 years. In vitro genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells; in vivo studies were conducted to measure sex-linked recessive lethal mutations in Drosophila melanogaster, chromosomal aberrations and micronucleated erythrocytes in mouse bone marrow, and micronucleated erythrocytes in mouse peripheral blood. The results of 13-week inhalation studies with glutaraldehyde were reported previously (NTP, 1993 -- TOX-25 ). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 250, 500, or 750 ppb glutaraldehyde vapor by inhalation, 6 hours per day, 5 days per week, for 104 weeks. Survival of 500 and 750 ppb female rats was less than that of the chamber controls. Mean body weights of all exposed groups of male rats and 500 and 750 ppb female rats were generally less than those of the chamber controls. Some female rats exposed to 750 ppb were thin to emaciated at the time they were killed moribund. Increased incidences of nonneoplastic nasal lesions occurred primarily within the anterior section of the nose in 500 and 750 ppb rats and to a lesser extent in 250 ppb rats. The more significant lesions included hyperplasia and inflammation of the squamous and respiratory epithelia and squamous metaplasia of the respiratory epithelium. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 62.5, 125, or 250 ppb glutaraldehyde vapor by inhalation, 6 hours per day, 5 days per week, for 104 weeks. Survival of exposed mice was similar to that of the chamber controls. Mean body weights of female mice exposed to 250 ppb were generally less than those of the chamber controls throughout the study. Incidences of squamous meta-plasia of the respiratory epithelium were increased in 250 ppb males and females and 125 ppb females. Incidences of hyaline degeneration of the respiratory epithelium were increased in all exposed groups of females. The incidence of inflammation of the nose was marginally increased in 250 ppb females. GENETIC TOXICOLOGY: In genetic toxicity studies, glutaraldehyde was muta-genic with and without S9 metabolic activation in S. typhimurium strains TA100, TA102, and TA104. Glutaraldehyde was mutagenic in mouse L5178Y lymphoma cells in the absence of S9 and induced sister chromatid exchanges in cultured Chinese hamster ovary cells with and without S9. No increase in chromosomal aberrations was induced by glutaraldehyde in cultured Chinese hamster ovary cells with or without S9 at one laboratory; at another laboratory, chromosomal aberrations were induced in the absence of S9 only. Glutaraldehyde did not induce sex-linkedrecessive lethal mutations in germ cells of male D. melanogaster treated as adults by feeding or injection or treated as larvae by feeding. In vivo, glutaraldehyde induced a significant increase in chromosomal aberrations in mouse bone marrow cells 36 hours after a single intraperitoneal injection. In a subset of the 36-hour chromosomal aberrations test, there was a small increase in the number of micronucleated bone marrow polychromatic eryth-rocytes, which was judged to be equivocal. Addi-tional short-term (3-day) and subchronic (13-week) micronucleus tests in mice, using the intraperitoneal or inhalation routes, respectively, yielded negative results. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activin

1999-09-01

404

Textile dye degradation by bacterial consortium and subsequent toxicological analysis of dye and dye metabolites using cytotoxicity, genotoxicity and oxidative stress studies.  

PubMed

The present study aims to evaluate Red HE3B degrading potential of developed microbial consortium SDS using two bacterial cultures viz. Providencia sp. SDS (PS) and Pseudomonas aeuroginosa strain BCH (PA) originally isolated from dye contaminated soil. Consortium was found to be much faster for decolorization and degradation of Red HE3B compared to the individual bacterial strain. The intensive metabolic activity of these strains led to 100% decolorization of Red HE3B (50 mg l(-1)) with in 1h. Significant induction of various dye decolorizing enzymes viz. veratryl alcohol oxidase, laccase, azoreductase and DCIP reductase compared to control, point out towards their involvement in overall decolorization and degradation process. Analytical studies like HPLC, FTIR and GC-MS were used to scrutinize the biodegradation process. Toxicological studies before and after microbial treatment was studied with respect to cytotoxicity, genotoxicity, oxidative stress, antioxidant enzyme status, protein oxidation and lipid peroxidation analysis using root cells of Allium cepa. Toxicity analysis with A. cepa signifies that dye Red HE3B exerts oxidative stress and subsequently toxic effect on the root cells where as biodegradation metabolites of the dye are relatively less toxic in nature. Phytotoxicity studies also indicated that microbial treatment favors detoxification of Red HE3B. PMID:21144656

Phugare, Swapnil S; Kalyani, Dayanand C; Patil, Asmita V; Jadhav, Jyoti P

2011-02-15

405

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

PubMed

Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--mal