Science.gov

Sample records for preclinical toxicology studies

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

    PubMed Central

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

    2015-01-01

    A two-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased WBC levels, a class effect of benzimidazole anthelminthics, returned to normal during the recovery period. The NOAEL was determined to be >5 but < 25 mg/kg/d and the MTD 100 mg/kg/d. The highest dose, 200 mg/kg/d resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after seven days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma or rat micronucleus assays, nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases. PMID:25701764

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  4. Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology.

    PubMed

    Selby, Mark J; Engelhardt, John J; Johnston, Robert J; Lu, Li-Sheng; Han, Minhua; Thudium, Kent; Yao, Dapeng; Quigley, Michael; Valle, Jose; Wang, Changyu; Chen, Bing; Cardarelli, Pina M; Blanset, Diann; Korman, Alan J

    2016-01-01

    The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies. PMID:27610613

  5. Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

    PubMed Central

    Selby, Mark J.; Engelhardt, John J.; Johnston, Robert J.; Lu, Li-Sheng; Han, Minhua; Thudium, Kent; Yao, Dapeng; Quigley, Michael; Valle, Jose; Wang, Changyu; Chen, Bing; Cardarelli, Pina M.; Blanset, Diann; Korman, Alan J.

    2016-01-01

    The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies. PMID:27610613

  6. Metabolomics in toxicology and preclinical research.

    PubMed

    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

    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

  7. Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication

    PubMed Central

    Koszalka, George W.; Johnson, Nelson W.; Good, Steven S.; Boyd, Leslie; Chamberlain, Stanley C.; Townsend, Leroy B.; Drach, John C.; Biron, Karen K.

    2002-01-01

    1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg/kg/day, and the no-effect dose in a 1-month monkey study was 180 mg/kg/day. Toxic effects were limited to increases in liver weights, neutrophils, and monocytes at higher doses in female rats. 1263W94 was not genotoxic in the Ames or micronucleus assays. In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix. Mean oral bioavailability of 1263W94 was >90% in rats and ∼50% in monkeys. Clearance in rats and monkeys was primarily by biliary secretion, with evidence of enterohepatic recirculation. In 1-month studies in rats and monkeys, mean peak concentrations and exposures to 1263W94 increased in near proportion to dose. Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans. 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier. In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively. The high level of binding by 1263W94 to human plasma proteins (primarily albumin) was readily reversible, with less protein binding seen in the monkey, rat, and mouse. Results of these studies demonstrate a favorable safety profile for 1263W94. PMID:12121907

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

    SciTech Connect

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

    2014-10-15

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

  9. [Preclinical study of noopept toxicity].

    PubMed

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

    2002-01-01

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

  10. Toxicologic studies of SRC materials

    SciTech Connect

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

    1980-02-01

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

  11. Toxicological study of Fluorosilicone

    SciTech Connect

    London, J.E.

    1986-05-01

    Fluorosilicone was nonirritating in rabbit eye application studies. Primary skin irritation studies in the rabbit showed the material to be a mild irritant. The materials did not induce sensitization in the guinea pig assay. 2 refs., 1 tab.

  12. Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

    PubMed

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

    2015-10-01

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

  13. Preclinical antileukemic activity, toxicology, toxicokinetics and formulation development of triptolide derivative MRx102

    PubMed Central

    Fidler, John M.; An, Jinhua; Cater, Bing Z.; Andreeff, Michael

    2014-01-01

    Purpose Triptolide induces cancer cell apoptosis by inhibiting RNA synthesis and signaling pathways like NF-κB. We compared triptolide prodrug MRx102 to triptolide to determine if it displayed comparable efficacy and improved toxicology and toxicokinetic profiles. Methods MV4–11 AML cells and cells from AML patients were analyzed for MRx102− and triptolide-induced cytotoxicity/apoptosis. MRx102 and triptolide were compared in toxicology/toxicokinetics studies in rat and dog using a new emulsion formulation. Results MRx102 induced cytotoxicity in MV4–11 cells (IC50 = 15.2 nM, 7.29 nM for triptolide) and apoptosis in cells from AML patients (EC50 = 40.6 nM and 2.13 nM for triptolide). MRx102 and triptolide induced apoptosis in CD34+CD38− AML stem/progenitor cells with a similar difference in activity (EC50, MRx102 = 40.8 nM, triptolide = 2.14 nM). In a rat toxicology comparison using a new intravenous emulsion formulation, the MRx102 MTD was 4.5 mg/kg for males, 3 mg/kg for females; the triptolide MTD was 0.63 mg/kg for males, 0.317 mg/kg for females. The MRx102 NOAEL was 1.5–3.0 mg/kg, and the triptolide NOAEL was 0.05–0.15 mg/kg. Mean plasma concentrations for both MRx102 and triptolide decreased rapidly from a high Cmax following i.v. injection. Plasma triptolide levels stabilized at a consistent level through 2 hours after MRx102 injection. Triptolide T1/2,e values for MRx102-injected rats (~0.85 to ~3.7 hours) were markedly greater than triptolide injected rats (~0.15 to ~0.39 hours), indicating more extended triptolide exposure with MRx102. MRx102 dog toxicology and toxicokinetics results are presented. Conclusions MRx102 was 20− to 60-fold safer than triptolide comparing rat NOAELs. This may be due to the improved toxicokinetic profile of MRx102 compared to triptolide using the emulsion formulation, with no high Cmax and more consistent early exposure to triptolide. PMID:24619497

  14. Preclinical studies of low back pain

    PubMed Central

    2013-01-01

    Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. These involve application of nucleus pulposus material near the lumbar dorsal root ganglia (DRG), chronic compression of the DRG, or localized inflammation of the DRG. These models, which are primarily implemented in rats, have many common features including behavioral hypersensitivity of the hindpaw, enhanced excitability and spontaneous activity of sensory neurons, and locally elevated levels of inflammatory mediators including cytokines. Clinically, epidural injection of steroids (glucocorticoids) is commonly used when more conservative treatments fail, but clinical trials evaluating these treatments have yielded mixed results. There are relatively few preclinical studies of steroid effects in low back pain models. One preclinical study suggests that the mineralocorticoid receptor, also present in the DRG, may have pro-inflammatory effects that oppose the activation of the glucocorticoid receptor. Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain. PMID:23537369

  15. 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

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

    2013-04-01

    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.

  16. Oncolysis by paramyxoviruses: preclinical and clinical studies

    PubMed Central

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

    2015-01-01

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

  17. Preclinical toxicology and tissue platinum distribution of novel oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates.

    PubMed

    McKeage, M J; Morgan, S E; Boxall, F E; Murrer, B A; Hard, G C; Harrap, K R

    1994-01-01

    The preclinical toxicology and tissue platinum distribution of a series of six orally given antitumour platinum complexes [ammine/amine platinum(IV) dicarboxylates] with structural variations of their alicyclic amine (c-C5, c-C6 or c-C7), axial dicarboxylate (CH3, C3H7 or NHC2H5) or leaving substituents (Cl2 or OCOOCO) was studied in the mouse. Platinum tissue levels measured at 48 h after a single oral dose at 0.5 of the MTD were highest in the liver (6.0-19 micrograms/g) and second highest in the kidney (2.8-12 micrograms/g), and these levels were up to 5 times higher than those reported with equi-toxic doses of i.v. cisplatin and i.v. carboplatin. Platinum levels in the lung, heart, spleen, skin, skeletal muscle and brain were all < or = 3.1 micrograms/g at this dose level. Liver platinum levels measured at 2 h, 2 days, 6 days and 10 days after a single oral dose at the MTD ranged widely (from 15 to 109 micrograms platinum/g), were related to the number of carbon atoms in the axial dicarboxylate and alicyclic amine groups (r = 0.9389) and showed a diversity of time-course profiles. Elevations of plasma ALT activity were recorded with single oral doses of JM225 and JM256 at the MTD. Accumulation of platinum in the liver with repeated oral dosing weekly for 4 consecutive weeks at 0.5 of the MTD occurred with JM269 (3.3-fold increase, P < 0.05) and JM225 (2.4-fold increase, P < 0.05), and elevated plasma ALT activity (44 +/- 33 IU/l) was recorded with repeated oral doses of JM269. JM216 was selected from this series of analogues for further study on the basis of the elevated plasma ALT activity (JM225, JM256 and JM269), liver platinum accumulation (JM269 and JM225), poor activity against human ovarian carcinoma xenografts (JM291) or severe emetogenesis (JM221) of other examples. Following a single oral dose of JM216 at the MTD, transient reductions in the WBC (nadir, 1.6 x 10(9)/l, 2 days, 74% reduction), platelet count (nadir, 613 x 10(9)/l, 10 days, 33% reduction

  18. Love Canal: environmental and toxicological studies

    SciTech Connect

    Kim, C.S.

    1981-01-01

    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.

  19. Toxicological studies on cefuroxime sodium.

    PubMed

    Capel-Edwards, K; Atkinson, R M; Pratt, D A

    1979-05-01

    The intravenous LD50 of cefuroxime sodium for mice was 10.4 g/kg. The maximum dosage administered in other acute toxicity tests was well tolerated by mice (10 g/kg, subcutaneous), by rats (4 g/kg, intravenous, 5 g/kg, subcutaneous) and by cats, dogs and monkeys (2 g/kg, intramuscularly). Cefuroxime sodium was administered subcutaneously (s.c.) or intramuscularly (i.m.) for 3 months to rats (100, 300 or 900 mg/kg/day) followed by a recovery period, and also for 6 months to rats and dogs (50, 150 or 450 mg/kg/day) and for 1 month to monkeys (150 or 450 mg/kg/day). In all these tests there were no serious toxic effects. Minor haematological changes were attributable in part if not entirely to haemorrhage and tissue reaction at the site of injection of large doses. In rats large doses caused some increase in urine volume and electrolyte excretion, and slightly aggravated an age related nephropathy. Administration to rats intravenously (i.v.) for1 month of up to 400 mg/kg/day had no toxic effects. In reproduction studies on mice and rabbits there were no adverse effects on fertility, organogenesis or the rearing of young.

  20. Guidance on assessing the methodological and reporting quality of toxicologically relevant studies: A scoping review.

    PubMed

    Samuel, Gbeminiyi O; Hoffmann, Sebastian; Wright, Robert A; Lalu, Manoj Mathew; Patlewicz, Grace; Becker, Richard A; DeGeorge, George L; Fergusson, Dean; Hartung, Thomas; Lewis, R Jeffrey; Stephens, Martin L

    2016-01-01

    Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect to four types of studies: in vivo and in vitro, (quantitative) structure-activity relationships ([Q]SARs), physico-chemical, and human observational studies. Our aims were to identify the available guidance in this diverse literature, briefly summarize each document, and distill the common elements of these documents for each study type. In general, we found considerable guidance for in vivo and human studies, but only one paper addressed in vitro studies exclusively. The guidance for (Q)SAR studies and physico-chemical studies was scant but authoritative. There was substantial overlap across guidance documents in the proposed criteria for both methodological and reporting quality. Some guidance documents address toxicology research directly, whereas others address preclinical research generally or clinical research and therefore may not be fully applicable to the toxicology context without some translation. Another challenge is the degree to which assessments of methodological quality in toxicology should focus on risk of bias - as in clinical medicine and healthcare - or be broadened to include other quality measures, such as confirming the identity of test substances prior to exposure. Our review is intended primarily for those in toxicology and risk assessment seeking an entry point into the extensive and diverse literature on methodological and reporting quality applicable to their work. PMID:27039952

  1. Guidance on assessing the methodological and reporting quality of toxicologically relevant studies: A scoping review.

    PubMed

    Samuel, Gbeminiyi O; Hoffmann, Sebastian; Wright, Robert A; Lalu, Manoj Mathew; Patlewicz, Grace; Becker, Richard A; DeGeorge, George L; Fergusson, Dean; Hartung, Thomas; Lewis, R Jeffrey; Stephens, Martin L

    2016-01-01

    Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect to four types of studies: in vivo and in vitro, (quantitative) structure-activity relationships ([Q]SARs), physico-chemical, and human observational studies. Our aims were to identify the available guidance in this diverse literature, briefly summarize each document, and distill the common elements of these documents for each study type. In general, we found considerable guidance for in vivo and human studies, but only one paper addressed in vitro studies exclusively. The guidance for (Q)SAR studies and physico-chemical studies was scant but authoritative. There was substantial overlap across guidance documents in the proposed criteria for both methodological and reporting quality. Some guidance documents address toxicology research directly, whereas others address preclinical research generally or clinical research and therefore may not be fully applicable to the toxicology context without some translation. Another challenge is the degree to which assessments of methodological quality in toxicology should focus on risk of bias - as in clinical medicine and healthcare - or be broadened to include other quality measures, such as confirming the identity of test substances prior to exposure. Our review is intended primarily for those in toxicology and risk assessment seeking an entry point into the extensive and diverse literature on methodological and reporting quality applicable to their work.

  2. Analgesia in Amphibians: Preclinical Studies and Clinical Applications

    PubMed Central

    Stevens, Craig W.

    2010-01-01

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

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

    PubMed

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

    2015-12-01

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

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

    PubMed

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

    2015-12-01

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

  5. Genetically engineered humanized mouse models for preclinical antibody studies.

    PubMed

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

    2014-04-01

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

  6. [Latrepirdine: a systematic review of the preclinical studies].

    PubMed

    Cano-Cuenca, Nieves; Solís-García del Pozo, Julián; Jordán, Joaquín

    2015-01-01

    We conduct a systematic review of the preclinical studies published to date involving the use of latrepirdine (Dimebon ®). Latrepirdine is capable of modulating different targets, such as those related with mitochondria, acetylcholinesterase activity or intraneuronal calcium levels, perhaps thanks to its action upon the N-methyl-D-aspartate-type receptor, which belongs to the glutamate family. The findings published on the possible effect of latrepirdine in protein aggregation processes in disorders such as Alzheimer's disease and Parkinson's disease are quite controversial. Likewise, the possible neuroprotective effect of latrepirdine has been evaluated in animal models of neurodegenerative diseases, again with heterogeneous results. Consequently, it can be concluded that no preclinical scientific evidence has been found to justify carrying out clinical trials.

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

    PubMed Central

    2014-01-01

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

  8. Optimized design and analysis of preclinical intervention studies in vivo

    PubMed Central

    Laajala, Teemu D.; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

    2016-01-01

    Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID:27480578

  9. Optimized design and analysis of preclinical intervention studies in vivo.

    PubMed

    Laajala, Teemu D; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

    2016-01-01

    Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID:27480578

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

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2015-10-01

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

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

    SciTech Connect

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

    2007-11-01

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

  13. A toxicological study of gadolinium nitrate

    SciTech Connect

    London, J.E.

    1988-05-01

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

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

    PubMed

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

    2008-06-01

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

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

    PubMed

    Niwa, Toshiyuki; Hashimoto, Naofumi

    2008-02-28

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

  16. Preclinical studies on new proteins as carrier for glycoconjugate vaccines.

    PubMed

    Tontini, M; Romano, M R; Proietti, D; Balducci, E; Micoli, F; Balocchi, C; Santini, L; Masignani, V; Berti, F; Costantino, P

    2016-07-29

    Glycoconjugate vaccines are made of carbohydrate antigens covalently bound to a carrier protein to enhance their immunogenicity. Among the different carrier proteins tested in preclinical and clinical studies, five have been used so far for licensed vaccines: Diphtheria and Tetanus toxoids, the non-toxic mutant of diphtheria toxin CRM197, the outer membrane protein complex of Neisseria meningitidis serogroup B and the Protein D derived from non-typeable Haemophilus influenzae. Availability of novel carriers might help to overcome immune interference in multi-valent vaccines containing several polysaccharide-conjugate antigens, and also to develop vaccines which target both protein as well saccharide epitopes of the same pathogen. Accordingly we have conducted a study to identify new potential carrier proteins. Twenty-eight proteins, derived from different bacteria, were conjugated to the model polysaccharide Laminarin and tested in mice for their ability in inducing antibodies against the carbohydrate antigen and eight of them were subsequently tested as carrier for serogroup meningococcal C oligosaccharides. Four out of these eight were able to elicit in mice satisfactory anti meningococcal serogroup C titers. Based on immunological evaluation, the Streptococcus pneumoniae protein spr96/2021 was successfully evaluated as carrier for serogroups A, C, W, Y and X meningococcal capsular saccharides. PMID:27317455

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

    PubMed

    Wang, Raymond M; Christman, Karen L

    2016-01-15

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

  18. Protective efficacy of Modified Vaccinia virus Ankara in preclinical studies.

    PubMed

    Volz, Asisa; Sutter, Gerd

    2013-09-01

    Modified Vaccinia virus Ankara (MVA) is a tissue culture-derived, highly attenuated strain of vaccinia virus (VACV) exhibiting characteristic defective replication in cells from mammalian hosts. In the 1960s MVA was originally generated as a candidate virus for safer vaccination against smallpox. Now, MVA is widely used in experimental vaccine development targeting important infectious diseases and cancer. Versatile technologies for genetic engineering, large-scale production, and quality control facilitate R&D of recombinant and non-recombinant MVA vaccines matching today's requirements for new biomedical products. Such vaccines are attractive candidates for delivering antigens from pathogens against which no, or no effective vaccine is available, including emerging infections caused by highly pathogenic influenza viruses, chikungunya virus, West Nile virus or zoonotic orthopoxviruses. Other directions are seeking valuable vaccines against highly complex diseases such as AIDS, malaria, and tuberculosis. Here, we highlight examples of MVA candidate vaccines against infectious diseases, and review the efforts made to assess both the efficacy of vaccination and immune correlates of protection in preclinical studies.

  19. Toxicological studies on debitterized Neem oil (Azadirachta indica).

    PubMed

    Chinnasamy, N; Harishankar, N; Kumar, P U; Rukmini, C

    1993-04-01

    Azadirachta indica, popularly known as 'Neem' in India, is widely grown all over the tropics. The seed contains 45% oil and is a minor oil of considerable potential. Neem oil is bitter and inedible. Recently, a method has been developed to completely remove the bitter and odoriferous principles and leave a bitterless, odourless and colourless oil. The nutritional and chemical evaluation of debitterized neem oil (NO) was reported earlier (C. Rukmini, Food Chemistry 1987, 26, 119). We report here a three-generation study, carried out according to WHO/FDA protocol in groups of 15 male and 15 female rats fed a diet containing 10% NO or groundnut oil (GNO). Reproductive toxicology was monitored for three generations. The results obtained in both the matings in all the three generations did not show any adverse effects on the reproductive parameters studied in rats fed NO and were similar to those observed in rats fed GNO. The mean organ weights and the histopathological evaluation of all the organs were similar to those of the control (GNO-fed) rats. A mutagenicity test of NO was also found to be negative in Ames test as reported earlier (K. Polasa and C. Rukmini, Food and Chemical Toxicology 1987, 25, 763). These studies indicate that NO devoid of all the bitter and odoriferous principles, may be recommended as safe for consumption by humans. PMID:8477918

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

    PubMed

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

    2014-01-01

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

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

    PubMed

    Dobrovolskaia, Marina A

    2015-12-28

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

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

    PubMed

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

    2013-01-01

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

  3. Personal reflections on 50 years of study of benzene toxicology.

    PubMed Central

    Parke, D V

    1996-01-01

    The metabolism of benzene is reviewed, and the objectives of a quantitative balance study begun in 1945 are outlined; problems of toxicology and metabolism research of some 50 years ago are considered. The quantitative metabolism of 14C-benzene in the rabbit is annotated and compared with that of unlabeled benzene quantified by nonisotopic methods. The anomalies of phenylmercapturic acid and trans-trans-muconic acid as metabolites of benzene are examined in detail by isotopic and nonisotopic methods; these compounds are true but minor metabolites of benzene. Oxygen radicals are involved in both the metabolism of benzene and its toxicity; the roles of CYP2E1, the redox cycling of quinone metabolites, glutathione oxidation, and oxidative stress in the unique radiomimetic, hematopoietic toxicity of benzene are discussed. Differences between the toxicity of benzene and the halobenzenes are related to fundamental differences in their electronic structures and to the consequent pathways of metabolic activation and detoxication. PMID:9118881

  4. Rodent treadmill for inhalation toxicological studies and respirometry

    SciTech Connect

    Mautz, W.J.; Phalen, R.F.; McClure, T.R.; Bufalino, C.

    1985-02-01

    A 10-runway treadmill was enclosed for inhalation toxicological studies of rodents under exercise exposure to environmental pollutants. The exposure system was lined with sheet stainless steel to minimize scrubbing of charged particles and reactive gases. Average metabolic gas exchange of exercising animals was derived from measurements of inlet or outlet airflow and data from an O/sub 2/ analyzer in conjunction with either a CO/sub 2/ or N/sub 2/ analyzer. An airflow rate of 400 l x min-1 ensured a response time of 1 min to reach 95% of a step change in metabolic rate and held scrubbing losses of an O/sub 3/ test atmosphere to less than 2% of treadmill inlet concentration. Gas exchange averaged for 10 rats during incremental exercise up to their highest collective performance was similar to published data for rats tested individually.

  5. Cassava starch fermentation wastewater: characterization and preliminary toxicological studies.

    PubMed

    Avancini, S R P; Faccin, G L; Vieira, M A; Rovaris, A A; Podestá, R; Tramonte, R; de Souza, N M A; Amante, E R

    2007-11-01

    Cassava starch fermentation wastewater is an industrial residue composed mainly of lactic acid bacteria with predominance of the genera Lactobacillus, and organic acids. To evaluate the safety of this residue for possible production of probiotic beverages, acute in mice and sub-chronic (28-day repeated dose) toxicity studies in rats were carried. The administration of a single dose of 5 g/kg/body weight did not produce mortality in mice. Rats treated with water containing 0 (control), 25%, 50%, and 100% of the residue for 28 days, did not present alterations in behaviour or in food and water consumption. There were no treatment-related changes of toxicological significance in the relative weight of the organs neither in the haematological nor in the biochemical parameters. Histopathologic alterations observed in the small intestine did not seem to be associated with the treatment.

  6. 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...

  7. Environmental Toxicology

    NASA Astrophysics Data System (ADS)

    Wright, David A.; Welbourn, Pamela

    2002-03-01

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

  8. Developmental Toxicology##

    EPA Science Inventory

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

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

    PubMed Central

    Amornphimoltham, Panomwat; Masedunskas, Andrius; Weigert, Roberto

    2010-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Kue, Chin Siang; Tan, Kae Yi; Lam, May Lynn; Lee, Hong Boon

    2015-01-01

    The chick embryo chorioallantoic membrane (CAM) is a preclinical model widely used for vascular and anti-vascular effects of therapeutic agents in vivo. In this study, we examine the suitability of CAM as a predictive model for acute toxicology studies of drugs by comparing it to conventional mouse and rat models for 10 FDA-approved anticancer drugs (paclitaxel, carmustine, camptothecin, cyclophosphamide, vincristine, cisplatin, aloin, mitomycin C, actinomycin-D, melphalan). Suitable formulations for intravenous administration were determined before the average of median lethal dose (LD50) and median survival dose (SD(50)) in the CAM were measured and calculated for these drugs. The resultant ideal LD(50) values were correlated to those reported in the literature using Pearson's correlation test for both intravenous and intraperitoneal routes of injection in rodents. Our results showed moderate correlations (r(2)=0.42 - 0.68, P<0.005-0.05) between the ideal LD(50) values obtained using the CAM model with LD(50) values from mice and rats models for both intravenous and intraperitoneal administrations, suggesting that the chick embryo may be a suitable alternative model for acute drug toxicity screening before embarking on full toxicological investigations in rodents in development of anticancer drugs. PMID:25736707

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

    PubMed Central

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

    2016-01-01

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

  13. Toxicology study of the high-energy plasticizer FEFO

    SciTech Connect

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

    1989-03-01

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

  14. Digital toxicology education tools: education, training, case studies, and tutorials.

    PubMed

    Sharpe, J F; Eaton, D L; Marcus, C B

    2001-01-12

    This review presents a brief and non-comprehensive overview of a representative sampling of some of the broad array of toxicology-related learning, tutorial and information resources now becoming widely available to educators, health professionals, students and the general public in digital media and/or via the Internet. A broad variety of useful learning and reference resources in the general fields of toxicology and the environmental health sciences is provided to introduce the reader to the diverse types of information currently available. The sources and Internet links contained in this review will hopefully constitute a useful resource of basic toxicology information that should be readily accessible to most if not all readers.

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

    PubMed Central

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

    2014-01-01

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

  16. Models for preclinical studies in aging-related disorders: One is not for all

    PubMed Central

    Santulli, Gaetano; Borras, Consuelo; Bousquet, Jean; Calzà, Laura; Cano, Antonio; Illario, Maddalena; Franceschi, Claudio; Liotta, Giuseppe; Maggio, Marcello; Molloy, William D.; Montuori, Nunzia; O’Caoimh, Rónán; Orfila, Francesc; Rauter, Amelia P.; Santoro, Aurelia; Iaccarino, Guido

    2015-01-01

    Preclinical studies are essentially based on animal models of a particular disease. The primary purpose of preclinical efficacy studies is to support generalization of treatment–effect relationships to human subjects. Researchers aim to demonstrate a causal relationship between an investigational agent and a disease-related phenotype in such models. Numerous factors can muddle reliable inferences about such cause-effect relationships, including biased outcome assessment due to experimenter expectations. For instance, responses in a particular inbred mouse might be specific to the strain, limiting generalizability. Selecting well-justified and widely acknowledged model systems represents the best start in designing preclinical studies, especially to overcome any potential bias related to the model itself. This is particularly true in the research that focuses on aging, which carries unique challenges, mainly attributable to the fact that our already long lifespan makes designing experiments that use people as subjects extremely difficult and largely impractical. PMID:27042427

  17. Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

    PubMed

    Molinuevo, José L; Cami, Jordi; Carné, Xavier; Carrillo, Maria C; Georges, Jean; Isaac, Maria B; Khachaturian, Zaven; Kim, Scott Y H; Morris, John C; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

    2016-05-01

    Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.

  18. Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

    PubMed

    Molinuevo, José L; Cami, Jordi; Carné, Xavier; Carrillo, Maria C; Georges, Jean; Isaac, Maria B; Khachaturian, Zaven; Kim, Scott Y H; Morris, John C; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

    2016-05-01

    Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID:26988427

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

    PubMed Central

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

    2014-01-01

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

  20. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    PubMed

    Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

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

  1. Drugs under preclinical and clinical study for treatment of acute and chronic lymphoblastic leukemia

    PubMed Central

    Jacob, Joe Antony; Salmani, Jumah Masoud Mohammad; Chen, Baoan

    2016-01-01

    Targeted therapy has modernized the treatment of both chronic and acute lymphoblastic leukemia. The introduction of monoclonal antibodies and combinational drugs has increased the survival rate of patients. Preclinical studies with various agents have resulted in positive outputs with Phase III trial drugs and monoclonal antibodies entering clinical trials. Most of the monoclonal antibodies target the CD20 and CD22 receptors. This has led to the approval of a few of these drugs by the US Food and Drug Administration. This review focuses on the drugs under preclinical and clinical study in the ongoing efforts for treatment of acute and chronic lymphoblastic leukemia. PMID:27382259

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

    ERIC Educational Resources Information Center

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

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

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

    SciTech Connect

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

    2011-01-15

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

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

    ERIC Educational Resources Information Center

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

    2014-01-01

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

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

    EPA Science Inventory

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

  6. Organic acids and bases: Review of toxicological studies

    SciTech Connect

    Leung, H.W.; Paustenbach, D.J. )

    1990-01-01

    Organic acids and bases are among the most frequently used chemicals in the manufacturing industries. However, the toxicology of only a number of them has been fully characterized, and for fewer still have occupational exposure limits been established. This paper reviews the acute and chronic toxicity data of the organic acids and bases, and considers the mechanism by which these chemicals produce their effects. A methodology for establishing preliminary occupational exposure limits based on the physicochemical properties of these chemicals is presented. Workplace exposure limits for 20 organic acids and bases which currently have no exposure guidelines are suggested. Advice regarding appropriate medical treatment of exposure to these materials is discussed. 98 references.

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

    PubMed

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

    2005-04-01

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

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

    USGS Publications Warehouse

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

    2008-01-01

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

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

    PubMed

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

    2013-04-01

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

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

    PubMed

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

    2013-04-01

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

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

    SciTech Connect

    Medin, Paul M.; Boike, Thomas P.

    2011-04-01

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

  12. 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...

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

    2013-01-01

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

  15. Feasibility of a porcine oral mucosa equivalent: a preclinical study.

    PubMed

    Kinikoglu, Beste; Hemar, Julie; Hasirci, Vasif; Breton, Pierre; Damour, Odile

    2012-08-01

    Oral tissue engineering aims to treat and fill tissue deficits caused by congenital defects, facial trauma, or malignant lesion surgery, as well as to study the biology of oral mucosa. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require a large animal model to evaluate cell-based devices, including tissue-engineered oral mucosa, prior to initiating human clinical studies. Porcine oral mucosa is non-keratinized and resembles that of humans more closely than any other animal in terms of structure and composition; however, there have not been any reports on the reconstruction of a porcine oral mucosa equivalent, probably due to the difficulty to culture porcine fibroblasts. In this study, we demonstrate the feasibility of a 3D porcine oral mucosa equivalent based on a collagen-GAG-chitosan scaffold, as well as reconstructed porcine epithelium by using an amniotic membrane as support, or without any support in form of epithelial cell sheets by using thermoresponsive culture plates. Explants technique was used for the isolation of the porcine fibroblasts and a modified fibroblast medium containing 20% fetal calf serum was used for their culture. The histological and transmission electron microscopic analyses of the resulting porcine oral mucosa models showed the presence of non-keratinized epithelia expressing keratin 13, the major differentiation marker of non-keratinized oral mucosa, in all models, and the presence of newly synthesized collagen fibers in the lamina propria equivalent of the full-thickness model, indicating the functionality of porcine fibroblasts. PMID:22309108

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

    SciTech Connect

    Pruss, T.; Wolf, P.S.

    1983-07-01

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

  17. Biocompatibility and toxicological studies of carbon nanotubes doped with nitrogen.

    PubMed

    Carrero-Sanchez, J C; Elías, A L; Mancilla, R; Arrellín, G; Terrones, H; Laclette, J P; Terrones, M

    2006-08-01

    In this report, we compare the toxicological effects between pure carbon multiwalled nanotubes (MWNTs) and N-doped multiwalled carbon (CNx) nanotubes. Different doses of tubes were administered in various ways to mice: nasal, oral, intratracheal, and intraperitoneal. We have found that when MWNTs were injected into the mice's trachea, the mice could die by dyspnea depending on the MWNTs doses. However, CNx nanotubes never caused the death of any mouse. We always found that CNx nanotubes were far more tolerated by the mice when compared to MWNTs. Extremely high concentrations of CNx nanotubes administrated directly into the mice's trachea only induced granulomatous inflammatory responses. Importantly, all other routes of administration did not induce signs of distress or tissue changes on any treated mouse. We therefore believe that CNx nanotubes are less harmful than MWNTs or SWNTs and might be more advantageous for bioapplications.

  18. Relation between preclinical atherosclerosis and venous thromboembolism in patients with thrombophilias - longitudinal study.

    PubMed

    Auzký, O; Dembovská, R; Mrázková, J; Nováková, Š; Pagáčová, L; Piťha, J

    2014-01-01

    Preclinical atherosclerosis may represent a risk factor for venous thromboembolism (VTE). In longitudinal study we followed longitudinally 96 patients (32 men) with thrombophilias with (n=51) and without (n=45) history of VTE. In both groups we studied the changes of preclinical atherosclerosis at peripherally located arteries detected by ultrasound. In addition, we assessed changes in selected risk factors of atherosclerosis. During the mean follow-up of 56.0+/-7.62 months we did not find significant change in preclinical atherosclerosis defined as Belcaro score in either group (-3 % in the VTE group vs 0 % in non VTE group). Significant increase in body mass index (1.03+/-1.98 kg*m(-2), resp. 1.21+/-1.67 kg*m(-2), p<0.01) and non-significant increase in systolic blood pressure were detected in both groups. Waist circumference increased significantly only in patients without VTE (4.11+/-7.84 cm, p<0.05). No differences in changes of risk factors under study between both groups were detected. In summary, patients with thrombophilia and history of VTE showed no evidence of greater progression of atherosclerosis or increase in traditional risk factors of atherosclerosis than patients with thrombophilia without history of VTE. Unfavorable changes of body mass index, waist circumference and systolic blood pressure were detected in both groups during study period.

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

    PubMed Central

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

    2014-01-01

    Background: Bibliometric studies are increasingly being used for research assessments. Bibliometric indicators involve the application of statistical methods to scientific publications to obtain the bibliographics for each journal. The main objective of this study was to conduct a bibliometric evaluation of Human & Experimental Toxicology retrieved from the Scopus database. Methods: This study obtained data from Scopus published from 1 January 2003 till 31 December 2012. The keywords entered in Scopus to accomplish the objective of this study were ‘Human’, ‘Experimental’ and ‘Toxicology’ as ‘Source Title’. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analysing (a) total and trends in Human & Experimental Toxicology contributions in research between 2003 and 2012; (b) Human & Experimental Toxicology authorship patterns and productivity; (c) collaboration patterns; and (d) the citations received by the publications. Results: There were 1229 research articles published in Human & Experimental Toxicology. Of the articles included, 947 (77.1%) were original articles and 104 (8.5%) were review articles. The Hirsch-index of the retrieved documents was 35. The largest number of publications in Human & Experimental Toxicology was from the United States (19.6%), followed by India (12.8%) and Turkey (10.9%). The total number of citations was 9119, with a median (interquartile range) of 3 (1–9) in 6797 documents. The highest median (interquartile range) number of citations was 8 (2.7–12.7) for France, followed by 7.5 (2–22.5) for Iran and 6 (3–13.5) for the United Kingdom. The country most often citing articles that were published in Human & Experimental Toxicology was the United States, which made citations in 1508 documents, followed by India with citations in 792 documents. Conclusion: The documents in Human & Experimental Toxicology focus principally on original data, with very few

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

    PubMed

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

    2016-01-01

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

  1. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

    PubMed Central

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  2. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies.

    PubMed

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) - a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances - can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  3. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies.

    PubMed

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) - a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances - can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

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

    NASA Technical Reports Server (NTRS)

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

    2010-01-01

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

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

    PubMed

    Sheth, Neha

    2009-01-01

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

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

    PubMed

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

    2016-01-22

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

  7. Contaminant and nutrient concentrations of natural ingredient rat and mouse diet used in chemical toxicology studies.

    PubMed

    Rao, G N; Knapka, J J

    1987-08-01

    The NIH-07 open formula natural ingredient rat and mouse ration is the standard diet for chemical toxicity and carcinogenicity studies conducted for the National Toxicology Program (NTP). Contaminant and nutrient concentrations were determined in 2 to 94 lots of this diet used in the NTP toxicology studies. All nutrient concentrations were equivalent to or greater than the requirements for rats and mice as set forth by the National Research Council. Aflatoxins, Hg, chlorinated hydrocarbons except methoxychlor, organophosphates except malathion, estrogenic activity, and Salmonella sp. were not present at the detectable levels. Fluorine, As, Cd, Pb, Se, N-nitrosodimethylamine, N-nitrosopyrrolidine, N-nitrosomorpholine, nitrate, nitrite, butylated hydroxyanisole, butylated hydroxytoluene, ethylene dibromide, methoxychlor, malathion, and trypsin inhibitor activity were present at or above the detectable levels. Five lots of diet had nitrosamine content of 100 to 273 ppb and 7 lots had 2.08 to 3.37 ppm of Pb. All other lots of NIH-07 diet used for NTP toxicology studies contained low levels of the contaminants. After determination of the contaminant concentrations in the 94 lots of diet and the contaminant concentrations in natural ingredients used in formulating NIH-07 diet, maximum allowable levels of contaminants were established and a flexible scoring system for acceptability of each lot of diet for chemical toxicology studies was developed. By prescreening ingredients such as fish meal for heavy metals and nitrosamines, and applying the flexible scoring system proposed, more than 95% of the lots of NIH-07 diet produced during the last 3 years had scores of greater than or equal to 95 out of 100 points and were considered acceptable for toxicology studies.

  8. Regulatory forum opinion piece: blind reading of histopathology slides in general toxicology studies.

    PubMed

    Neef, Natasha; Nikula, Kristen J; Francke-Carroll, Sabine; Boone, Laura

    2012-06-01

    With the intention of reducing bias, a recent European Food Safety Authority draft guidance document included a recommendation for blinded evaluation of histopathology slides in general toxicology studies (EFSA 2011). Although blinding as to treatment status reduces bias in many types of scientific experiment and is sometimes also appropriate in toxicologic pathology (Holland and Holland 2011), it is most unlikely to help achieve the overall goal of improved human safety when used for routine histopathology evaluation of tissues in general toxicology studies. This is the case because (1) blinding is not applicable to the inductive reasoning process used to identify test article effects in the tissues and would dramatically reduce the chances of these being successfully identified; and (2) in any case, the bias that would be reduced by blinding is actually a bias favoring diagnosis of a toxicological hazard and a conservative safety evaluation, which is appropriate in this context. Other unintended consequences of blinding histopathology evaluation include reductions in sensitivity for a variety of additional reasons and increased subjectivity of the pathology data.

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  11. Preclinical electrogastrography in experimental pigs

    PubMed Central

    Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

    2010-01-01

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

  12. Genetic toxicology: web resources.

    PubMed

    Young, Robert R

    2002-04-25

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

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

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    2013-03-01

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

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

    PubMed

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

    2013-03-01

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

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

    PubMed

    Tuthill, Cynthia

    2007-09-01

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

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

    PubMed

    Tuthill, Cynthia

    2007-09-01

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

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

    PubMed Central

    Hartung, Thomas

    2013-01-01

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

  19. Endothelin receptor antagonists in clinical research--lessons learned from preclinical and clinical kidney studies.

    PubMed

    Reichetzeder, Christoph; Tsuprykov, Oleg; Hocher, Berthold

    2014-11-24

    Endothelin receptor antagonists (ETRAs) are approved for the treatment of pulmonary hypertension and scleroderma-related digital ulcers. The efforts to approve this class of drugs for renal indications, however, failed so far. Preclinical studies were promising. Transgenic overexpression of ET-1 or ET-2 in rodents causes chronic renal failure. Blocking the ET system was effective in the treatment of renal failure in rodent models. However, various animal studies indicate that blocking the renal tubular ETAR and ETBR causes water and salt retention partially mediated via the epithelial sodium transporter in tubular cells. ETRAs were successfully tested clinically in renal indications in phase 2 trials for the treatment of diabetic nephropathy. They showed efficacy in terms of reducing albumin excretion on top of guideline based background therapy (RAS blockade). However, these promising results could not be translated to successful phase III trials so far. The spectrum of serious adverse events was similar to other phase III trials using ETRAs. Potential underlying reasons for these failures and options to solve these issues are discussed. In addition preclinical and clinical studies suggest caution when addressing renal patient populations such as patients with hepatorenal syndrome, patients with any type of cystic kidney disease and patients at risk of contrast media induced nephropathy. The lessons learned in renal indications are also important for other potential promising indications of ETRAs like cancer and heart failure.

  20. Overview of the "epigenetic end points in toxicologic pathology and relevance to human health" session of the 2014 Society Of Toxicologic Pathology Annual Symposium.

    PubMed

    Hoenerhoff, Mark J; Hartke, James

    2015-01-01

    The theme of the Society of Toxicologic Pathology 2014 Annual Symposium was "Translational Pathology: Relevance of Toxicologic Pathology to Human Health." The 5th session focused on epigenetic end points in biology, toxicity, and carcinogenicity, and how those end points are relevant to human exposures. This overview highlights the various presentations in this session, discussing integration of epigenetics end points in toxicologic pathology studies, investigating the role of epigenetics in product safety assessment, epigenetic changes in cancers, methodologies to detect them, and potential therapies, chromatin remodeling in development and disease, and epigenomics and the microbiome. The purpose of this overview is to discuss the application of epigenetics to toxicologic pathology and its utility in preclinical or mechanistic based safety, efficacy, and carcinogenicity studies.

  1. From mouse to man: predictions of human pharmacokinetics of orally administered docetaxel from preclinical studies.

    PubMed

    Koolen, S L W; van Waterschoot, R A B; van Tellingen, O; Schinkel, A H; Beijnen, J H; Schellens, J H M; Huitema, A D R

    2012-03-01

    Intravenously administered docetaxel is approved for the treatment of various types of cancer. An oral regimen, in combination with ritonavir, is being evaluated in clinical trials. The pharmacokinetics of docetaxel are determined by the activity of the metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug efflux transporter P-glycoprotein (P-gp). The effects of these proteins on the pharmacokinetics of docetaxel were investigated in different mouse models that lack 1 or both detoxifying systems. Docetaxel was given to these mice orally or intravenously with or without a strong CYP3A inhibitor, ritonavir. The data of these 2 preclinical studies were pooled and analyzed using nonlinear mixed-effects modeling. The results of the preclinical studies could be integrated successfully, with only a small difference in residual error (33% and 26%, respectively). Subsequently, the model was used to predict human exposure using allometric scaling and this was compared with clinical trial data. This model led to adequate predictions of docetaxel exposure in humans.

  2. Neuropharmacological Aspects of Crocus sativus L.: A Review of Preclinical Studies and Ongoing Clinical Research.

    PubMed

    Singh, Damanpreet

    2015-01-01

    Crocus sativus L. (Iridaceae) is an important member of the genus Crocus having high medicinal value. Its dried stigmas, known as "saffron" are being widely used form past many centuries as a food additive, coloring agent, flavoring agent and a potential source of traditional medicine. The stigmas along with other botanical parts of Crocus sativus are being extensively used in ethnomedical treatment of varied central nervous system diseases. In line with its ethnomedical importance, several preclinical studies have been carried out to validate its traditional uses, identify active principle(s), understand pharmacological basis of therapeutic action and explore novel medicinal uses. The bioactive components of Crocus sativus have been found to modulate several synaptic processes via direct/indirect interplay with neurotransmitter receptor functions, interaction with neuronal death/survival pathways and alteration in neuronal proteins expression. Many clinical studies proving beneficial effect of Crocus sativus in depressive disorders, Alzheimer's disease and some other neurological abnormalities have also been carried out. Based on the vast literature reports available, an attempt has been made to comprehend the fragmented information on neuropharmacological aspects, chemistry and safety of Crocus sativus. Although the plant has been well explored, but still a large scope of future preclinical and clinical research exist to explore its potential in neurological diseases, that has been discussed in depth in the present review.

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

    PubMed

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

    2016-01-01

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

  4. Toxicological findings in fatal motor vehicle collisions in ontario, Canada: a one-year study.

    PubMed

    Woodall, Karen L; Chow, Betty L C; Lauwers, Albert; Cass, Dan

    2015-05-01

    Drug-impaired driving is a complex area of forensic toxicology due in part to limited data concerning the type of drugs involved and the concentrations detected. This study analyzed toxicological findings in drivers from fatal motor vehicle collisions (FMVCs) in Ontario, Canada, over a one-year period using a standardized protocol. Of the 229 cases included in the study, 56% were positive for alcohol and/or drugs. After alcohol, cannabis was the most frequently encountered substance (27%), followed by benzodiazepines (17%) and antidepressants (17%). There were differences in drugs detected by age but no marked difference in drugs detected between single and multiple FMVC's. Not all drugs detected were considered impairing either due to drug type, concentration or case history. The findings indicate the importance of comprehensive drug testing in FMVCs and highlight the need to consider a variety of factors, in addition to drug type and concentration, when assessing the role of drugs in driving impairment. PMID:25693690

  5. Automated weighing procedure for toxicological studies on small animals, using a minicomputer.

    PubMed

    Lewi, P J; Marsboom, R

    1975-08-01

    A compact system was designed for weighing procedures in toxicological studies on small animals that integrated 4 basic functions: data acquistion, record keeping, statistical analysis, and report preparation. An electric balance, a minicomputer, and a typewriter were incorporated into the system. Elimination of clerical work and accelerated flow of information between planning, operation, and evaluation of experiments were found to be the main advantages. PMID:1152423

  6. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... other non-target domestic organisms if, relative to all previously submitted studies, they show an... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of...

  7. Educational Challenges in Toxicology.

    ERIC Educational Resources Information Center

    Dixon, Robert L.

    1984-01-01

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-09-01

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

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

    PubMed

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

    2015-05-01

    Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued.

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

    PubMed

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

    2015-05-01

    Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued. PMID:25724157

  13. ToxEvaluator: an integrated computational platform to aid the interpretation of toxicology study-related findings

    PubMed Central

    Pelletier, D.; Wiegers, T. C.; Enayetallah, A.; Kibbey, C.; Gosink, M.; Koza-Taylor, P.; Mattingly, C. J.; Lawton, M.

    2016-01-01

    Attempts are frequently made to investigate adverse findings from preclinical toxicology studies in order to better understand underlying toxicity mechanisms. These efforts often begin with limited information, including a description of the adverse finding, knowledge of the structure of the chemical associated with its cause and the intended pharmacological target. ToxEvaluator was developed jointly by Pfizer and the Comparative Toxicogenomics Database (http://ctdbase.org) team at North Carolina State University as an in silico platform to facilitate interpretation of toxicity findings in light of prior knowledge. Through the integration of a diverse set of in silico tools that leverage a number of public and proprietary databases, ToxEvaluator streamlines the process of aggregating and interrogating diverse sources of information. The user enters compound and target identifiers, and selects adverse event descriptors from a safety lexicon and mapped MeSH disease terms. ToxEvaluator provides a summary report with multiple distinct areas organized according to what target or structural aspects have been linked to the adverse finding, including primary pharmacology, structurally similar proprietary compounds, structurally similar public domain compounds, predicted secondary (i.e. off-target) pharmacology and known secondary pharmacology. Similar proprietary compounds and their associated in vivo toxicity findings are reported, along with a link to relevant supporting documents. For similar public domain compounds and interacting targets, ToxEvaluator integrates relationships curated in Comparative Toxicogenomics Database, returning all direct and inferred linkages between them. As an example of its utility, we demonstrate how ToxEvaluator rapidly identified direct (primary pharmacology) and indirect (secondary pharmacology) linkages between cerivastatin and myopathy. PMID:27161010

  14. Behavioral toxicology

    SciTech Connect

    Needleman, H.L.

    1995-09-01

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

  15. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of a... the median lethal dose (LD50), median lethal concentration (LC50) or irritation indices, are not... lethal dose (LD50), median lethal concentration (LC50), or median effective concentration (EC50). (2)...

  16. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of a... the median lethal dose (LD50), median lethal concentration (LC50) or irritation indices, are not... lethal dose (LD50), median lethal concentration (LC50), or median effective concentration (EC50). (2)...

  17. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... terrestrial plants show adverse effects on plant life cycle functions and growth such as germination... effects on plant life cycle functions and growth such as germination, emergence, plant vigor, reproduction... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of...

  18. 40 CFR 159.165 - Toxicological and ecological studies.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... terrestrial plants show adverse effects on plant life cycle functions and growth such as germination... effects on plant life cycle functions and growth such as germination, emergence, plant vigor, reproduction... under the criteria of 40 CFR 156.62. (b) Ecological studies. The results of a study of the toxicity of...

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

    EPA Science Inventory

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

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

    PubMed

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

    2014-05-01

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

  1. Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

    PubMed

    Coleman, C Norman; Higgins, Geoff S; Brown, J Martin; Baumann, Michael; Kirsch, David G; Willers, Henning; Prasanna, Pataje G S; Dewhirst, Mark W; Bernhard, Eric J; Ahmed, Mansoor M

    2016-07-01

    There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138-47. ©2016 AACR. PMID:27154913

  2. Toxicology and carcinogenesis studies of pentachlorophenol in rats.

    PubMed

    Chhabra, R S; Maronpot, R M; Bucher, J R; Haseman, J K; Toft, J D; Hejtmancik, M R

    1999-03-01

    Pentachlorophenol (PCP) has been used as an herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and molluscicide. A 28-day toxicity study of PCP in F344/N rats of both sexes was conducted to select dose levels for a carcinogenicity study. Groups of 10 male and 10 female rats were given 0, 200, 400, 800, 1600, or 3200 ppm PCP in feed for 28 days. The incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3200-ppm groups were increased. For carcinogenicity studies, groups of 50 male and 50 female F344/N rats were fed diets containing 200, 400, or 600 PCP for 2 years. A stop-exposure group of 60 male and 60 female rats received 1000 ppm of PCP in feed for 52 weeks and control feed thereafter for the remainder of the 2-year studies; 10 male and 10 female rats were evaluated at 7 months. Survival of 600-ppm males was significantly greater than that of the controls; survival of all other exposed groups was similar to that of the control groups. Mean body weights of the 400- and 600-ppm groups were generally less than those of the controls throughout the studies. There was no evidence of carcinogenic activity of PCP in male or female rats fed diets containing 200, 400, or 600 ppm for 2 years. Stop-exposure study males and females regained a transitory body weight reduction by the end of the 2 year study, and males had better survival than the controls. At a 7-month interim evaluation, the incidences of centrilobular hypertrophy in stop-exposure males and females exceeded those in the controls. At 2 years, malignant mesothelioma originating from the tunica vaginalis was present in 9 1000-ppm males and 1 control male (p = 0.014). Nasal squamous cell carcinomas were present in five 1000-ppm males and 1 control male. This incidence was not significantly increased but exceeded the historical control range (0-4%). Based on the increased

  3. Toxicology and carcinogenesis studies of pentachlorophenol in rats.

    PubMed

    Chhabra, R S; Maronpot, R M; Bucher, J R; Haseman, J K; Toft, J D; Hejtmancik, M R

    1999-03-01

    Pentachlorophenol (PCP) has been used as an herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and molluscicide. A 28-day toxicity study of PCP in F344/N rats of both sexes was conducted to select dose levels for a carcinogenicity study. Groups of 10 male and 10 female rats were given 0, 200, 400, 800, 1600, or 3200 ppm PCP in feed for 28 days. The incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3200-ppm groups were increased. For carcinogenicity studies, groups of 50 male and 50 female F344/N rats were fed diets containing 200, 400, or 600 PCP for 2 years. A stop-exposure group of 60 male and 60 female rats received 1000 ppm of PCP in feed for 52 weeks and control feed thereafter for the remainder of the 2-year studies; 10 male and 10 female rats were evaluated at 7 months. Survival of 600-ppm males was significantly greater than that of the controls; survival of all other exposed groups was similar to that of the control groups. Mean body weights of the 400- and 600-ppm groups were generally less than those of the controls throughout the studies. There was no evidence of carcinogenic activity of PCP in male or female rats fed diets containing 200, 400, or 600 ppm for 2 years. Stop-exposure study males and females regained a transitory body weight reduction by the end of the 2 year study, and males had better survival than the controls. At a 7-month interim evaluation, the incidences of centrilobular hypertrophy in stop-exposure males and females exceeded those in the controls. At 2 years, malignant mesothelioma originating from the tunica vaginalis was present in 9 1000-ppm males and 1 control male (p = 0.014). Nasal squamous cell carcinomas were present in five 1000-ppm males and 1 control male. This incidence was not significantly increased but exceeded the historical control range (0-4%). Based on the increased

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  5. [Preclinical study of the safety of the new Soviet tranquilizer gindarin].

    PubMed

    Arzamastsev, E V; Mironova, M I; Krepkova, L V; Bortnikova, V V; Kuznetsov, Iu V

    1983-01-01

    The Soviet plant tranquilizer gindarin (an isoquinoline series alkaloid I-tetrahydropalmatine) isolated from the tubers of Stephania glabra Miers was subjected to a preclinical study. As regards the toxicity measured during a single administration to the laboratory animals, gindarin may be classified with moderately toxic substances. Daily intragastric administration of gindarin to rats in doses of 20 and 60 mg/kg for 3 months is likely to give rise to the changes in functions of the CNS, liver and blood. In doses of 1--50 mg/kg gindarin does not exhibit any allergizing, mutagenic or teratogenic properties. Administration of the drug in doses of 1--50 mg/kg from the 1st to the 20th day of pregnancy has shown it to produce marked embryotoxic action. In view of this fact gindarin is contraindicated in pregnancy.

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

    PubMed Central

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

    2014-01-01

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

  7. Electrochemotherapy in pancreatic adenocarcinoma treatment: pre-clinical and clinical studies

    PubMed Central

    Leongito, Maddalena; Granata, Vincenza; Barbieri, Antonio; del Vecchio, Vitale; Falco, Michela; Nasto, Aurelio; Albino, Vittorio; Piccirillo, Mauro; Palaia, Raffaele; Amore, Alfonso; Giacomo, Raimondo di; Lastoria, Secondo; Setola, Sergio Venanzio; Fusco, Roberta; Petrillo, Antonella; Izzo, Francesco

    2016-01-01

    Background Pancreatic adenocarcinoma is currently one of the deadliest cancers with high mortality rate. This disease leads to an aggressive local invasion and early metastases, and is poorly responsive to treatment with chemotherapy or chemo-radiotherapy. Radical resection is still the only curative treatment for pancreatic cancer, but it is generally accepted that a multimodality strategy is necessary for its management. Therefore, new alternative therapies have been considered for local treatment. Conclusions Chemotherapeutic resistance in pancreatic cancer is associated to a low penetration of drugs into tumour cells due to the presence of fibrotic stroma surrounding cells. In order to increase the uptake of chemotherapeutic drugs into tumour cells, electrochemotherapy can be used for treatment of pancreatic adenocarcinoma leading to an increased tumour response rate. This review will summarize the published papers reported in literature on the efficacy and safety of electrochemotherapy in pre-clinical and clinical studies on pancreatic cancer. PMID:27069445

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

    PubMed Central

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

    1993-01-01

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

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

    PubMed Central

    Group, E F

    1986-01-01

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

  10. Environmental fate and aquatic toxicology studies on phthalate esters

    SciTech Connect

    Group, E.F. Jr.

    1986-03-01

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

  11. Toxicological studies of pesticides on cytoplasmic streaming in Nitella.

    PubMed

    Pandey, Sudhir Kumar; Fatma, Tasneem

    2004-07-01

    In the present study, changes in velocity of cytoplasmic streaming in the giant internodal cells of Nitella for varying concentration of the pesticides, 2,4-D, dieldrin, malathion, methyl parathion and endosulfan, were measured. Marked decrease in the velocity of cytoplasmic streaming was found at the concentrations of 0.01, 0.1, 1, 10 and 100mM. Dieldrin was the most toxic to all the pesticides investigated, followed by methyl parathion, endosulfan, malathion and 2,4-D. Threshold values for dieldrin, methylparathion, endosulfan, malathion and 2,4-D as indicated by the onset of decrease in the normal cytoplasmic streaming velocity were less than 6.25 x 10(-6), 2.5 x 10(-5), 5 x 10(-5), 5 x 10(-5) and 1.25 x 10(-5)M respectively. Cessation of streaming was noticed above 1mM in dieldrin and above 10mM when exposed to methylparathion and endosulfan. Cessation of streaming was not seen up to 100mM concentration of 2,4-D and malathion.

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

    SciTech Connect

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

    1990-12-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Di Giulio, Richard T; Clark, Bryan W

    2015-01-01

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

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

    PubMed

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

    2010-01-01

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

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

    PubMed

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

    2002-10-01

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

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

    PubMed

    Di Giulio, Richard T; Clark, Bryan W

    2015-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

  20. Nonindustry-Sponsored Preclinical Studies on Statins Yield Greater Efficacy Estimates Than Industry-Sponsored Studies: A Meta-Analysis

    PubMed Central

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

    2014-01-01

    Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966–April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I2 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

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

    PubMed

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

    2014-09-01

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

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

    PubMed

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

    2014-09-01

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

  3. Using Bayesian analysis in repeated preclinical in vivo studies for a more effective use of animals.

    PubMed

    Walley, Rosalind; Sherington, John; Rastrick, Joe; Detrait, Eric; Hanon, Etienne; Watt, Gillian

    2016-05-01

    Whilst innovative Bayesian approaches are increasingly used in clinical studies, in the preclinical area Bayesian methods appear to be rarely used in the reporting of pharmacology data. This is particularly surprising in the context of regularly repeated in vivo studies where there is a considerable amount of data from historical control groups, which has potential value. This paper describes our experience with introducing Bayesian analysis for such studies using a Bayesian meta-analytic predictive approach. This leads naturally either to an informative prior for a control group as part of a full Bayesian analysis of the next study or using a predictive distribution to replace a control group entirely. We use quality control charts to illustrate study-to-study variation to the scientists and describe informative priors in terms of their approximate effective numbers of animals. We describe two case studies of animal models: the lipopolysaccharide-induced cytokine release model used in inflammation and the novel object recognition model used to screen cognitive enhancers, both of which show the advantage of a Bayesian approach over the standard frequentist analysis. We conclude that using Bayesian methods in stable repeated in vivo studies can result in a more effective use of animals, either by reducing the total number of animals used or by increasing the precision of key treatment differences. This will lead to clearer results and supports the "3Rs initiative" to Refine, Reduce and Replace animals in research. Copyright © 2016 John Wiley & Sons, Ltd.

  4. Mouse Model for the Preclinical Study of Metastatic Disease | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Laboratory of Cancer Biology and Genetics, National Cancer Institute seeks partners for collaborative research to co-develop a mouse model that shows preclinical therapeutic response of residual metastatic disease.

  5. Joint models for toxicology studies with dose-dependent number of implantations.

    PubMed

    Allen, Andrew S; Barnhart, Huiman X

    2002-12-01

    Many chemicals interfere with the natural reproductive processes in mammals. The chemicals may prevent the fertilization of an egg or keep a zygote from implanting in the uterine wall. For this reason, toxicology studies with pre-implantation exposure often exhibit a dose-related trend in the number of observed implantations per litter. Standard methods for analyzing developmental toxicology studies are conditioned on the number of implantations in the litter and therefore cannot estimate this effect of the chemical on the reproductive process. This article presents a joint modeling approach to estimating risk in toxicology studies with pre-implantation exposure. In the joint modeling approach, both the number of implanted fetuses and the outcome of each implanted fetus is modeled. Using this approach we show how to estimate the overall risk of a chemical that incorporates the risk of lost implantation due to pre-implantation exposure. Our approach has several distinct advantages over previous methods: (1) it is based on fitting a model for the observed data and, therefore, diagnostics of model fit and selection apply; (2) all assumptions are explicitly stated; and (3) it can be fit using standard software packages We illustrate our approach by analyzing a dominant lethal assay data set (Luning et al., 1966, Mutation Research, 3, 444-451) and compare ourresults with those of Rai and Van Ryzin (1985, Biometrics, 41,1-9) and Dunson (1998, Biometrics, 54, 558-569). In a simulation study, our approach has smaller bias and variance than the multiple imputation procedure of Dunson.

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

    SciTech Connect

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

    1988-08-01

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

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

    PubMed Central

    Smith, Mark A.; Lynch, Wendy J.

    2012-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1972-01-01

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

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

    PubMed

    Britton, Gabrielle B

    2012-02-01

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

  10. Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy.

    PubMed

    Mattina, James; MacKinnon, Nathalie; Henderson, Valerie C; Fergusson, Dean; Kimmelman, Jonathan

    2016-08-15

    The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies

  11. Hepatoprotective and toxicological studies of Salvia bucharica methanolic extract in rabbits.

    PubMed

    Ahmad, Mansoor; Muhammed, Shafi; Mehjabeen, -; Jahan, Noor

    2014-11-01

    Most of the species of genus Salvia are famous for having medicinal properties due to their chemical constituents. Salvia bucharica (Lamiacea) is found in Balochistan near Quetta in Hannaurak and Kalat. It is used in traditional system of medicine and claims to cure liver ailments. In current study crude methanolic extract (CME) of Salvia bucharica was obtained from the leaves and tested for hepatoprotective activity and possible toxicity in rabbits. Liver toxicity was induced in rabbits by administration of carbon tetra chloride (CCl4) and evaluated by biochemical tests and histopathology of tissues. In this study rabbits were divided in to 3 groups (5 rabbit in each group). Rabbits of group I (control) were administered only vehicle (0.9% sodium chloride) orally. Rabbits of group II were given CCl4 and group III were treated with CCl4 and S. bucharica CME orally. For hepatoprotective effect serum enzyme level and total protein level were calculated. Histopathology of liver sections of rabbits was also carried out to observe protective effect. Biochemical, hematological and histoptahological parameters were studied on rabbits for toxicological studies. S. bucharica CME showed significant liver protection with reduction in total bilirubin, direct bilirubin, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), gamma glutamyl transpeptidase (γ-GT). And decrease in Albumin and globulin. In toxicological studies, biochemical and histoptahological parameters showed no significant toxicity in liver, heart and kidneys. It is concluded that S. bucharica CME showed hepatoprotective effects with nontoxic profile.

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

    NASA Astrophysics Data System (ADS)

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

    2011-02-01

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

  13. Standardization of the Filovirus Plaque Assay for Use in Preclinical Studies

    PubMed Central

    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

    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

  14. Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

    PubMed Central

    de Carvalho, Felipe Gonçalves; de Freitas, Gabriel Rodriguez

    2016-01-01

    Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field.

  15. Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

    PubMed Central

    de Carvalho, Felipe Gonçalves; de Freitas, Gabriel Rodriguez

    2016-01-01

    Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field. PMID:27698671

  16. Noninferiority of Shanghai Cingular biotech’s bovine pericardial valve preclinical study in juvenile ovine model

    PubMed Central

    Chen, Jin-Miao; Ding, Yu; Lu, Shu-Yang; Pan, Sun; Abudupataer, Mieradilijiang

    2016-01-01

    Background This study introduces a newly Chinese domestic-designed/manufactured bovine pericardial valve, the SCBC valve (Shanghai Cingular Biotech Corporation, Shanghai, China), and evaluates its hemodynamic performance and calcification potential compared with the Carpentier-Edwards (CE) PerimountTM valve (Edwards Lifesciences, Irvine, CA, USA) in juvenile sheep for preclinical study. Methods Five SCBC valves in study group and three CE PerimountTM valves (6900P with TFX) in control group were implanted in the mitral position of juvenile sheep and followed up for five months. Transthoracic echocardiography (TTE) for hemodynamic measurement was performed ten days, three months and five months postoperatively. Valve calcification was assessed by X-ray after euthanasia. Other collected data included macroscopic examination, blood analysis, microorganism culture and histological assessment. Results All sheep in two groups lived to sacrifice without evidence of valvular dysfunction. The SCBC valve had similar hemodynamic performance and susceptibility of calcification compared with the CE PerimountTM valve in juvenile ovine model. In all other parameters, the SCBC valve also exhibited no significant difference compared with the CE PerimountTM valve. Conclusions Our study demonstrated that the SCBC valve can exhibit similar mid-term satisfactory safety and efficacy compared with the CE PerimountTM valve in the mitral position of juvenile sheep model. PMID:27293835

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

    PubMed

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

    2015-05-01

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

  18. Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis.

    PubMed

    Cunha-Júnior, Edézio Ferreira; Martins, Thiago Martino; Canto-Cavalheiro, Marilene Marcuzzo; Marques, Paulo Roberto; Portari, Elyzabeth Avvad; Coelho, Marsen Garcia Pinto; Netto, Chaquip Daher; Costa, Paulo Roberto Ribeiro; Sabino, Katia Costa de Carvalho; Torres-Santos, Eduardo Caio

    2016-06-01

    Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and anti-leukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis. PMID:27067332

  19. Green toxicology.

    PubMed

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

    2014-01-01

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

  20. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.

    PubMed

    Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201. PMID:27626799

  1. Reference values of clinical pathology parameters in cynomolgus monkeys (Macaca fascicularis) used in preclinical studies.

    PubMed

    Park, Hyun-Kyu; Cho, Jae-Woo; Lee, Byoung-Seok; Park, Heejin; Han, Ji-Seok; Yang, Mi-Jin; Im, Wan-Jung; Park, Do-Yong; Kim, Woo-Jin; Han, Su-Cheol; Kim, Yong-Bum

    2016-06-01

    Nonhuman primates are increasingly used in biomedical research since they are highly homologous to humans compared to other rodent animals. However, there is limited reliable reference data of the clinical pathology parameters in cynomolgus monkeys, and in particular, only some coagulation and urinalysis parameters have been reported. Here, we reported the reference data of clinical chemical, hematological, blood coagulation, and urinalysis parameters in cynomolgus monkeys. The role of sex differences was analyzed and several parameters (including hematocrit, hemoglobin, red blood cell, blood urea nitrogen, total bilirubin, alkaline phosphatase, creatinine kinase, gamma-glutamyl tranferase, and lactate dehydrogenase) significantly differed between male and female subjects. In addition, compared to previous study results, lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase showed significant variation. Interstudy differences could be affected by several factors, including age, sex, geographic origin, presence/absence of anesthetics, fasting state, and the analytical methods used. Therefore, it is important to deliberate with the overall reference indices. In conclusion, the current study provides a comprehensive and updated reference data of the clinical pathology parameters in cynomolgus monkeys and provides improved assessment criteria for evaluating preclinical studies or biomedical research. PMID:27382375

  2. Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study

    PubMed Central

    Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José

    2016-01-01

    Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentration in vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

  3. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study

    PubMed Central

    Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201’s cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201. PMID:27626799

  4. Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study.

    PubMed

    Davanço, Marcelo Gomes; Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José; Peccinini, Rosângela Gonçalves

    2016-04-01

    Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentrationin vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

  5. High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies.

    PubMed

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

    2014-01-01

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

  6. Reference values of clinical pathology parameters in cynomolgus monkeys (Macaca fascicularis) used in preclinical studies

    PubMed Central

    Park, Hyun-Kyu; Cho, Jae-Woo; Lee, Byoung-Seok; Park, Heejin; Han, Ji-Seok; Yang, Mi-Jin; Im, Wan-Jung; Park, Do-Yong; Kim, Woo-Jin; Han, Su-Cheol

    2016-01-01

    Nonhuman primates are increasingly used in biomedical research since they are highly homologous to humans compared to other rodent animals. However, there is limited reliable reference data of the clinical pathology parameters in cynomolgus monkeys, and in particular, only some coagulation and urinalysis parameters have been reported. Here, we reported the reference data of clinical chemical, hematological, blood coagulation, and urinalysis parameters in cynomolgus monkeys. The role of sex differences was analyzed and several parameters (including hematocrit, hemoglobin, red blood cell, blood urea nitrogen, total bilirubin, alkaline phosphatase, creatinine kinase, gamma-glutamyl tranferase, and lactate dehydrogenase) significantly differed between male and female subjects. In addition, compared to previous study results, lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase showed significant variation. Interstudy differences could be affected by several factors, including age, sex, geographic origin, presence/absence of anesthetics, fasting state, and the analytical methods used. Therefore, it is important to deliberate with the overall reference indices. In conclusion, the current study provides a comprehensive and updated reference data of the clinical pathology parameters in cynomolgus monkeys and provides improved assessment criteria for evaluating preclinical studies or biomedical research. PMID:27382375

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

    PubMed

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

    2016-04-01

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

  8. Preclinical endodontic teaching

    PubMed Central

    Narayanaraopeta, Udaya; AlShwaimi, Emad

    2015-01-01

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

  9. Imaging and morphology in reproductive toxicology - progress to date and future directions.

    PubMed

    French, Julian M

    2014-09-01

    This review looks at the recent development and application of imaging techniques for the morphological examination of fetuses from preclinical regulatory reproductive toxicology studies. Full replacement of the examination methods currently used in routine studies (microdissection, Bouin's fluid fixation/sectioning and alizarin red S/alcian blue preparations) by imaging techniques has yet to be achieved. Progress, especially in the application of micro-CT for skeletal examination, has been made but challenges, particularly the financial investment required, remain. Despite this apparent lack of progress the application of imaging techniques to "non-routine" preclinical reproductive toxicology studies has been used to good effect. The ability to acquire multiple images over a time course i.e. longitudinally has enabled the fate, particularly of skeletal features, to be determined. The additional evidence gained from such studies can be used to better inform the prenatal developmental hazard assessment of test compounds.

  10. National Toxicology Program

    MedlinePlus

    ... improved search is live. Try it now! NTP Cell Phone Radiofrequency Radiation Studies The National Toxicology Program (NTP) ... rats and mice on potential health hazards from cell phone radiofrequency radiation. The NTP released a report on ...

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

    PubMed Central

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

    2006-01-01

    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

  12. Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies

    PubMed Central

    Tse, Gary; Liu, Tong; Li, Ka H. C.; Laxton, Victoria; Chan, Yin W. F.; Keung, Wendy; Li, Ronald A.; Yan, Bryan P.

    2016-01-01

    Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na+ channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na+, K+, Ca2+, and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge. Three hypotheses based on abnormal depolarization, abnormal repolarization, and current-load-mismatch have been put forward to explain the electrophysiological mechanisms responsible for BrS. Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening VT/VF. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction and based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers. PMID:27803673

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

    PubMed

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

    2016-02-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

    Schindler, Suzanne Elizabeth; Fagan, Anne M.

    2015-01-01

    Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF Aβ42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD. PMID:26175713

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

    PubMed Central

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

    2014-01-01

    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

  17. Preclinical animal study and clinical trail of modified extraoral craniofacial implants.

    PubMed

    Petrovic, L; Schlegel, K A; Wiltfang, J; Neukam, F W; Rupprecht, S

    2007-01-01

    We report on our experience using a new endosseous implant designed to provide sufficient retention to various types of facial prostheses. In a preclinical animal experiment implants (N=12, 4 x 3.5 mm) were placed in the frontal calvarial region of nine adult pigs. The animals were sacrificed at 2, 4 and 8 weeks to evaluate the implant incorporation microradiographically. The clinical outcome and patient satisfaction of implant-retained prostheses were evaluated in a group of 10 patients with facial defects by using clinical assessment and standardized questionnaires for patients and relatives. In the prospective clinical study 33 identical modified implants for extraoral anchorage were placed for the fixation of various prostheses in the midfacial (eye, nose) and ear regions in the course of a clinical trial and observed over a follow-up period of 34 months. The bone-implant contact in the animal experiment reached 31% (+/-2) at 2 weeks, 39% (+/-1) after 4 weeks and 51% (+/-5) at 8 weeks. In the clinical trial, no implants were lost and all implants remained osseointegrated as confirmed clinically and radiographically, providing a stable prosthetic restoration. The analysis of the questionnaire indicates an improvement of the quality of life of patients with respect to aesthetic and psychological well-being. The results demonstrate that extraoral implants not only achieve sufficient osseointegration but also show good clinical handling and easy fixation possibilities for prosthetic anchorage. PMID:17392045

  18. Stem cell therapy for ischaemic stroke: translation from preclinical studies to clinical treatment.

    PubMed

    Balami, Joyce S; Fricker, Rosemary A; Chen, Ruoli

    2013-03-01

    No pharmacological intervention has been shown convincingly to improve neurological outcome in stroke patients after the brain tissue is infarcted. While conventional therapeutic strategies focus on preventing brain damage, stem cell treatment has the potential to repair the injured brain tissue. Stem cells not only produce a source of trophic molecules to minimize brain damage caused by ischaemia/reperfusion and promote recovery, but also potentially turn to new cells to replace those lost in ischaemic core. Although preclinical studies have shown promise, stem cell therapy for stroke treatment in human is still at an early stage and it is difficult to draw conclusions from current clinical trials about the efficacy of the different treatments used in humans. This article reviews the potential of various types of stem cells, from embryonic to adult to induced pluripotent stem cells, in stroke therapy, highlights new evidence from the ongoing clinical trials and discusses some of the problems associated with translating stem cell technology to a clinical therapy for stroke. PMID:23394533

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

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2011-08-01

    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.

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

    PubMed

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

    2015-10-01

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

  2. Carbon Nanotubes Exposure Risk Assessment: From Toxicology to Epidemiologic Studies (Overview of the Current Problem)

    PubMed Central

    Fatkhutdinova, L. M.; Khaliullin, T. O.; Shvedova, A. A.

    2015-01-01

    Nanoscale size and fiber like structure of carbon nanotubes (CNTs) may determine high reactivity and penetration, as well as the pathogenicity of asbestos and other mineral fibers. Despite many in vitro and in vivo studies, the absence of full-scale data on CNT effects on human health clearly point out the necessity for epidemiological studies. Currently, several projects are initiated worldwide on studying health risks associated with the inhalation of industrial CNTs, including NIOSH-promoted research (United States), the European CANTES study, and the Russian CNT-ERA project. Studies comprising several successive steps, such as CNT exposure assessment in occupational settings, toxicological evaluation, and epidemiological observations, are critical for determining material safety and use criteria. PMID:26457172

  3. Meta-Analysis and Systematic Review of Neural Stem Cells therapy for experimental ischemia stroke in preclinical studies

    PubMed Central

    Chen, Lukui; Zhang, Guilong; Gu, Yuchun; Guo, Xiaoyuan

    2016-01-01

    To evaluate the preclinical studies using NSCs transplantation therapy for experimental ischemic stroke, and determine the effect size of NSCs therapy and the correlations between different clinical measures. We firstly searched literatures to identify studies of NSCs therapy in animal cerebral ischemia models, and then calculated the quality score of studies, assessed the effect size of NSCs therapy relative to behavioral and histologic endpoints by meta-analysis. A total of 37 studies and 54 independent treated interventions were used for systematic review and meta-analysis. The median quality score was 5 of 10. 36 studies (53 intervention arms) reported functional outcome, 22 studies (34 intervention arms) reported structural outcome. After adjusted by subgroup and sensitivity analysis, the mean effect sizes were improved by 1.35 for mNSS, 1.84 for rotarod test, 0.61 for cylinder test, and 0.84 for infarct volume. Furthermore, effect size had a certain interaction with clinical variables, for example early NSCs therapy etc. In this preclinical studies, we demonstrated that transplanted NSCs significantly improved outcomes (both functional and structural outcome) in ischemic stroke. It is suggested that future preclinical animal model studies of stroke should improve study quality validity and reduce potentially confounded publication bias. PMID:27554433

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

    NASA Astrophysics Data System (ADS)

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

    1991-06-01

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

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

    PubMed

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

    2016-01-01

    The methanolic extract of dried fruit pulp of Citrullus colocyn this (Cucurbitaceae) has been studied with respect to antimicrobial and toxicological properties. The antimicrobial profile was investigated against thirty bacterial isolates (10 Gram +ve and 20 Gram-ve) and five fungal species. None of the bacterial or fungal culture used in the study showed sensitivity against the extract. Acute toxicity studies carried out in Albino mice NMRI indicated the highly toxic nature of the colocynth. A very significant decrease in body weight of test animals was noted at P<0.05. The LD(50) was calculated as 1000mg/kg body weight. Within four days of experimentation mortality was 100%. Histopathological studies confirmed the toxic nature of extract. Gross changes in histology of Heart, Liver and Kidneys were noted. Section of spleen did not exhibit any abnormality.

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

    PubMed

    Polednak, A P; Janerich, D T

    1983-01-01

    The uses of available record systems in epidemiologic studies of reproductive toxicology are described with reference to New York State. The available record systems (and relevant reproductive end points) described include: a newborn screening program for metabolic diseases and hemoglobinopathies (relevant to point mutations); chromosome registries and prenatal cytogenetics (for chromosome anomalies); live birth certificates (for birth defects, birthweight, sex ratio, etc); fetal death certificates (for spontaneous fetal deaths); and a statewide cancer registry (for childhood cancers and transplacental carcinogenesis). The uses and limitations of these record systems are discussed, along with examples of their use in descriptive and analytic epidemiologic studies. Descriptive studies outlined include investigations of temporal and geographic trends in birth defects, birth weight, and fetal deaths, with reference to environmental questions (eg, Love Canal, nuclear power plants). Analytic studies described concern parental occupation in relation to specific birth defects (neural tube defects and Down syndrome) and maternal use of contraceptive drugs. PMID:6220602

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

    SciTech Connect

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

    1983-01-01

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

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

    PubMed

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

    2016-01-01

    The methanolic extract of dried fruit pulp of Citrullus colocyn this (Cucurbitaceae) has been studied with respect to antimicrobial and toxicological properties. The antimicrobial profile was investigated against thirty bacterial isolates (10 Gram +ve and 20 Gram-ve) and five fungal species. None of the bacterial or fungal culture used in the study showed sensitivity against the extract. Acute toxicity studies carried out in Albino mice NMRI indicated the highly toxic nature of the colocynth. A very significant decrease in body weight of test animals was noted at P<0.05. The LD(50) was calculated as 1000mg/kg body weight. Within four days of experimentation mortality was 100%. Histopathological studies confirmed the toxic nature of extract. Gross changes in histology of Heart, Liver and Kidneys were noted. Section of spleen did not exhibit any abnormality. PMID:26826821

  9. Computational Toxicology

    EPA Science Inventory

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

  10. Magnetic Drug Targeting: Preclinical in Vivo Studies, Mathematical Modeling, and Extrapolation to Humans.

    PubMed

    Al-Jamal, Khuloud T; Bai, Jie; Wang, Julie Tzu-Wen; Protti, Andrea; Southern, Paul; Bogart, Lara; Heidari, Hamed; Li, Xinjia; Cakebread, Andrew; Asker, Dan; Al-Jamal, Wafa T; Shah, Ajay; Bals, Sara; Sosabowski, Jane; Pankhurst, Quentin A

    2016-09-14

    A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev-Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5-8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting. PMID:27541372

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

    PubMed Central

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

    2015-01-01

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

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

    SciTech Connect

    Oris, J.T.

    1997-10-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

    Linsenbardt, David N; Boehm, Stephen L

    2014-09-01

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

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

    NASA Astrophysics Data System (ADS)

    Meißner, Tobias; Oelschlägel, Kathrin; Potthoff, Annegret

    2014-08-01

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

  16. Ovarian toxicity and carcinogenicity in eight recent national toxicology program studies

    SciTech Connect

    Maronpot, R.R.

    1987-08-01

    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.

  17. Development of Immunoassays for the Quantitative Assessment of Amyloid-β in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies

    PubMed Central

    Bogstedt, Anna; Groves, Maria; Tan, Keith; Narwal, Rajesh; McFarlane, Mary; Höglund, Kina

    2015-01-01

    Abstract Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-β (Aβ)42 peptide. Here we present the introduction of novel pre-treatment steps to ensure drug-tolerant immunoassays and describe the validation of the complete experimental procedures to measure total Aβ42 concentration (bound and unbound) in cerebrospinal fluid (CSF) and plasma, free Aβ42 concentration (unbound) in CSF, and Aβ40 concentration in CSF. The difference in composition of the matrices (CSF and plasma) and antigen levels therein, in combination with the hydrophobic properties of Aβ protein, adds to the complexity of validation. Monitoring pharmacodynamics of an Aβ42 specific monoclonal antibody in a non-human primate toxicology study using these assays, we demonstrated a 1500-fold and a 3000-fold increase in total Aβ42 in plasma, a 4-fold and 8-fold increase in total Aβ42 in CSF together with a 95% and 96% reduction of free Aβ42 in CSF following weekly intravenous injections of 10 mg/kg and 100 mg/kg, respectively. Levels of Aβ40 were unchanged. The accuracy of these data is supported by previous pre-clinical studies as well as predictive pharmacokinetic/pharmacodynamics modeling. In contrast, when analyzing the same non-human primate samples excluding the pre-treatment steps, we were not able to distinguish between free and total Aβ42. Our data clearly demonstrate the importance of thorough evaluation of antibody interference and appropriate validation to monitor different types of biomarkers in the presence of a therapeutic antibody. PMID:26402635

  18. Development of Immunoassays for the Quantitative Assessment of Amyloid-β in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies.

    PubMed

    Bogstedt, Anna; Groves, Maria; Tan, Keith; Narwal, Rajesh; McFarlane, Mary; Höglund, Kina

    2015-01-01

    Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-β (Aβ)42 peptide. Here we present the introduction of novel pre-treatment steps to ensure drug-tolerant immunoassays and describe the validation of the complete experimental procedures to measure total Aβ42 concentration (bound and unbound) in cerebrospinal fluid (CSF) and plasma, free Aβ42 concentration (unbound) in CSF, and Aβ40 concentration in CSF. The difference in composition of the matrices (CSF and plasma) and antigen levels therein, in combination with the hydrophobic properties of Aβ protein, adds to the complexity of validation. Monitoring pharmacodynamics of an Aβ42 specific monoclonal antibody in a non-human primate toxicology study using these assays, we demonstrated a 1500-fold and a 3000-fold increase in total Aβ42 in plasma, a 4-fold and 8-fold increase in total Aβ42 in CSF together with a 95% and 96% reduction of free Aβ42 in CSF following weekly intravenous injections of 10 mg/kg and 100 mg/kg, respectively. Levels of Aβ40 were unchanged. The accuracy of these data is supported by previous pre-clinical studies as well as predictive pharmacokinetic/pharmacodynamics modeling. In contrast, when analyzing the same non-human primate samples excluding the pre-treatment steps, we were not able to distinguish between free and total Aβ42. Our data clearly demonstrate the importance of thorough evaluation of antibody interference and appropriate validation to monitor different types of biomarkers in the presence of a therapeutic antibody. PMID:26402635

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

    PubMed

    Lippmann, Morton

    2014-09-01

    Airborne fibers, when sufficiently biopersistent, can cause chronic pleural diseases, as well as excess pulmonary fibrosis and lung cancers. Mesothelioma and pleural plaques are caused by biopersistent fibers thinner than ∼0.1 μm and longer than ∼5 μm. Excess lung cancer and pulmonary fibrosis are caused by biopersistent fibers that are longer than ∼20 μm. 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 μm, and those thinner than 0.1 μm, based on the fiber types. PMID:25168068

  20. Preclinical screening methods in cancer

    PubMed Central

    Kumar, Sachin; Bajaj, Sakshi; Bodla, Ramesh Babu

    2016-01-01

    Cancer, a group of diseases of unregulated cell proliferation, is a leading cause of death worldwide. More than 80% of compounds which have shown promising effects in preclinical studies could not get through Phase II of clinical trials. Such high attrition rate is due to improper or selective use of preclinical modalities in anticancer drug screening. The various preclinical screening methods available such as in vitro human cancer cell lines, in vivo tumor xenograft model, or genetically engineered mouse model have their respective pros and cons. Scrupulous use of these preclinical screening methods vis-à-vis efficacy of potential anticancer compound with diverse mechanism of action can help in bringing down the rate of failure of anticancer compound at clinical phase. This article provides an insight into the various preclinical methods used in anticancer studies along with their advantages and disadvantages. PMID:27721530

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

    PubMed Central

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

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

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

    PubMed

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2009-06-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2004-06-01

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

  6. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

    PubMed Central

    Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola; Wang, Hongjie; Gough, Michael; Baldessari, Audrey; Cattaneo, Roberto; Lee, Frank; Wang, Chung-Huei Katherine; Jang, Haishan; Astier, Anne; Gopal, Ajay; Carter, Darrick; Lieber, André

    2016-01-01

    Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the

  7. 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...

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

    PubMed

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

    2015-03-01

    Memory changes in preclinical Alzheimer's disease (AD) are often characterized by heterogenous trajectories. However, data regarding the nature and determinants of predominant trajectories of memory changes in preclinical AD are lacking. We analyzed data from 333 cognitively healthy older adults who participated in a multicenter prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments. Latent growth mixture modeling revealed 3 predominant trajectories of memory change: a below average, subtly declining memory trajectory (30.9%); a below average, rapidly declining memory trajectory (3.6%); and an above average, stable memory trajectory (65.5%). Compared with the stable memory trajectory, high Αβ (relative risk ratio [RRR] = 2.1), and lower Mini-Mental State Examination (RRR = 0.6) and full-scale IQ (RRR = 0.9) scores were independently associated with the subtly declining memory trajectory; and high Αβ (RRR = 8.3), APOE ε4 carriage (RRR = 6.1), and greater subjective memory impairment (RRR = 1.2) were independently associated with the rapidly declining memory trajectory. Compared with the subtly declining memory trajectory group, APOE ε4 carriage (RRR = 8.4), and subjective memory complaints (RRR = 1.2) were associated with a rapidly declining memory trajectory. These results suggest that the preclinical phase of AD may be characterized by 2 predominant trajectories of memory decline that have common (e.g., high Αβ) and unique (e.g., APOE ε4 genotype) determinants. PMID:25585532

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

    SciTech Connect

    Lovely, R.H.

    1988-01-01

    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.

  10. Testing the equivalencies of concentration response distributions in aquatic toxicology studies

    SciTech Connect

    Oris, J.T.; Diamond, S.A.; Bailer, A.J.

    1995-12-31

    The purpose of this study was to describe statistical procedures to test the equivalencies of concentration response distributions in aquatic toxicology studies. Commonly the only endpoint compared in acute toxicity testing is the concentration associated with the mean adverse response (LC50) between two test populations. However, other endpoint comparisons may be more meaningful in a risk assessment context (eg., LC10). In addition, assessing the equivalency of slopes between concentration response distributions may lend insight into the characteristics of the overall population mortality response to a toxicant. A regression model that allowed for the examination of equivalence of slopes and intercepts of the responses between populations was developed using probit and logistic regression. Test statistics were derived from comparing nested regression models. This procedure was used to test the equivalency of the fluoranthene concentration versus acute mortality response relationships between two populations of fish, one of which had experienced long-term low-level fluoranthene exposure and putatively had developed genetically-based tolerance to fluoranthene toxicity. Results from this study indicated that this procedure can be used to acquire hazard assessment information from acute toxicity studies that cannot be obtained utilizing standard analysis techniques.

  11. Going GLP: Conducting Toxicology Studies in Compliance with Good Laboratory Practices.

    PubMed

    Carroll, Erica Eggers

    2016-01-01

    Good laboratory practice standards are US federal regulations enacted as part of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR Part 160), the Toxic Substance Control Act (40 CFR Part 792), and the Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58) to support protection of public health in the areas of pesticides, chemicals, and drug investigations in response to allegations of inaccurate data acquisition. Essentially, good laboratory practices (GLPs) are a system of management controls for nonclinical research studies involving animals to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of data collected as part of chemical (including pharmaceuticals) tests, from in vitro through acute to chronic toxicity tests. The GLPs were established in the United States in 1978 as a result of the Industrial Bio-Test Laboratory scandal which led to congressional hearings and actions to prevent fraudulent data reporting and collection. Although the establishment of infrastructure for GLPs compliance is labor-intensive and time-consuming, achievement and maintenance of GLP compliance ensures the accuracy of the data collected from each study, which is critical for defending results, advancing science, and protecting human and animal health. This article describes how and why those in the US Army Medical Department responsible for protecting the public health of US Army and other military personnel made the policy decision to have its toxicology laboratory achieve complete compliance with GLP standards, the first such among US Army laboratories. The challenges faced and how they were overcome are detailed. PMID:27613211

  12. Going GLP: Conducting Toxicology Studies in Compliance with Good Laboratory Practices.

    PubMed

    Carroll, Erica Eggers

    2016-01-01

    Good laboratory practice standards are US federal regulations enacted as part of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR Part 160), the Toxic Substance Control Act (40 CFR Part 792), and the Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58) to support protection of public health in the areas of pesticides, chemicals, and drug investigations in response to allegations of inaccurate data acquisition. Essentially, good laboratory practices (GLPs) are a system of management controls for nonclinical research studies involving animals to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of data collected as part of chemical (including pharmaceuticals) tests, from in vitro through acute to chronic toxicity tests. The GLPs were established in the United States in 1978 as a result of the Industrial Bio-Test Laboratory scandal which led to congressional hearings and actions to prevent fraudulent data reporting and collection. Although the establishment of infrastructure for GLPs compliance is labor-intensive and time-consuming, achievement and maintenance of GLP compliance ensures the accuracy of the data collected from each study, which is critical for defending results, advancing science, and protecting human and animal health. This article describes how and why those in the US Army Medical Department responsible for protecting the public health of US Army and other military personnel made the policy decision to have its toxicology laboratory achieve complete compliance with GLP standards, the first such among US Army laboratories. The challenges faced and how they were overcome are detailed.

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

    PubMed

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

    2014-12-01

    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

  14. Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]fluorocholine in mice.

    PubMed

    Silveira, Marina B; Ferreira, Soraya M Z M D; Nascimento, Leonardo T C; Costa, Flávia M; Mendes, Bruno M; Ferreira, Andrea V; Malamut, Carlos; Silva, Juliana B; Mamede, Marcelo

    2016-10-01

    [(18)F]Fluorocholine ([(18)F]FCH) has been proven to be effective in prostate cancer. Since [(18)F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil.

  15. Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]fluorocholine in mice.

    PubMed

    Silveira, Marina B; Ferreira, Soraya M Z M D; Nascimento, Leonardo T C; Costa, Flávia M; Mendes, Bruno M; Ferreira, Andrea V; Malamut, Carlos; Silva, Juliana B; Mamede, Marcelo

    2016-10-01

    [(18)F]Fluorocholine ([(18)F]FCH) has been proven to be effective in prostate cancer. Since [(18)F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil. PMID:27509594

  16. Aerospace Toxicology and Microbiology

    NASA Technical Reports Server (NTRS)

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

    2007-01-01

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

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

    PubMed

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

    2013-04-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium

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

    PubMed

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

    2013-04-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium

  19. Forced Degradation Studies of Ivabradine and In Silico Toxicology Predictions for Its New Designated Impurities.

    PubMed

    Pikul, Piotr; Jamrógiewicz, Marzena; Nowakowska, Joanna; Hewelt-Belka, Weronika; Ciura, Krzesimir

    2016-01-01

    All activities should aim to eliminate genotoxic impurities and/or protect the API against degradation. There is a necessity to monitor impurities from all classification groups, hence ivabradine forced degradation studies were performed. Ivabradine was proved to be quite durable active substance, but still new and with insufficient stability data. Increased temperature, acid, base, oxidation reagents and light were found to cause its degradation. Degradation products were determined with the usage of HPLC equipped with Q-TOF-MS detector. Calculations of pharmacological and toxicological properties were performed for six identified degradation products. Target prediction algorithm was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation channels, as well as more general parameters like logP and aqueous solubility. Ames test and five cytochromes activities were calculated for toxicity assessment for selected degradation products. Pharmacological activity of photodegradation product (UV4), which is known as active metabolite, was qualified and identified. Two other degradation compounds (Ox1 and N1), which were formed during degradation process, were found to be pharmacologically active. PMID:27199759

  20. Forced Degradation Studies of Ivabradine and In Silico Toxicology Predictions for Its New Designated Impurities

    PubMed Central

    Pikul, Piotr; Jamrógiewicz, Marzena; Nowakowska, Joanna; Hewelt-Belka, Weronika; Ciura, Krzesimir

    2016-01-01

    All activities should aim to eliminate genotoxic impurities and/or protect the API against degradation. There is a necessity to monitor impurities from all classification groups, hence ivabradine forced degradation studies were performed. Ivabradine was proved to be quite durable active substance, but still new and with insufficient stability data. Increased temperature, acid, base, oxidation reagents and light were found to cause its degradation. Degradation products were determined with the usage of HPLC equipped with Q-TOF-MS detector. Calculations of pharmacological and toxicological properties were performed for six identified degradation products. Target prediction algorithm was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation channels, as well as more general parameters like logP and aqueous solubility. Ames test and five cytochromes activities were calculated for toxicity assessment for selected degradation products. Pharmacological activity of photodegradation product (UV4), which is known as active metabolite, was qualified and identified. Two other degradation compounds (Ox1 and N1), which were formed during degradation process, were found to be pharmacologically active. PMID:27199759

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  3. Toxicological studies of "Chondrokola Rosh", an Ayurvedic preparation on liver function tests of rats.

    PubMed

    Nasrin, S; Bachar, S C; Choudhuri, M S K

    2011-01-01

    Chondrokola Rosh (CKR) is a traditional metallic Ayurvedic preparation widely used by the rural and ethnic people of Bangladesh in dysuria. It is a preparation of various roasted metals (Hg and Cu), non-metal (sulphur and Mica) and medicinal herbs. Considering the controversy over the risk of toxic heavy metals in Ayurvedic herbo-mineral preparations, toxicological parameters on liver functions were investigated. A single dose of 100mg/kg body weight of the preparation was administered orally to the rats of both sexes for ninety days. In this evaluation a statistically significant (p<0.001) increase of serum albumin levels in male (17%) and female (15%) rat groups were observed. On the other hand, the plasma bilirubin level was decreased 50% and 28% respectively in both rats groups. But no remarkable differences were observed in plasma protein, sGPT, sGOT and ALP activities from their corresponding control values. This study showed that CKR had no remarkable toxic effect on liver of the animals despite the presence of traces of transformed heavy metals. PMID:22754071

  4. Advanced toxicology for health compliance officers (instructor manual)

    SciTech Connect

    Brown, E.M.

    1980-03-15

    The course includes an overview of the Toxic Substances Control Act; the biologic transformation mechanisms; some of the chemical hazards encountered in the workplace; an overview of human biochemistry; the kinetics of toxication; and finally the toxicology of metal dust. The general classification of pesticides is also discussed. The course is divided into 16 lessons. The specific titles of the course are as follows: Legislation, Organ physiology (overview), Organ physiology blood, Liver, Kidney, Organ system physiology, Nervous system, Biochemistry (overview), Dose response relationship, Toxification and biotransformation, Experimental studies, Special toxicology problems, Biological monitoring, Toxicology of gases, Toxicology of dusts, Toxicology of solvents, Toxicology of metals, Toxicology of pesticides, Toxicology of miscellaneous substances.

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

    PubMed

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

    2007-01-01

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

  6. Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale, preclinical studies and clinical applications.

    PubMed

    Tortora, Giampaolo; Ciardiello, Fortunato; Gasparini, Giampietro

    2008-09-01

    Cellular heterogeneity, redundancy of molecular pathways and effects of the microenvironment contribute to the survival, motility and metastasis of cells in solid tumors. It is unlikely that tumors are entirely dependent on only one abnormally activated signaling pathway; consequently, treatment with an agent that interferes with a single target may be insufficient. Combined blockade of functionally linked and relevant multiple targets has become an attractive therapeutic strategy. The EGFR and ERBB2 (HER2) pathways and VEGF-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and has demonstrated a suggested role for VEGF in the acquired resistance to anti-ERBB drugs when these receptors are pharmacologically blocked. Combined inhibition of ERBB and VEGF signaling interferes with a molecular feedback loop responsible for acquired resistance to anti-ERBB agents and promotes apoptosis while ablating tumor-induced angiogenesis. To this aim, either two agents highly selective against VEGF and ERBB respectively, or, alternatively, a single multitargeted agent, can be used. Preclinical studies have proven the efficacy of both these approaches and early clinical studies have provided encouraging results. This Review discusses the experimental rationale for, preclinical studies of and clinical trials on combined blockade of ERBB and VEGF signaling.

  7. Cardiac arterial spin labeling using segmented ECG-gated Look-Locker FAIR: variability and repeatability in preclinical studies.

    PubMed

    Campbell-Washburn, Adrienne E; Price, Anthony N; Wells, Jack A; Thomas, David L; Ordidge, Roger J; Lythgoe, Mark F

    2013-01-01

    MRI is important for the assessment of cardiac structure and function in preclinical studies of cardiac disease. Arterial spin labeling techniques can be used to measure perfusion noninvasively. In this study, an electrocardiogram-gated Look-Locker sequence with segmented k-space acquisition has been implemented to acquire single slice arterial spin labeling data sets in 15 min in the mouse heart. A data logger was introduced to improve data quality by: (1) allowing automated rejection of respiration-corrupted images, (2) providing additional prospective gating to improve consistency of acquisition timing, and (3) allowing the recombination of uncorrupted k-space lines from consecutive data sets to reduce respiration corruption. Finally, variability and repeatability of perfusion estimation within-session, between-session, between-animal, and between image rejection criteria were assessed in mice. The criterion used to reject images from the T(1) fit was shown to affect the perfusion estimation. These data showed that the between-animal coefficient of variability (24%) was greater than the between-session variability (17%) and within-session variability (11%). Furthermore, the magnitude of change in perfusion required to detect differences was 30% (within-session) and 55% (between-session) according to Bland-Altman repeatability analysis. These technique developments and repeatability statistics will provide a platform for future preclinical studies applying cardiac arterial spin labeling.

  8. Analytical toxicology.

    PubMed

    Flanagan, R J; Widdop, B; Ramsey, J D; Loveland, M

    1988-09-01

    1. Major advances in analytical toxicology followed the introduction of spectroscopic and chromatographic techniques in the 1940s and early 1950s and thin layer chromatography remains important together with some spectrophotometric and other tests. However, gas- and high performance-liquid chromatography together with a variety of immunoassay techniques are now widely used. 2. The scope and complexity of forensic and clinical toxicology continues to increase, although the compounds for which emergency analyses are needed to guide therapy are few. Exclusion of the presence of hypnotic drugs can be important in suspected 'brain death' cases. 3. Screening for drugs of abuse has assumed greater importance not only for the management of the habituated patient, but also in 'pre-employment' and 'employment' screening. The detection of illicit drug administration in sport is also an area of increasing importance. 4. In industrial toxicology, the range of compounds for which blood or urine measurements (so called 'biological monitoring') can indicate the degree of exposure is increasing. The monitoring of environmental contaminants (lead, chlorinated pesticides) in biological samples has also proved valuable. 5. In the near future a consensus as to the units of measurement to be used is urgently required and more emphasis will be placed on interpretation, especially as regards possible behavioural effects of drugs or other poisons. Despite many advances in analytical techniques there remains a need for reliable, simple tests to detect poisons for use in smaller hospital and other laboratories.

  9. Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats

    PubMed Central

    Gao, Yan; Shen, Jacson K.; Choy, Edwin; Zhang, Zhan; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng

    2016-01-01

    Overexpression of P-glycoprotein (Pgp) increases multidrug resistance (MDR) in cancer, which greatly impedes satisfactory clinical treatment and outcomes of cancer patients. Due to unknown pharmacokinetics, the use of Pgp inhibitors to overcome MDR in the clinical setting remains elusive despite promising in vitro results. The purpose of our current preclinical study is to investigate the pharmacokinetics and tolerability of NSC23925b, a novel and potent P-glycoprotein inhibitor, in rodents. Plasma pharmacokinetic studies of single-dose NSC23925b alone or in combination with paclitaxel or doxorubicin were conducted in male BALB/c mice and Sprague-Dawley rats. Additionally, inhibition of human cytochrome P450 (CYP450) by NSC23925b was examined in vitro. Finally, the maximum tolerated dose (MTD) of NSC23925b was determined. NSC23925b displayed favorable pharmacokinetic profiles after intraperitoneal/intravenous (I.P./I.V.) injection alone or combined with chemotherapeutic drugs. The plasma pharmacokinetic characteristics of the chemotherapy drugs were not affected when co-administered with NSC23925b. All the animals tolerated the I.P./I.V. administration of NSC23925b. Moreover, the enzymatic activity of human CYP450 was not inhibited by NSC23925b. Our results demonstrated that Pgp inhibitor NSC23925b exhibits encouraging preclinical pharmacokinetic characteristics and limited toxicity in vivo. NSC23925b has the potential to treat cancer patients with MDR in the future. PMID:27157103

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

    PubMed

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

    2015-07-01

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

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

    SciTech Connect

    Bellward, G.D.

    1995-12-31

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

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

    EPA Science Inventory

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

  13. 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...

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

    SciTech Connect

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

    1987-11-01

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

  15. Genetic toxicology.

    PubMed

    Kramer, P J

    1998-04-01

    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

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

    PubMed

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

    2012-09-01

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

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

    PubMed

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

    2012-09-01

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

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

    PubMed

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

    2014-11-01

    Indiscriminate use of vanadium oxide nanoparticles (NPs) in steel industries and their release during combustion of fossil fuels makes it essential to study their toxic potential. Herein, we assessed the toxicological effects of two types of in-house synthesized vanadium oxide NPs in Wistar rats exposed to NPs through inhalation route. V2O5 and VO2 NPs exhibited rod and spherical symmetry, respectively with a mean diameter of 50±20 and 30±10 nm. Assessment of bronchoalveolar lavage fluid parameters demonstrated that VO2 NP-exposed animals had higher levels of lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase as compared to V2O5 NP-exposed animals. The levels of oxidative stress markers malondialdehyde and reduced glutathione also indicated higher toxic potential of VO2 NPs. Moreover, after 7-day recovery, the levels of the above parameters were closer to normal levels only in V2O5-exposed animals. Interestingly, histopathological and immune-histopathology analysis (TNF-α) 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.

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

    PubMed Central

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

    2013-01-01

    The Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA) project assessed primary and secondary particulate by simulating the chemical reactions that a plume from a source might undergo during atmospheric transport and added other atmospheric constituents that might interact with it. Three coal-fired power plants with different coal and different emission controls were used. Male Sprague-Dawley rats were exposed for 6 h to either filtered air or aged aerosol from the power plant. Four exposure scenarios were studied: primary particles (P); primary + secondary (oxidized) particles (PO); primary + secondary (oxidized) particles + SOA (POS); and primary + secondary (oxidized) particles neutralized + SOA (PONS). Exposure concentrations varied by scenario to a maximum concentration of 257.1 ± 10.0 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

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

    PubMed

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

    2015-02-01

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

  1. Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

    PubMed Central

    Shagisultanova, Elena; Gaponova, Anna V.; Gabbasov, Rashid; Nicolas, Emmanuelle; Golemis, Erica A

    2015-01-01

    Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease. PMID:25967390

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

    PubMed

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

    2015-02-01

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

  3. Studies of the toxicological potential of capsinoids: VII. A 13-week toxicity study of dihydrocapsiate in rats.

    PubMed

    Kodama, Terutaka; Watanabe, Eri; Tsubuku, Shoji; Otabe, Akira; Mochizuki, Masahiro; Masuyama, Takeshi; Bernard, Bruce K

    2008-01-01

    To evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2), a 13-week gavage toxicity study was conducted in Sprague-Dawley rats (10/sex/group). Test subjects received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle by gavage and were observed for antemortem and postmortem signs of toxicity, which included changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. No changes attributable to the test article were observed in clinical signs, body weights, food consumption, water intake, ophthalmology, urinalysis, hematology, or histopathology. A number of sporadic blood chemistry differences were observed at the high dose between treated and controls, but were not of toxicological significance and were not attributable to the test article. These included increased alanine aminotransferase (ALT) activity in males; increased total protein in males and females; increased calcium, percentage of albumin fraction, and A/G (albumin/globulin) ratio and decreased percentage of gamma-globulin fraction in female rats. An effect, which was attributable to the test article, was increases in both absolute and relative liver weights in the high dose (both sexes). In the absence of histopathological changes attributable to the test article, the liver weight changes were considered adaptive (physiological) in nature and not of toxicological significance. It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both male and female rats in this 13-week gavage study. PMID:19037801

  4. [Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].

    PubMed

    Ternovoĭ, K S; Kryzhanovskiĭ, G N; Musiĭchuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

    1998-01-01

    The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented.

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

    PubMed Central

    2011-01-01

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

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

    PubMed

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

    2015-11-01

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

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

    SciTech Connect

    Tian, Dayong; Lin, Zhifen; Zhou, Xianghong; Yin, Daqiang

    2013-10-15

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

  8. The study of forensic toxicology should not be neglected in Japanese universities.

    PubMed

    Ishihara, Kenji; Yajima, Daisuke; Abe, Hiroko; Nagasawa, Sayaka; Nara, Akina; Iwase, Hirotaro

    2015-04-01

    Forensic toxicology is aimed at identifying the relationship between drugs or poison and the cause of death or crime. In the authors' toxicology laboratory at Chiba University, the authors analyze almost every body for drugs and poisons. A simple inspection kit was used in an attempt to ascertain drug abuse. A mass spectrometer is used to perform highly accurate screening. When a poison is detected, quantitative analyses are required. A recent topic of interest is new psychoactive substances (NPS). Although NPS-related deaths may be decreasing, use of NPS as a cause of death is difficult to ascertain. Forensic institutes have recently begun to perform drug and poison tests on corpses. However, this approach presents several problems, as are discussed here. The hope is that highly accurate analyses of drugs and poisons will be performed throughout the country.

  9. (99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study.

    PubMed

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

    2015-08-30

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

  10. (99m)Tc-amitrole as a novel selective imaging probe for solid tumor: In silico and preclinical pharmacological study.

    PubMed

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

    2015-08-30

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

  11. Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents.

    PubMed

    Weh, Katherine M; Clarke, Jennifer; Kresty, Laura A

    2016-01-01

    Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered. PMID:27548236

  12. Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents.

    PubMed

    Weh, Katherine M; Clarke, Jennifer; Kresty, Laura A

    2016-08-18

    Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered.

  13. Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents

    PubMed Central

    Weh, Katherine M.; Clarke, Jennifer; Kresty, Laura A.

    2016-01-01

    Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered. PMID:27548236

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2014-03-01

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

  17. Systems toxicology.

    PubMed

    Hartung, Thomas; van Vliet, Erwin; Jaworska, Joanna; Bonilla, Leo; Skinner, Nigel; Thomas, Russell

    2012-01-01

    The need for a more mechanistic understanding of the ways in which chemicals modulate biological pathways is urgent if we are to identify and better assess safety issues relating to a wide range of substances developed by the pharmaceutical, chemical, agri-bio, and cosmetic industries. Omics technologies provide a valuable opportunity to refine existing methods and provide information for so-called integrated testing strategies via the creation of signatures of toxicity. By mapping these signatures to underlying pathways of toxicity, some of which have been identified by toxicologists over the last few decades, and bringing them together with pathway information determined from biochemistry and molecular biology, a "systems toxicology" approach will enable virtual experiments to be conducted that can improve the prediction of hazard and the assessment of compound toxicity. PMID:22562485

  18. Space Toxicology

    NASA Technical Reports Server (NTRS)

    James, John T.

    2011-01-01

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

  19. 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. ...

  20. Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease

    PubMed Central

    Golpanian, Samuel; Schulman, Ivonne H.; Ebert, Ray F.; Heldman, Alan W.; DiFede, Darcy L.; Yang, Phillip C.; Wu, Joseph C.; Bolli, Roberto; Perin, Emerson C.; Simari, Robert D.; Wolf, Ariel; Hare, Joshua M.

    2016-01-01

    An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions. Significance Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials. PMID:26683870

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

    PubMed Central

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

    2015-01-01

    Background and Objective. Dental stem cell-based tissue engineered constructs are emerging as a promising alternative to autologous bone transfer for treating bone defects. The purpose of this review is to systematically assess the preclinical in vivo and in vitro studies which have evaluated the efficacy of dental stem cells on bone regeneration. Methods. A literature search was conducted in Ovid Medline, Embase, PubMed, and Web of Science up to October 2014. Implantation of dental stem cells in animal models for evaluating bone regeneration and/or in vitro studies demonstrating osteogenic potential of dental stem cells were included. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to ensure the quality of the search. Modified ARRIVE (Animal research: reporting in invivo experiments) and CONSORT (Consolidated reporting of trials) were used to critically analyze the selected studies. Results. From 1914 citations, 207 full-text articles were screened and 137 studies were included in this review. Because of the heterogeneity observed in the studies selected, meta-analysis was not possible. Conclusion. Both in vivo and in vitro studies indicate the potential use of dental stem cells in bone regeneration. However well-designed randomized animal trials are needed before moving into clinical trials. PMID:26106427

  2. Toxicologic evaluation of ofloxacin.

    PubMed

    Davis, G J; McKenzie, B E

    1989-12-29

    Results of studies conducted to characterize local, systemic, reproductive, and mutagenic effects indicate that ofloxacin is well tolerated within reasonable multiples of the intended clinical dose. Quinolone-associated arthropathic effects characterized by blister, erosion, and increased synovial fluid occurred in rats and dogs and appeared to be both age- and dose-related. Maternal toxicity and embryotoxicity were noted, but there was no teratogenicity in rats or rabbits. There was no impairment of fertility, and no adverse effects on late fetal development, labor, delivery, lactation, neonatal viability, or growth of offspring occurred. Target-organ studies revealed no evidence of ocular toxicity in rats, nephrotoxicity in rabbits, or antigenicity or ototoxicity in guinea pigs. Overall, the toxicologic evaluation of ofloxacin has shown this compound to be a drug with a low toxicologic potential.

  3. Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies

    PubMed Central

    Wingstrand, Vibe Lindeblad; Jensen, David H.; Bork, Kristian; Sebbesen, Lars; Balle, Jesper; Fischer-Nielsen, Anne; von Buchwald, Christian

    2016-01-01

    Objectives Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. Data Sources PubMed, Embase, the Cochrane Library and Google Scholar were searched. Methods Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Results Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. Conclusion The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies. PMID:27631373

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

    PubMed Central

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

    2015-01-01

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

  5. Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

    PubMed

    Solomon, Howard M; Makris, Susan L; Alsaid, Hasan; Bermudez, Oscar; Beyer, Bruce K; Chen, Antong; Chen, Connie L; Chen, Zhou; Chmielewski, Gary; DeLise, Anthony M; de Schaepdrijver, Luc; Dogdas, Belma; French, Julian; Harrouk, Wafa; Helfgott, Jonathan; Henkelman, R Mark; Hesterman, Jacob; Hew, Kok-Wah; Hoberman, Alan; Lo, Cecilia W; McDougal, Andrew; Minck, Daniel R; Scott, Lelia; Stewart, Jane; Sutherland, Vicki; Tatiparthi, Arun K; Winkelmann, Christopher T; Wise, L David; Wood, Sandra L; Ying, Xiaoyou

    2016-06-01

    During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology. PMID:26930635

  6. Exhumation of Wistar rats experimentally exposed to the carbamate pesticides aldicarb and carbofuran: A pathological and toxicological study.

    PubMed

    de Siqueira, Adriana; Rodrigues, Karina Borges Almeida; Gonçalves-Júnior, Vagner; Calefi, Atilio Sersun; Fukushima, André Rinaldi; Cuevas, Silvia Elena Campusano; Spinosa, Helenice de Souza; Maiorka, Paulo César

    2016-06-01

    Exhumation is required for the investigation of suspicions deaths when a body is buried and is usually performed under court order. Exhumation of animals is not a routine practice in forensic pathology. In this study, 30 male 70-day-old Wistar rats were experimentally exposed to the carbamate pesticides aldicarb and carbofuran. Toxicological, macroscopic and microscopic examinations were performed. Groups of 3 animals (2 exposed and 1 control) were evaluated at 24h, 3days, 5days, 7days and 10days post-mortem. In histopathological examination, the brain, liver, lungs and kidneys were assessed, and for toxicological analysis, the gastric contents, liver, vitreous humor, skeletal muscle and larvae (when available) were collected. The pesticides were detected by HPLC and quantified in the analyzed matrices, and a possible delay in tissue putrefaction due to the pesticides was observed. This study has revealed that it is possible to exhume animals for investigations of possible poisoning by carbamates and has demonstrated that the exhumation of an animal in a suspected case of poisoning should not be ruled out. The increasing demand for investigations of suspicious animal deaths, e.g., in cases of poisoning, will likely lead to an increase in the use of this type of procedure in veterinary pathology. PMID:27020045

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

    SciTech Connect

    Miller, Janine D.; Scull, Heather

    2007-11-01

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

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

    PubMed Central

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

    2013-01-01

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

  9. Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat.

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2015-12-01

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

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

    PubMed Central

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

    2015-01-01

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

  13. Animal-free toxicology: the use of human tissue to replace the use of animals - examples from human biomonitoring and human placental transport studies.

    PubMed

    Knudsen, Lisbeth E

    2013-12-01

    Human data on exposure and adverse effects are the most appropriate for human risk assessment, and modern toxicology focuses on human pathway analysis and the development of human biomarkers. Human biomonitoring and human placental transport studies provide necessary information for human risk assessment, in accordance with the legislation on chemical, medicine and food safety. Toxicology studies based on human mechanistic and exposure information can replace animal studies. These animal-free approaches can be further supplemented by new in silico methods and chemical structure-activity relationships. The inclusion of replacement expertise in the international Three Rs centres, the ongoing exploration of alternatives to animal research, and the improvement of conditions for research animals, all imply the beginning of a paradigm shift in toxicology research toward the use of human data.

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

    PubMed

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

    2014-03-01

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

  15. Reform in Teaching Preclinical Pathophysiology

    ERIC Educational Resources Information Center

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

    2015-01-01

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

  16. Volume cerebral blood flow reduction in pre-clinical stage of Alzheimer disease: evidence from an ultrasonographic study.

    PubMed

    Maalikjy Akkawi, Nabil; Borroni, B; Agosti, C; Magoni, M; Broli, M; Pezzini, A; Padovani, A

    2005-05-01

    The association of decreased cerebral blood flow with the development of Alzheimer's disease (AD) has been a recent target of interest. By using neuroimaging techniques, growing attention has been devoted to the identification of preclinical AD. In this study, color duplex sonography of cervical arteries was used to measure mean cerebral blood flow (CBF) on 55 amnestic Mild Cognitive Impairment (MCI) patients. Two years after enrollment, excluding patients who progressed to dementia other than AD, two subgroups were identified, patients who developed AD (MCI converters) and patients with preserved cognitive and functional level (MCI non-converters). Examining the mean difference of CBF measured at baseline in the two subgroups obtained, a significant difference was noticed (MCI converters 539.3 +/- 114.3 vs MCI non converters 636.0 +/- 143.9, p < 0.05). MCI patients with CBF higher than median value (558 ml/min) had lower risk of developing AD (specificity 72.2%, sensitivity 68.4%) within a two year follow-up. Ultrasonography of the cervical arteries is a simple, non invasive and widespread technique useful in detecting CBF decline during the MCI stage, thus identifying patients who later will convert to AD.

  17. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

    PubMed

    Cheng, Hao; Xie, Zhiliang; Jones, William P; Wei, Xiaohui Tracey; Liu, Zhongfa; Wang, Dasheng; Kulp, Samuel K; Wang, Jiang; Coss, Christopher C; Chen, Ching-Shih; Marcucci, Guido; Garzon, Ramiro; Covey, Joseph M; Phelps, Mitch A; Chan, Kenneth K

    2016-05-01

    AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

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

    PubMed Central

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

    2015-01-01

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

  19. Toxicological approaches to complex mixtures.

    PubMed Central

    Mauderly, J L

    1993-01-01

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

  20. Toxicological approaches to complex mixtures.

    PubMed

    Mauderly, J L

    1993-12-01

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

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

    PubMed

    Gautam, M K; Goel, R K

    2014-01-01

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

  2. Biomarkers in Computational Toxicology

    EPA Science Inventory

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

  3. Toxicology Education Foundation

    MedlinePlus

    ... to Toxicology Excellence for Risk Assessment for website design. Donate Now OUR MISSION AND VISION Our mission is to enhance public understanding of toxicology through access to objective, science-based information on the safety of chemicals and other agents ...

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

    PubMed

    Coen, Muireann

    2015-02-01

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

  5. Validation of the Filovirus Plaque Assay for Use in Preclinical Studies

    PubMed Central

    Shurtleff, Amy C.; Bloomfield, Holly A.; Mort, Shannon; Orr, Steven A.; Audet, Brian; Whitaker, Thomas; Richards, Michelle J.; Bavari, Sina

    2016-01-01

    A plaque assay for quantitating filoviruses in virus stocks, prepared viral challenge inocula and samples from research animals has recently been fully characterized and standardized for use across multiple institutions performing Biosafety Level 4 (BSL-4) studies. After standardization studies were completed, Good Laboratory Practices (GLP)-compliant plaque assay method validation studies to demonstrate suitability for reliable and reproducible measurement of the Marburg Virus Angola (MARV) variant and Ebola Virus Kikwit (EBOV) variant commenced at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). The validation parameters tested included accuracy, precision, linearity, robustness, stability of the virus stocks and system suitability. The MARV and EBOV assays were confirmed to be accurate to ±0.5 log10 PFU/mL. Repeatability precision, intermediate precision and reproducibility precision were sufficient to return viral titers with a coefficient of variation (%CV) of ≤30%, deemed acceptable variation for a cell-based bioassay. Intraclass correlation statistical techniques for the evaluation of the assay’s precision when the same plaques were quantitated by two analysts returned values passing the acceptance criteria, indicating high agreement between analysts. The assay was shown to be accurate and specific when run on Nonhuman Primates (NHP) serum and plasma samples diluted in plaque assay medium, with negligible matrix effects. Virus stocks demonstrated stability for freeze-thaw cycles typical of normal usage during assay retests. The results demonstrated that the EBOV and MARV plaque assays are accurate, precise and robust for filovirus titration in samples associated with the performance of GLP animal model studies. PMID:27110807

  6. Validation of the Filovirus Plaque Assay for Use in Preclinical Studies.

    PubMed

    Shurtleff, Amy C; Bloomfield, Holly A; Mort, Shannon; Orr, Steven A; Audet, Brian; Whitaker, Thomas; Richards, Michelle J; Bavari, Sina

    2016-04-01

    A plaque assay for quantitating filoviruses in virus stocks, prepared viral challenge inocula and samples from research animals has recently been fully characterized and standardized for use across multiple institutions performing Biosafety Level 4 (BSL-4) studies. After standardization studies were completed, Good Laboratory Practices (GLP)-compliant plaque assay method validation studies to demonstrate suitability for reliable and reproducible measurement of the Marburg Virus Angola (MARV) variant and Ebola Virus Kikwit (EBOV) variant commenced at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). The validation parameters tested included accuracy, precision, linearity, robustness, stability of the virus stocks and system suitability. The MARV and EBOV assays were confirmed to be accurate to ±0.5 log10 PFU/mL. Repeatability precision, intermediate precision and reproducibility precision were sufficient to return viral titers with a coefficient of variation (%CV) of ≤30%, deemed acceptable variation for a cell-based bioassay. Intraclass correlation statistical techniques for the evaluation of the assay's precision when the same plaques were quantitated by two analysts returned values passing the acceptance criteria, indicating high agreement between analysts. The assay was shown to be accurate and specific when run on Nonhuman Primates (NHP) serum and plasma samples diluted in plaque assay medium, with negligible matrix effects. Virus stocks demonstrated stability for freeze-thaw cycles typical of normal usage during assay retests. The results demonstrated that the EBOV and MARV plaque assays are accurate, precise and robust for filovirus titration in samples associated with the performance of GLP animal model studies.

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

    PubMed

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

    2016-02-01

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

  8. Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline

    PubMed Central

    Febo, Marcelo; Foster, Thomas C.

    2016-01-01

    Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline. PMID:27468264

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

    PubMed

    Nesan, Dinushan; Ng, Dominic S

    2014-12-01

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

  10. Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline.

    PubMed

    Febo, Marcelo; Foster, Thomas C

    2016-01-01

    Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline. PMID:27468264

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

    PubMed

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

    2015-11-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    SciTech Connect

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

    1988-11-01

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

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

    SciTech Connect

    Mast, T.J.

    1987-12-01

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

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

    SciTech Connect

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

    1989-01-01

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

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

    SciTech Connect

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

    1989-02-01

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

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

    PubMed Central

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

    2013-01-01

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

  18. Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies

    PubMed Central

    Dang, Michelle; Henderson, Rachel E.; Garraway, Levi A.

    2016-01-01

    ABSTRACT Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAFV600E inhibitor, Vemurafenib, in adult zebrafish harboring BRAFV600E melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases. PMID:27482819

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

    PubMed

    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

    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.

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

    PubMed Central

    Casey, BJ; Glatt, Charles E.; Lee, Francis S.

    2015-01-01

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

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

    PubMed

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

    2015-06-17

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

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

    PubMed

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

    2009-03-01

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

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

    NASA Astrophysics Data System (ADS)

    Amara, Francis

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

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

    PubMed

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

    2015-12-01

    Vagus nerve stimulation (VNS) is a treatment for refractory epilepsy and depression. Previous studies using invasive recording electrodes showed that VNS induces laryngeal motor-evoked potentials (LMEPs) through the co-activation of the recurrent laryngeal nerve and subsequent contractions of the laryngeal muscles. The present study investigates the feasibility of recording LMEPs in chronically VNS-implanted rats, using a minimally-invasive technique, to assess effective current delivery to the nerve and to determine optimal VNS output currents for vagal fiber activation. Three weeks after VNS electrode implantation, signals were recorded using an electromyography (EMG) electrode in the proximity of the laryngeal muscles and a reference electrode on the skull. The VNS output current was gradually ramped up from 0.1 to 1.0 mA in 0.1 mA steps. In 13/27 rats, typical LMEPs were recorded at low VNS output currents (median 0.3 mA, IQR 0.2-0.3 mA). In 11/27 rats, significantly higher output currents were required to evoke electrophysiological responses (median 0.7 mA, IQR 0.5-0.7 mA, p < 0.001). The latencies of these responses deviated significantly from LMEPs (p < 0.05). In 3/27 rats, no electrophysiological responses to simulation were recorded. Minimally invasive LMEP recordings are feasible to assess effective current delivery to the vagus nerve. Furthermore, our results suggest that low output currents are sufficient to activate vagal fibers.

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

    NASA Astrophysics Data System (ADS)

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

    2012-11-01

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

  6. A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies.

    PubMed

    Post, Anke; Smart, Trevor S; Krikke-Workel, Judith; Dawson, Gerard R; Harmer, Catherine J; Browning, Michael; Jackson, Kimberley; Kakar, Rishi; Mohs, Richard; Statnick, Michael; Wafford, Keith; McCarthy, Andrew; Barth, Vanessa; Witkin, Jeffrey M

    2016-06-01

    Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD.

  7. Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M.

    PubMed

    Porter, M C; Hartnagel, R E; Clemens, G R; Kowalski, R L; Bare, J J; Halliwell, W E; Kitchen, D N

    1983-01-01

    The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.

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

    NASA Astrophysics Data System (ADS)

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

    2006-02-01

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

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

    NASA Astrophysics Data System (ADS)

    Soler, Luc; Marescaux, Jacques

    2006-04-01

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

  10. HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies

    PubMed Central

    Kim, SoRa; Kim, Dae Hoon; Kim, Young-Seok; Ha, Tae-Young; Yang, Jin; Park, Soo Hyun; Jeong, Kwang Won; Rhee, Jae-Keol

    2014-01-01

    G-protein coupled receptor 119 (GPR119) has emerged as a novel target for the treatment of type 2 diabetes mellitus. GPR119 is involved in glucose-stimulated insulin secretion (GSIS) from the pancreatic β-cells and intestinal cells. In this study, we identified a novel small-molecule GPR119 agonist, HD047703, which raises intracellular cAMP concentrations in pancreatic β-cells and can be expected to potentiate glucose-stimulated insulin secretion from human GPR119 receptor stably expressing cells (CHO cells). We evaluated the acute efficacy of HD047703 by the oral glucose tolerance test (OGTT) in normal C57BL/6J mice. Then, chronic administrations of HD047703 were performed to determine its efficacy in various diabetic rodent models. Single administration of HD047703 caused improved glycemic control during OGTT in a dose-dependent manner in normal mice, and the plasma GLP-1 level was also increased. With respect to chronic efficacy, we observed a decline in blood glucose levels in db/db, ob/ob and DIO mice. These results suggest that HD047703 may be a potentially promising anti-diabetic agent. PMID:25414769

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

    PubMed Central

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

    2015-01-01

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

  12. The Tyrosine Kinase Inhibitor Sunitinib Affects Ovulation but Not Ovarian Reserve in Mouse: A Preclinical Study

    PubMed Central

    Bernard, Valérie; Bouilly, Justine; Kramer, Piet; Carré, Nadège; Schlumberger, Martin; Visser, Jenny A.; Young, Jacques; Binart, Nadine

    2016-01-01

    The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-week-old female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti Müllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women. PMID:27035144

  13. The Tyrosine Kinase Inhibitor Sunitinib Affects Ovulation but Not Ovarian Reserve in Mouse: A Preclinical Study.

    PubMed

    Bernard, Valérie; Bouilly, Justine; Kramer, Piet; Carré, Nadège; Schlumberger, Martin; Visser, Jenny A; Young, Jacques; Binart, Nadine

    2016-01-01

    The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-week-old female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti Müllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women. PMID:27035144

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-01-01

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

  16. Electric field characteristics of electroconvulsive therapy with individualized current amplitude: a preclinical study.

    PubMed

    Lee, Won Hee; Lisanby, Sarah H; Laine, Andrew F; Peterchev, Angel V

    2013-01-01

    This study examines the characteristics of the electric field induced in the brain by electroconvulsive therapy (ECT) with individualized current amplitude. The electric field induced by bilateral (BL), bifrontal (BF), right unilateral (RUL), and frontomedial (FM) ECT electrode configurations was computed in anatomically realistic finite element models of four nonhuman primates (NHPs). We generated maps of the electric field strength relative to an empirical neural activation threshold, and determined the stimulation strength and focality at fixed current amplitude and at individualized current amplitudes corresponding to seizure threshold (ST) measured in the anesthetized NHPs. The results show less variation in brain volume stimulated above threshold with individualized current amplitudes (16-36%) compared to fixed current amplitude (30-62%). Further, the stimulated brain volume at amplitude-titrated ST is substantially lower than that for ECT with conventional fixed current amplitudes. Thus individualizing the ECT stimulus current could compensate for individual anatomical variability and result in more focal and uniform electric field exposure across different subjects compared to the standard clinical practice of using high, fixed current for all patients.

  17. The usefulness of systematic reviews of animal experiments for the design of preclinical and clinical studies.

    PubMed

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

    2014-01-01

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

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

    PubMed

    Geresu, Berhanu

    2015-11-01

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

  19. Methods to Evaluate the Antitumor Activity of Immune Checkpoint Inhibitors in Preclinical Studies.

    PubMed

    Allard, Bertrand; Allard, David; Stagg, John

    2016-01-01

    Immune checkpoint inhibitors (ICI) are a new class of drugs characterized by their ability to enhance antitumor immune responses through the blockade of critical cell surface receptors involved in the maintenance of peripheral tolerance. The recent approval of ICI targeting CTLA-4 or PD-1 for the treatment of cancer constitutes a major breakthrough in the field of oncology and demonstrates the potential of immune-mediated therapies in achieving durable cancer remissions. The identification of new immune regulatory pathways that could be targeted to reactivate or boost antitumor immunity is now a very active field of research. In this context, the use of syngeneic mouse models and immune monitoring techniques are the cornerstone of proof-of-concept studies. In this chapter, we describe the general methodology to evaluate antitumor activity of ICI in immunocompetent mice. We outline protocols to reliably establish tumors in mice and generate lung metastasis through tail vein injections with the aim of testing the efficacy of ICI. We also present methods to analyze the composition of the tumor immune-infiltrate by multicolor flow cytometry. PMID:27581021

  20. Confidentiality in preclinical Alzheimer disease studies: when research and medical records meet.

    PubMed

    Arias, Jalayne J; Karlawish, Jason

    2014-02-25

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

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

    PubMed

    Silveri, Marisa M

    2014-08-01

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

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

    PubMed Central

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

    2013-01-01

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

  3. Preclinical Studies Suggest Complex Nutraceutical Strategies May Have Potential for Preventing and Managing Sepsis.

    PubMed

    McCarty, Mark F

    2015-01-01

    An analysis of signaling mechanisms triggered by toll receptor 4 (TLR4) in macrophages, as well as of pertinent cell-culture and rodent studies, suggests that various nutraceuticals may have clinical potential for preventing and treating Gram-negative sepsis. Endotoxin activation of TLR4 results in induction of nitric oxide synthase (iNOS); cyclooxygenase 2 (COX-2); tissue factor (TF); and a range of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-1 β (IL-1β), and interleukin 6 (IL-6), that collaborate to generate the clinical picture of sepsis. Upstream activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contributes importantly to those effects by inducing superoxide production that promotes activation of p38 mitogen-activated protein (MAP) kinase and nuclear factor (NF) κΒ. Bilirubin generated intracellularly by activation of heme oxygenase 1 (HO-1) functions to provide feedback inhibition of NAPDH-oxidase complexes. Exogenous bilirubin, or its precursor, biliverdin, is protective in rodent models of sepsis. One nutraceutical, phycocyanobilin (PhyCB), is a biliverdin derivative that functions as a light-gathering chromophore in cyanobacteria such as spirulina and can be converted intracellularly to a compound structurally homologous to bilirubin that likewise inhibits NADPH-oxidase complexes. In rodent studies, administration of phycocyanin, to which PhyCB is covalently attached, has likewise been shown to be protective in rodent models of sepsis. Other nutraceuticals provide benefits in counteracting the effects of TLR4. Phase 2-inductive nutraceuticals, such as lipoic acid, have the potential to induce HO-1 activity in macrophages, promoting bilirubin production. They may also antagonize the upregulatory impact of reactive oxygen species (ROS) on macrophage signaling by boosting glutathione synthesis. Another nutraceutical, glycine, helps counter the TLR4-triggered calcium influx that occurs through

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

    PubMed

    1989-08-01

    Hexachloroethane is used in organic synthesis as a retarding agent in fermentation, as a camphor substitute in nitrocellulose, in pyrotechnics and smoke devices, in explosives, and as a solvent. In previous long-term gavage studies with B6C3F1 mice and Osbourne-Mendel rats (78 weeks of exposure followed by 12-34 weeks of observation), hexachloroethane caused increased incidences of hepatocellular carcinomas in mice. However, survival of low and high dose rats was reduced compared with that of vehicle controls, and the effects on rats were inconclusive. Therefore, additional toxicology and carcinogenesis studies were conducted in F344/N rats by administering hexachloroethane (approximately 99% pure) in corn oil by gavage to groups of males and females for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Urinalysis was performed in conjunction with the 13-week studies. Sixteen-Day Studies: In the 16-day studies (dose range, 187-3,000 mg/kg), all rats that received 1,500 or 3,000 mg/kg and 1/5 males and 2/5 females that received 750 mg/kg died before the end of the studies. Final mean body weights of rats that received 750 mg/kg were 25% lower than that of vehicle controls for males and 37% lower for females. Compound-related clinical signs seen at 750 mg/kg or more included dyspnea, ataxia, prostration, and excessive lacrimation. Other compound-related effects included hyaline droplet formation in the tubular epithelial cells in all dosed males and tubular cell regeneration and granular casts in the tubules at the corticomedullary junction in the kidney in males receiving 187 and 375 mg/kg. Thirteen-Week Studies: In the 13-week studies (dose range, 47-750 mg/kg), 5/10 male rats and 2/10 female rats that received 750 mg/kg died before the end of the studies. The final mean body weight of male rats that received 750 mg/kg was 19% lower than that of vehicle controls. Compound

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

    PubMed

    Chiu, Chi-Tso; Chuang, De-Maw

    2010-11-01

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

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

    Chiu, Chi-Tso; Chuang, De-Maw

    2011-01-01

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed

    Wu, J; Polefka, T G

    2008-02-01

    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.

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

    PubMed

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

    2004-12-15

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

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

    PubMed

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

    2004-12-15

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

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

    PubMed

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

    2014-03-15

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

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

    PubMed

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

    2015-06-01

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

  14. Preclinical Comparative Study of (68)Ga-Labeled DOTA, NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA.

    PubMed

    Ray Banerjee, Sangeeta; Chen, Zhengping; Pullambhatla, Mrudula; Lisok, Ala; Chen, Jian; Mease, Ronnie C; Pomper, Martin G

    2016-06-15

    (68)Ga-labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET). The goal of this study was to compare the pharmacokinetics of three PSMA-targeted radiotracers: (68)Ga-1, using DOTA-monoamide as the chelating agent; (68)Ga-2, containing the macrocyclic chelating agent p-SCN-Bn-NOTA; and (68)Ga-DKFZ-PSMA-11, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC. The PSMA-targeting scaffold for all three agents utilized a similar Glu-urea-Lys-linker construct. Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT). (68)Ga-2 demonstrated the fastest rate of clearance from all tissues in this series and displayed higher uptake in PSMA+ PC3 PIP tumor compared to (68)Ga-1 at 1 h post-injection. There was no significant difference in PSMA+ PC3 PIP tumor uptake for the three agents at 2 and 3 h post-injection. (68)Ga-DKFZ-PSMA-11 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, and salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection. In this preclinical evaluation (68)Ga-2 had the most advantageous characteristics for PSMA-targeted PET imaging. PMID:27076393

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

    PubMed

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

    2012-01-01

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

  16. 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...

  17. Toxicological effects and recovery of the corneal epithelium in Cyprinus carpio communis Linn. exposed to monocrotophos: an scanning electron microscope study.

    PubMed

    Uppal, Ravneet Kaur; Johal, Mohinder Singh; Sharma, Madan Lal

    2015-05-01

    This study was conducted based on the evidence of fish habitats in North India being affected by organophosphate pesticides draining from agricultural fields into bodies of water, especially during the rainy season. Various tissues of fish such as scales, gills ovaries, kidney, and liver have been studied from the toxicological point of view, but the toxicological effects of aquatic pollutants on fish cornea have not been investigated to date. We conducted comparative toxicological studies on the cornea of Cyprinus carpio communis using two sublethal (0.038 and 0.126 ppm) concentrations of monocrotophos pesticide for 30 days. Corneas from all the groups were evaluated by a scanning electron microscope. The fish exposed to the monocrotophos pesticide developed corneal necrosis due to the formation of crystalloid-like structures, thinning and shrinkage of microridges on the corneal epithelium. After 30 days, fish from the monocrotophos-treated tank were transferred to normal environmental conditions. After 60 days under natural condition, epithelial cells did not fully recover. In conclusion, exposure to monocrotophos induces irreversible changes in the cornea of C. carpio communis. As fish and mammalian visual systems share many similarities, the reported finding may offer useful insights for further toxicological and ophthalmological studies in humans.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    1989-05-01

    Ochratoxin A is a naturally occurring fungal toxin that is a contaminant in corn, peanuts, storage grains, cottonseed, meats, dried fish, and nuts. Toxicology and carcinogenesis studies were conducted by administering ochratoxin A (98% pure) in corn oil by gavage to groups of F344/N rats of each sex for 16 days, 13 weeks, 9 months, 15 months, or 2 years. Only rats were studied because ochratoxin A has been shown to be carcinogenic in mice. Genetic toxicology tests were performed with bacterial and mammalian cells. Urinalysis, hematologic and serum chemical analyses, and bone marrow cellularity determinations were conducted at 9, 15, and 24 months in the 2-year studies. Sixteen-Day and Thirteen-Week Studies: Rats were administered 0, 1, 4, or 16 mg/kg ochratoxin A in corn oil by gavage 5 days per week for a total of 12 doses over 16 days. All rats that received 16 mg/kg ochratoxin A died within 6 days. Rats that received 4 mg/kg lost weight. Compound-related lesions in rats included bone marrow hyperplasia, thymic atrophy, necrosis and hyperplasia of the forestomach epithelium, renal tubular cell degenerative and regenerative changes (nephropathy), and adrenal gland hemorrhage. Renal tubular changes were most severe in animals that received 4 mg/kg. Rats that received 16 mg/kg had less severe renal lesions than those at 4 mg/kg, perhaps because the acute toxicity and early death did not allow sufficient time for full development of lesions. No compound-related deaths occurred in the 13-week studies (doses were 0 and 0.0625 to 1 mg/kg). The final mean body weight of rats that received 0.25, 0.5, or 1 mg/kg was 7%, 11%, or 19% lower than that of vehicle controls for males and 3%, 4%, or 9% lower for females. Compound-related lesions in the kidney were characterized as degeneration and regeneration of the epithelium of the proximal convoluted tubules with individual cell necrosis of moderate severity (see page 3 of the Technical Report). Karyomegaly of tubular

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

    PubMed Central

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

    2009-01-01

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

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

    SciTech Connect

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

    1987-11-01

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

  2. History of wildlife toxicology.

    PubMed

    Rattner, Barnett A

    2009-10-01

    The field of wildlife toxicology can be traced to the late nineteenth and early twentieth centuries. Initial reports included unintentional poisoning of birds from ingestion of spent lead shot and predator control agents, alkali poisoning of waterbirds, and die-offs from maritime oil spills. With the advent of synthetic pesticides in the 1930s and 1940s, effects of DDT and other pesticides were investigated in free-ranging and captive wildlife. In response to research findings in the US and UK, and the publication of Silent Spring in 1962, public debate on the hazards of pollutants arose and national contaminant monitoring programs were initiated. Shortly thereafter, population-level effects of DDT on raptorial and fish-eating birds were documented, and effects on other species (e.g., bats) were suspected. Realization of the global nature of organochlorine pesticide contamination, and the discovery of PCBs in environmental samples, launched long-range studies in birds and mammals. With the birth of ecotoxicology in 1969 and the establishment of the Society of Environmental Toxicology and Chemistry in 1979, an international infrastructure began to emerge. In the 1980s, heavy metal pollution related to mining and smelting, agrichemical practices and non-target effects, selenium toxicosis, and disasters such as Chernobyl and the Exxon Valdez dominated the field. Biomarker development, endocrine disruption, population modeling, and studies with amphibians and reptiles were major issues of the 1990s. With the turn of the century, there was interest in new and emerging compounds (pharmaceuticals, flame retardants, surfactants), and potential population-level effects of some compounds. Based upon its history, wildlife toxicology is driven by chemical use and misuse, ecological disasters, and pollution-related events affecting humans. Current challenges include the need to more thoroughly estimate and predict exposure and effects of chemical-related anthropogenic

  3. Inter-study variability of preclinical in vivo safety studies and translational exposure–QTc relationships – a PKPD meta-analysis

    PubMed Central

    Gotta, V; Cools, F; van Ammel, K; Gallacher, D J; Visser, S A G; Sannajust, F; Morissette, P; Danhof, M; van der Graaf, P H

    2015-01-01

    Background and Purpose Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans. Experimental Approach We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER) with 95% confidence intervals (95%CI) for 3 Kv11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2–6 studies including 10–32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER. Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature. Key Results The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1–69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline. Conclusions and Implications Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical–clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments. PMID:26076100

  4. Applications of Proteomic Technologies to Toxicology

    EPA Science Inventory

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

  5. Swine as models in biomedical research and toxicology testing.

    PubMed

    Swindle, M M; Makin, A; Herron, A J; Clubb, F J; Frazier, K S

    2012-03-01

    Swine are considered to be one of the major animal species used in translational research, surgical models, and procedural training and are increasingly being used as an alternative to the dog or monkey as the choice of nonrodent species in preclinical toxicologic testing of pharmaceuticals. There are unique advantages to the use of swine in this setting given that they share with humans similar anatomic and physiologic characteristics involving the cardiovascular, urinary, integumentary, and digestive systems. However, the investigator needs to be familiar with important anatomic, histopathologic, and clinicopathologic features of the laboratory pig and minipig in order to put background lesions or xenobiotically induced toxicologic changes in their proper perspective and also needs to consider specific anatomic differences when using the pig as a surgical model. Ethical considerations, as well as the existence of significant amounts of background data, from a regulatory perspective, provide further support for the use of this species in experimental or pharmaceutical research studies. It is likely that pigs and minipigs will become an increasingly important animal model for research and pharmaceutical development applications.

  6. Preclinical and clinical studies of photodynamic action on some pathogenic micro-organisms of the oral cavity

    NASA Astrophysics Data System (ADS)

    Ovchinnikov, Ilya S.; Tuchin, Valery V.; Ivanov, Krill I.; Titorenko, Vladimir A.

    2001-10-01

    The work is devoted to an analysis of pre-clinical and clinical experiments on photodynamic action of HeNe laser radiation in aggregate with a cation thiazinium dye Methylene Blue (MB) on a mix of pathogenic and conditionally pathogenic aerobic bacteria being activators of pyoinflammatory diseases of oral cavity. Concentration of photosensitizes at which there is no own bactericidal influence on dying microflora, and parameters of influence at which the efficiency of irradiated microflora defeat reaches 99% are determined.

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

    PubMed

    1998-10-01

    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

  8. Aquatic toxicology: fact or fiction

    SciTech Connect

    Macek, K.J.

    1980-02-01

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

  9. NTP Toxicology and Carcinogenesis Studies of Pentachlorophenol (CAS NO. 87-86-5) in F344/N Rats (Feed Studies).

    PubMed

    1999-04-01

    Pentachlorophenol has been used as an herbicide, algicide, defoliant, wood preservative, germicide, fungicide, and molluscicide. Pentachlorophenol was nominated by the National Cancer Institute for carcinogenicity testing based on its widespread use as a wood preservative, potential for entering the environment (pentachlorophenol residues have been found worldwide in soil, water, and air samples; in food products; and in human and animal tissues and body fluids), and likelihood of bioaccumulation in the environment (pentachlorophenol is persistent in soil, having a half-life of up to 5 years). Technical Report No. 349 contains the results of the 2-year studies of pentachlorophenol performed by the NTP with B6C3F1 mice. Male and female F344/N rats were exposed to pentachlorophenol (approximately 99% pure) in feed for 28 days or 2 years. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow cells. 28-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 200, 400, 800, 1,600, or 3,200 ppm pentachlorophenol, equivalent to average daily doses of approximately 20, 40, 75, 150, or 270 mg pentachlorophenol/kg body weight to males and females in feed for 28 days. With the exception of one male and two females exposed to 3,200 ppm, all rats survived until the end of the study. The final mean body weights and body weight gains of male rats exposed to 1,600 or 3,200 ppm and female rats exposed to 400, 800, 1,600, or 3,200 ppm were significantly less than those of the controls; rats exposed to 3,200 ppm lost weight during the study. Feed consumption by 3,200 ppm males was less than that by the control group throughout the study. The absolute and relative liver weights of 400, 800, and 1,600 ppm males and all exposed groups of females were significantly greater than those of the controls. Compared to the control groups, the incidences of minimal to mild

  10. NTP Toxicology and Carcinogenesis Studies of Pentachlorophenol (CAS NO. 87-86-5) in F344/N Rats (Feed Studies).

    PubMed

    1999-04-01

    Pentachlorophenol has been used as an herbicide, algicide, defoliant, wood preservative, germicide, fungicide, and molluscicide. Pentachlorophenol was nominated by the National Cancer Institute for carcinogenicity testing based on its widespread use as a wood preservative, potential for entering the environment (pentachlorophenol residues have been found worldwide in soil, water, and air samples; in food products; and in human and animal tissues and body fluids), and likelihood of bioaccumulation in the environment (pentachlorophenol is persistent in soil, having a half-life of up to 5 years). Technical Report No. 349 contains the results of the 2-year studies of pentachlorophenol performed by the NTP with B6C3F1 mice. Male and female F344/N rats were exposed to pentachlorophenol (approximately 99% pure) in feed for 28 days or 2 years. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow cells. 28-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 200, 400, 800, 1,600, or 3,200 ppm pentachlorophenol, equivalent to average daily doses of approximately 20, 40, 75, 150, or 270 mg pentachlorophenol/kg body weight to males and females in feed for 28 days. With the exception of one male and two females exposed to 3,200 ppm, all rats survived until the end of the study. The final mean body weights and body weight gains of male rats exposed to 1,600 or 3,200 ppm and female rats exposed to 400, 800, 1,600, or 3,200 ppm were significantly less than those of the controls; rats exposed to 3,200 ppm lost weight during the study. Feed consumption by 3,200 ppm males was less than that by the control group throughout the study. The absolute and relative liver weights of 400, 800, and 1,600 ppm males and all exposed groups of females were significantly greater than those of the controls. Compared to the control groups, the incidences of minimal to mild

  11. Pre-Clinical Lupus

    PubMed Central

    Bourn, Rebecka; James, Judith A.

    2015-01-01

    Purpose of review Systemic lupus erythematosus (SLE) is often preceded by immune dysregulation and clinical manifestations below the threshold for SLE classification. This review discusses current and evolving concepts about the pre-classification period of SLE, including clinical and mechanistic observations, and potential avenues for early identification and intervention. Recent findings Although incomplete lupus erythematosus (ILE) involves fewer clinical manifestations than SLE, ILE can cause organ damage and mortality. Common clinical features in ILE include antinuclear antibody seropositivity, polyarthritis, immunologic manifestations, and hematological disorders. Despite having lower disease activity and damage scores than SLE patients, ILE patients may develop pulmonary arterial hypertension or renal, neurological, or peripheral vascular damage. The recently proposed SLICC SLE classification criteria could shift the period considered “preclinical SLE”. Murine studies suggest that the balance of T helper/T regulatory cells, peroxisome proliferator-activated receptor γ activity, and plasmacytoid dendritic cell pathways may be valuable targets for early intervention. Summary Advances in our understanding of early SLE, including stages before clinical features are fully developed, will improve our ability to identify individuals at high risk of classification for potential prevention trials, provide necessary information to improve diagnostic testing, and perhaps identify novel targets for directed therapeutics in clinical SLE. PMID:26125103

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

    PubMed Central

    Fröhlich, Eleonore; Salar-Behzadi, Sharareh

    2014-01-01

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

  13. Nanotechnology: Toxicologic Pathology

    PubMed Central

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

    2015-01-01

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

  14. Microbiology & Toxicology: Space Environment

    NASA Video Gallery

    One key aspect in maintaining crew health and performance during spaceflight missions is the provision of a habitable environment with acceptably low concentrations of microbiological and toxicolog...

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

    PubMed Central

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

    2014-01-01

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

  16. Toxicological assessment of β-(1-->6)-glucan (lasiodiplodan) in mice during a 28-day feeding study by gavage.

    PubMed

    Túrmina, Janaína A; Carraro, Emerson; Alves da Cunha, Mário A; Dekker, Robert F H; Barbosa, Aneli M; Dos Santos, Fábio Seidel; Silva, Luiz A; Malfatti, Carlos R M

    2012-01-01

    Studies evaluating the toxicity caused by fungal exopolysaccharides of the β-(1-->6)-D-glucan type are rare. In this study, the toxicological effects of sub-chronic treatments with lasiodiplodan (β-(1-->6)-D-glucan from Lasiodiplodia theobromae MMPI) were evaluated in mice through the assessment of biochemical, hematological, and histopathological alterations. Thirty-two mice (16 male, 16 female) were used in this study divided in two groups; one group received lasiodiplodan (50 mg/kg body weight) daily for 28 days via gavage, and another (control group) received saline during the same period. Blood samples were collected via cardiac puncture for hematological and biochemical analyses. Liver, heart, kidney, and spleen were collected for histopathological analysis. Statistical analysis was performed through one-way analysis of variance and only p < 0.05 F-values were presented. Significant reduction in blood glucose in the male group (35%; p < 0.01), transaminases activity in both sexes (AST and ALT; ~35%; p < 0.05), and urea (20%; p < 0.01) in the female group was observed with the lasiodiplodan treatment. The results showed that sub-chronic treatments with lasiodiplodan did not generate hematological and histopathological alterations leading to signs of toxicity in healthy mice, independent of gender. PMID:23208465

  17. Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing.

    PubMed

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

    2016-01-01

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

  18. Toxicology of brotizolam

    PubMed Central

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

    1983-01-01

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

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

    PubMed

    McDonnell-Dowling, Kate; Kelly, John P

    2015-02-15

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

  20. Preclinical development strategies for novel gene therapeutic products.

    PubMed

    Pilaro, A M; Serabian, M A

    1999-01-01

    With over 220 investigational new drug applications currently active, gene therapy represents one of the fastest growing areas in biotherapeutic research. Initially conceived for replacing defective genes in diseases such as cystic fibrosis or inborn errors of metabolism with genes encoding the normal, or wild-type, gene product, gene therapy has expanded into other novel applications such as treatment of cancer or cardiovascular disease, where the risk:benefit profiles may be more acceptable in relation to the severity of the disease. Different types of vectors, including modified retroviruses, adenoviruses, adenovirus-associated viruses, and herpesviruses and plasmid DNA, are used to transfer foreign genetic material into patients' cells or tissues. Developing a toxicology program to determine the safety of these agents, therefore, requires a modified approach that encompasses the pharmacology and toxicity of both the gene product itself and the vector system used for delivery in the context of the application for the clinical trial. In general, the issues involved in designing and developing appropriate preclinical testing to determine the safety of these products are similar to those encountered for other recombinant molecules, including protein biotherapeutics. Limitations to some of the typical toxicology studies conducted for a traditional drug development program may exist for these agents, and nontraditional approaches may be required to demonstrate their safety. Many factors may affect the safety and clinical activity of these agents, including the route, frequency, and duration of exposure and the type of vector employed. Other safety considerations include quantitation of the duration and degree of expression of the vector in target and other tissues, the effects of gene expression on organ pathology and/or histology, evaluation of trafficking of gene-transduced cells or vector after injection, and interactions of the host immune system with the

  1. Preclinical Studies of Mesenchymal Stem Cell (MSC) Administration in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review and Meta-Analysis

    PubMed Central

    Liu, Xiangde; Fang, Qiuhong; Kim, Huijung

    2016-01-01

    Background In the last two decades, mesenchymal stem cells (MSCs) have been pre-clinically utilized in the treatment of a variety of kinds of diseases including chronic obstructive pulmonary disease (COPD). The aim of the current study was to systematically review and conduct a meta-analysis on the published pre-clinical studies of MSC administration in the treatment of COPD in animal models. Methods and Results A systematic search of electronic databases was performed. Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3). The pooled Hedges’s g with 95% confidence intervals (95% CIs) was adopted to assess the effect size. Random effect model was used due to the heterogeneity between the studies. A total of 20 eligible studies were included in the current systematic review. The overall meta-analysis showed that MSC administration was significantly in favor of attenuating acute lung injury (Hedges’s g = -2.325 ± 0.145 with 95% CI: -2.609 ~ -2.040, P < 0.001 for mean linear intercept, MLI; Hedges’s g = -3.488 ± 0.504 with 95% CI: -4.476 ~ -2.501, P < 0.001 for TUNEL staining), stimulating lung tissue repair (Hedges’s g = 3.249 ± 0.586 with 95% CI: 2.103~ 4.394, P < 0.001) and improving lung function (Hedges’s g = 2.053 ± 0.408 with 95% CI: 1.253 ~ 2.854, P< 0.001). The mechanism of MSC therapy in COPD is through ameliorating airway inflammation (Hedges’s g = -2.956 ± 0.371 with 95% CI: -3.683 ~ -2.229, P< 0.001) and stimulating cytokine synthesis that involves lung tissue repair (Hedges’s g = 3.103 ± 0.734 with 95% CI: 1.664 ~ 4.541, P< 0.001). Conclusion This systematic review and meta-analysis suggest a promising role for MSCs in COPD treatment. Although the COPD models may not truly mimic COPD patients, these pre-clinical studies demonstrate that MSC hold promise in the treatment of chronic lung diseases including COPD. The mechanisms of MSCs role in preclinical COPD treatment may be associated with

  2. Spatial Navigation in Preclinical Alzheimer's Disease

    PubMed Central

    Allison, Samantha L.; Fagan, Anne M.; Morris, John C.; Head, Denise

    2016-01-01

    Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD. PMID:26967209

  3. Processing nanoparticles with A4F-SAXS for toxicological studies: Iron oxide in cell-based assays.

    PubMed

    Knappe, Patrick; Boehmert, Linda; Bienert, Ralf; Kamutzki, Silvana; Karmutzki, Silvana; Niemann, Birgit; Lampen, Alfonso; Thünemann, Andreas F

    2011-07-01

    Nanoparticles are not typically ready-to-use for in vitro cell culture assays. Prior to their use in assays, powder samples containing nanoparticles must be dispersed, de-agglomerated, fractionated by size, and characterized with respect to size and size distribution. For this purpose we report exemplarily on polyphosphate-stabilized iron oxide nanoparticles in aqueous suspension. Fractionation and online particle size analysis was performed in a time-saving procedure lasting 50 min by combining asymmetrical flow field-flow fractionation (A4F) and small-angle X-ray scattering (SAXS). Narrowly distributed nanoparticle fractions with radii of gyration (R(g)) from 7 to 21 nm were obtained from polydisperse samples. The A4F-SAXS combination is introduced for the preparation of well-characterized sample fractions originating from a highly polydisperse system as typically found in engineered nanoparticles. A4F-SAXS processed particles are ready-to-use for toxicological studies. The results of preliminary tests of the effects of fractionated iron oxide nanoparticles with a R(g) of 15 nm on a human colon model cell line are reported.

  4. Toxicogenomics: transcription profiling for toxicology assessment.

    PubMed

    Zhou, Tong; Chou, Jeff; Watkins, Paul B; Kaufmann, William K

    2009-01-01

    Toxicogenomics, the application of transcription profiling to toxicology, has been widely used for elucidating the molecular and cellular actions of chemicals and other environmental stressors on biological systems, predicting toxicity before any functional damages, and classification of known or new toxicants based on signatures of gene expression. The success of a toxicogenomics study depends upon close collaboration among experts in different fields, including a toxicologist or biologist, a bioinformatician, statistician, physician and, sometimes, mathematician. This review is focused on toxicogenomics studies, including transcription profiling technology, experimental design, significant gene extraction, toxicological results interpretation, potential pathway identification, database input and the applications of toxicogenomics in various fields of toxicological study. PMID:19157067

  5. Toxicology ontology perspectives.

    PubMed

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

    2012-01-01

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

  6. Transcriptome–metabolome wide association study (TMWAS) of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism

    PubMed Central

    Roede, James R.; Uppal, Karan; Park, Youngja; Tran, ViLinh; Jones, Dean P.

    2016-01-01

    A combination of the herbicide paraquat (PQ) and fungicide maneb (MB) has been linked to Parkinson's disease. Previous studies show that this involves an additive toxicity with at least two different mechanisms. However, detailed understanding of mixtures is often difficult to elucidate because of the multiple ways by which toxic agents can interact. In the present study, we used a combination of transcriptomics and metabolomics to investigate mechanisms of toxicity of PQ and MB in a neuroblastoma cell line. Conditions were studied with concentrations of PQ and MB that each individually caused 20% cell death and together caused 50% cell death. Transcriptomic and metabolomic samples were collected at time points prior to significant cell death. Statistical and bioinformatic methods were applied to the resulting 30,869 transcripts and 1358 metabolites. Results showed that MB significantly changed more transcripts and metabolites than PQ, and combined PQ + MB impacted more than MB alone. Transcriptome–metabolome-wide association study (TMWAS) showed that significantly changed transcripts and metabolites mapped to two network substructures, one associating with significant effects of MB and the other included features significantly associated with PQ + MB. The latter contained 4 clusters of genes and associated metabolites, with one containing genes for two cation transporters and a cation transporter regulatory protein also recognized as a pro-apoptotic protein. Other clusters included stress response genes and transporters linked to cytoprotective mechanisms. MB also had a significant network structure linked to cell proliferation. Together, the results show that the toxicologic mechanism of the combined neurotoxicity of PQ and MB involves network level interactions and that TMWAS provides an effective approach to investigate such complex mechanisms.

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

    PubMed

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

    2016-04-01

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

  8. Optimization and qualification of an 8-color intracellular cytokine staining assay for quantifying T cell responses in rhesus macaques for pre-clinical vaccine studies

    PubMed Central

    Donaldson, Mitzi M.; Kao, Shing-Fen; Eslamizar, Leila; Gee, Connie; Koopman, Gerrit; Lifton, Michelle; Schmitz, Joern E.; Sylwester, Andrew W.; Wilson, Aaron; Hawkins, Natalie; Self, Steve G.; Roederer, Mario; Foulds, Kathryn E.

    2013-01-01

    Vaccination and SIV challenge of macaque species is the best animal model for evaluating candidate HIV vaccines in pre-clinical studies. As such, robust assays optimized for use in nonhuman primates are necessary for reliable ex vivo measurement of immune responses and identification of potential immune correlates of protection. We optimized and qualified an 8-color intracellular cytokine staining assay for the measurement of IFNγ, IL-2, and TNF from viable CD4 and CD8 T cells from cryopreserved rhesus macaque PBMC stimulated with peptides. After optimization, five laboratories tested assay performance using the same reagents and PBMC samples; similar results were obtained despite the use of flow cytometers with different configurations. The 8-color assay was then subjected to a pre-qualification study to quantify specificity and precision. These data were used to set positivity thresholds and to design the qualification protocol. Upon completion of the qualification study, the assay was shown to be highly reproducible with low inter-aliquot, inter-day, and inter-operator variability according to the qualification criteria with an overall variability of 20–40% for each outcome measurement. Thus, the 8-color ICS assay was formally qualified according to the ICH guidelines Q2 (R1) for specificity and precision indicating that it is considered a standardized/robust assay acceptable for use in pre-clinical trial immunogenicity testing. PMID:22955212

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

    NASA Astrophysics Data System (ADS)

    Dawidczyk, Charlene; Russell, Luisa; Searson, Peter

    2014-08-01

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

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

    PubMed

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

    2016-02-01

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

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

    EPA Science Inventory

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

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

    PubMed

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

    2015-08-01

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

  13. Preclinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with insulin-like growth factor receptor-1/insulin receptor selectivity.

    PubMed

    Schwartz, Gary K; Dickson, Mark A; LoRusso, Patricia M; Sausville, Edward A; Maekawa, Yoshimi; Watanabe, Yasuo; Kashima, Naomi; Nakashima, Daisuke; Akinaga, Shiro

    2016-04-01

    Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously; dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer. PMID:26850678

  14. 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...

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

    PubMed Central

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

    2011-01-01

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

  16. A toxicological study of 5,6,7,8 tetrafluoro- 1,4-benzodioxin

    SciTech Connect

    London, J.E.

    1988-05-01

    The acute oral LD/sub 50/ values for 5,6,7,8 tetrafluro-1,4 benzodioxin for mice and rats are less than 5 gkg. According to classical guidelines, the material is considered slightly toxic in both species. The sensitization study in the guinea pig did not show the material to have potential sensitizing properties. Skin application studies on the rabbit demonstrated that it was cutaneously mildly irritating. This material was very mildly irritating in the rabbit eye application studies. 4 refs., 2 tabs.

  17. Toxicological studies of the aqueous extract from Achyrocline satureioides (Lam.) DC (Marcela).

    PubMed

    Rivera, F; Gervaz, E; Sere, C; Dajas, F

    2004-12-01

    Achyrocline satureioides (Lam.) DC (Marcela) is known to possess a broad spectrum of pharmacological, medicinal and therapeutic properties. Previous studies have demonstrated various protective abilities of the marcela extracts against various pathological conditions. However, no extensive safety studies have been conducted on these extracts to date. In this paper, we evaluated the acute toxicity (dose levels of 30-300 mg/kg) of an aqueous extract of marcela, administered intraperitoneally and orally in mice and rats. The acute oral maximun tolerable dose in repeated administration during 4 h (1, 3 until 5 g/kg) was also studied in rats. The extract had low acute toxicity when administered intraperitoneally and no toxicity upon oral administration. The LD(50) of aqueous extracts of marcela was found to be greater than 5 g/kg when administered once via gastric intubation to rats. Weight gain, toxicity signs, enzymatic studies (transaminases and phosphatases) and histological evaluation of several organs indicated that the extract was devoid of acute toxicity. These acute studies demonstrated that an aqueous extract of marcela obtained after a 2% infusion is safe and did not cause any detrimental effects in vivo under the conditions investigated in this study.

  18. White matter changes in preclinical Alzheimer's disease: a magnetic resonance imaging-diffusion tensor imaging study on cognitively normal older people with positive amyloid β protein 42 levels.

    PubMed

    Molinuevo, José Luis; Ripolles, Pablo; Simó, Marta; Lladó, Albert; Olives, Jaume; Balasa, Mircea; Antonell, Anna; Rodriguez-Fornells, Antoni; Rami, Lorena

    2014-12-01

    The aim of this study was to use diffusion tensor imaging measures to determine the existence of white matter microstructural differences in the preclinical phases of Alzheimer's disease, assessing cognitively normal older individuals with positive amyloid β protein (Aβ42) levels (CN_Aβ42+) on the basis of normal cognition and cerebrospinal fluid Aβ42 levels below 500 pg/mL. Nineteen CN_Aβ42+ and 19 subjects with Aβ42 levels above 500 pg/mL (CN_Aβ42-) were included. We encountered increases in axial diffusivity (AxD) in CN_Aβ42+ relative to CN_Aβ42- in the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus bilaterally, and also in the left fornix, left uncinate fasciculus, and left inferior fronto-occipital fasciculus. However, no differences were found in other diffusion tensor imaging indexes. Cognitive reserve scores were positively associated with AxD exclusively in the CN_Aβ42+ group. The finding of AxD alteration together with preserved fractional anisotropy, mean diffusivity, and radial diffusivity indexes in the CN_Aβ42+ group may indicate that, subtle axonal changes may be happening in the preclinical phases of Alzheimer's disease, whereas white matter integrity is still widely preserved.

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

    SciTech Connect

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

    2009-02-01

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

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

    SciTech Connect

    London, J.E.

    1993-03-01

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

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

    SciTech Connect

    London, J.E.

    1993-03-01

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

  2. 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...

  3. 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...

  4. 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...

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

    SciTech Connect

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

    1994-04-01

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

  6. HEART RATE VARIABILITY IN RODENTS — USES AND CAVEATS IN TOXICOLOGICAL STUDIES

    EPA Science Inventory

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

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

    PubMed

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

    2015-08-01

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

  8. Toxicological evaluation of realistic emission source aerosols (TERESA)--power plant studies: assessment of breathing pattern.

    PubMed

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

    2011-08-01

    Our approach to study multi-pollutant aerosols isolates a single emissions source, evaluates the toxicity of primary and secondary particles derived from this source, and simulates chemical reactions that occur in the atmosphere after emission. Three U.S. coal-fired power plants utilizing different coals and with different emission controls were evaluated. Secondary organic aerosol (SOA) derived from α-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 R(2) 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.

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

    PubMed

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

    2014-03-01

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

  10. Toxicological studies on the purified protoberberine alkaloidal fraction of Enantia chlorantha Oliv (ANNONACEAE).

    PubMed

    Moody, J O; Ogundipe, O D; Akang, E U U; Agbedana, E O

    2007-12-01

    We have examined the cumulative effects of the protoberberine alkaloidal fraction (AF) of the stein bark ethanolic extracts of Enantia chlorantha on some body tissues and organs as well as on certain biochemical and metabolic parameters in mice. Acute and sub-chronic toxicity studies of the alkaloidal fractions of Enantia chlorantha were carried out in 120 mice using oral and intraperitoneal administrations. Fatality was not recorded in mice injected intraperitonealy with 100 mg kg(-1) and 150 mg kg(-1) dose level but larger doses resulted in death and the mean lethal dose (LD50) toxicity studies showed neither behavioural/untoward reactions nor death in any of the animals. The histopathological examination of the test animals when compared with the control revealed that, the sub-chronic use of the alkaloidal fractions does not have any pathological effects (lesion) on the organs examined (the stomach, the kidney, the oesophagus and the liver) except the lungs which showed mild and moderate oedema. The biochemical and metabolic analysis of the mice plasma did not show any significant difference when the corresponding values for the test mice were compared with the control mice (P > 0.05) at the end of the 14 days treatment using both 20 mg kg(-1) and 2 mg kg(-1) dose levels. The results obtained in this study suggest the relative safety of short-term use of preparations containing E. chlorantha, a very popular antimalarial herbal remedy in Southern Nigeria.

  11. Toxicologic evaluation of tungsten: 28-day inhalation study of tungsten blue oxide in rats.

    PubMed

    Rajendran, Narayanan; Hu, Shu-Chieh; Sullivan, Dennis; Muzzio, Miguel; Detrisac, Carol J; Venezia, Carmen

    2012-12-01

    The toxicity and toxicokinetics of tungsten blue oxide (TBO) were examined. TBO is an intermediate in the production of tungsten powder, and has shown the potential to cause cellular damage in in vitro studies. However, in vivo evidence seems to indicate a lack of adverse effects. The present study was undertaken to address the dearth of longer-term inhalation toxicity studies of tungsten oxides by investigating the biological responses induced by TBO when administered via nose-only inhalation to rats at levels of 0.08, 0.325, and 0.65 mg TBO/L of air for 6 h/day for 28 consecutive days, followed by a 14-day recovery period. Inhaled TBO was absorbed systemically and blood levels of tungsten increased as inhaled concentration increased. Among the tissues analyzed for tungsten levels, lung, femur and kidney showed increased levels, with lung at least an order of magnitude greater than kidney or femur. By exposure day 14, tungsten concentration in tissues had reached steady-state. Increased lung weight was noted for both terminal and recovery animals and was attributed to deposition of TBO in the lungs, inducing a macrophage influx. Microscopic evaluation of tissues revealed a dose-related increase in alveolar pigmented macrophages, alveolar foreign material and individual alveolar foamy macrophages in lung. After a recovery period there was a slight reduction in the incidence and severity of histopathological findings. Based on the absence of other adverse effects, the increased lung weights and the microscopic findings were interpreted as nonadverse response to exposure and were not considered a specific reaction to TBO.

  12. Handbook of toxicology

    SciTech Connect

    Haley, T.J.; Berndt, W.O.

    1987-01-01

    This book discusses the ongoing battle against the effects of pesticides, herbicides, fungicides, and other toxic agents. It points out gaps in present-day research, illustrate other diseases that can mimic chemical toxicity, and emphasize thorough consideration of all aspects in a given incident prior to administering an antidote. The book offers a compiled data on target organ toxicity involving the liver, kidneys, and lungs - detailing the rapid, recent progress in this area. The coverage also highlights reproductive toxicology, food additives, asphixiant gases, and pulmonary toxicology. The partial contents are: Absorption, distribution, Biotransformation, Conjugation, and Excretion of Xenobiotics, Hepatotoxicity, Pulmonary Toxiology, Reproductive and Perinatal toxicology, Toxicology of Insecticides, Rodenticides, Herbicides, and Fungicides, Mechanisms of Metal-Induced Cell Injury, Food Additives: A Benefit/Risk Dilemma, Animal Toxins, and Toxic Effects of Chemicals on the Immune System.

  13. Computational Toxicology (S)

    EPA Science Inventory

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

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

    SciTech Connect

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

    1988-02-01

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

  15. Hypotensive and toxicological study of citric acid and other constituents from Tagetes patula roots.

    PubMed

    Saleem, Rubeena; Ahmad, Mohammad; Naz, Aneela; Siddiqui, Humaira; Ahmad, Syed Iqbal; Faizi, Shaheen

    2004-10-01

    Study of the effects of the methanolic extract of Tagetes patula roots on blood pressure led to the isolation of well known citric (1) and malic acid (7) as hypotensive, and pyridine hydrochloride (4) as hypertensive constituents of the plant along with a new constituent, 2-hydroxy, 5-hydroxymethyl furan (9). Citric acid and malic acid caused 71% and 43% fall in Mean Arterial Blood Pressure (MABP) of rats at the doses of 15 mg/kg and 30 mg/kg respectively while pyridine hydrochloride produced 34% rise in the MABP of rats at the dose of 30 mg/kg. LD50 and LD100 of citric acid in mice have been determined as 545 mg/kg and 1000 mg/kg, respectively.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

    The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics, tumor accumulation, and biodistribution. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field. PMID:25202689

  18. Toxicology Study of Single-walled Carbon Nanotubes and Reduced Graphene Oxide in Human Sperm.

    PubMed

    Asghar, Waseem; Shafiee, Hadi; Velasco, Vanessa; Sah, Vasu R; Guo, Shirui; El Assal, Rami; Inci, Fatih; Rajagopalan, Adhithi; Jahangir, Muntasir; Anchan, Raymond M; Mutter, George L; Ozkan, Mihrimah; Ozkan, Cengiz S; Demirci, Utkan

    2016-01-01

    Carbon-based nanomaterials such as single-walled carbon nanotubes and reduced graphene oxide are currently being evaluated for biomedical applications including in vivo drug delivery and tumor imaging. Several reports have studied the toxicity of carbon nanomaterials, but their effects on human male reproduction have not been fully examined. Additionally, it is not clear whether the nanomaterial exposure has any effect on sperm sorting procedures used in clinical settings. Here, we show that the presence of functionalized single walled carbon nanotubes (SWCNT-COOH) and reduced graphene oxide at concentrations of 1-25 μg/mL do not affect sperm viability. However, SWCNT-COOH generate significant reactive superoxide species at a higher concentration (25 μg/mL), while reduced graphene oxide does not initiate reactive species in human sperm. Further, we demonstrate that exposure to these nanomaterials does not hinder the sperm sorting process, and microfluidic sorting systems can select the sperm that show low oxidative stress post-exposure. PMID:27538480

  19. The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies.

    PubMed

    Goldman, Jerome M; Murr, Ashley S; Cooper, Ralph L

    2007-04-01

    While 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 to exposure to a test compound. Assessment of vaginal cytology in regularly cycling animals also provides a means to establish a comparable endocrine milieu for animals at necropsy. The procedure for obtaining a vaginal smear is relatively non-invasive and is one to which animals can become readily accustomed. It requires few supplies, and with some experience the assessments can be easily performed in fresh, unstained smears, or in fixed, stained ones. When incorporated as an adjunct to other endpoint measures, a determination of a female's cycling status can contribute important information about the nature of a toxicant insult to the reproductive system. In doing so, it can help to integrate the data into a more comprehensive mechanistic portrait of the effect, and in terms of risk assessment, may provide some indication of a toxicant's impact on human reproductive physiology.

  20. [Clinical and toxicologic study of axillary plexus block with prilocaine or mepivacaine].

    PubMed

    Tryba, M; Kurth, H; Zenz, M

    1987-01-01

    A prospective controlled double-blind study was designed to compare the efficacy and the toxicity of mepivacaine and prilocaine for the axillary blockade of the brachial plexus. Twenty patients in each group received 40 ml of either 1.5% mepivacaine or 1.5% prilocaine. The sensory and the motor blockade achieved in both groups were comparable. The mean plasma levels attained following mepivacaine were significantly higher than those attained after prilocaine (peak-plasma level (mean +/- SD): 2.02 +/- 0.28 micrograms/ml vs 5.37 +/- 1.83 micrograms/ml). In four patients of the mepivacaine group, the plasma levels entered the toxic range. While no methemoglobinemia could be detected following mepivacaine, four of the patients receiving prilocaine developed methemoglobinemia with a maximum level of 10%. No complications due to methemoglobinemia were observed in any of the patients. Because of its significantly lower toxic potential, prilocaine seems to be the better local anaesthetic for axillary blockade of the brachial plexus.

  1. Toxicology Study of Single-walled Carbon Nanotubes and Reduced Graphene Oxide in Human Sperm

    PubMed Central

    Asghar, Waseem; Shafiee, Hadi; Velasco, Vanessa; Sah, Vasu R.; Guo, Shirui; El Assal, Rami; Inci, Fatih; Rajagopalan, Adhithi; Jahangir, Muntasir; Anchan, Raymond M.; Mutter, George L.; Ozkan, Mihrimah; Ozkan, Cengiz S.; Demirci, Utkan

    2016-01-01

    Carbon-based nanomaterials such as single-walled carbon nanotubes and reduced graphene oxide are currently being evaluated for biomedical applications including in vivo drug delivery and tumor imaging. Several reports have studied the toxicity of carbon nanomaterials, but their effects on human male reproduction have not been fully examined. Additionally, it is not clear whether the nanomaterial exposure has any effect on sperm sorting procedures used in clinical settings. Here, we show that the presence of functionalized single walled carbon nanotubes (SWCNT-COOH) and reduced graphene oxide at concentrations of 1–25 μg/mL do not affect sperm viability. However, SWCNT-COOH generate significant reactive superoxide species at a higher concentration (25 μg/mL), while reduced graphene oxide does not initiate reactive species in human sperm. Further, we demonstrate that exposure to these nanomaterials does not hinder the sperm sorting process, and microfluidic sorting systems can select the sperm that show low oxidative stress post-exposure. PMID:27538480

  2. Formulation and analysis of food-grade mineral hydrocarbons in toxicology studies.

    PubMed

    Walters, D G; Sherrington, K V; Worrell, N; Riley, R A

    1994-06-01

    Methods are presented for the formulation and rapid determination of mineral hydrocarbons (MHCs) in animal diet and tissue. Food grade white oils and low melting point waxes are mixed as liquids with powdered diet. Higher melting point waxes are first powdered using a novel atomization technique before dry mixing with diet. MHCs sufficiently soluble in carbon tetrachloride (CCl4) are determined in diet by ultrasonic solvent extraction, adsorption of polar material on Florisil and analysis of the residue by quantitative Fourier Transform Infra Red (FT-IR) spectroscopy. Quantification in tissue is achieved by aqueous saponification, followed by extraction, clean-up and FT-IR analysis as for diet samples. A 10-fold increase in sensitivity over previous methods is achieved, below 0.002% (w/w) in diet and 0.1 mg/g in tissue. Over 80% of the CCl4 used can be recovered and recycled. Control diet seems to contain approximately 0.003% (w/w) background MHC. The method was modified for one powdered wax, only sparingly soluble in CCl4, high concentrations being extracted from diet by flotation in aqueous cetrimide and determined gravimetrically with a limit of detection of 0.1% (w/w) in diet. Application of these methods to 90-day feeding studies is described, and future developments due to the phasing out of CCl4 are discussed.

  3. Toxicology Study of Single-walled Carbon Nanotubes and Reduced Graphene Oxide in Human Sperm

    NASA Astrophysics Data System (ADS)

    Asghar, Waseem; Shafiee, Hadi; Velasco, Vanessa; Sah, Vasu R.; Guo, Shirui; El Assal, Rami; Inci, Fatih; Rajagopalan, Adhithi; Jahangir, Muntasir; Anchan, Raymond M.; Mutter, George L.; Ozkan, Mihrimah; Ozkan, Cengiz S.; Demirci, Utkan

    2016-08-01

    Carbon-based nanomaterials such as single-walled carbon nanotubes and reduced graphene oxide are currently being evaluated for biomedical applications including in vivo drug delivery and tumor imaging. Several reports have studied the toxicity of carbon nanomaterials, but their effects on human male reproduction have not been fully examined. Additionally, it is not clear whether the nanomaterial exposure has any effect on sperm sorting procedures used in clinical settings. Here, we show that the presence of functionalized single walled carbon nanotubes (SWCNT-COOH) and reduced graphene oxide at concentrations of 1–25 μg/mL do not affect sperm viability. However, SWCNT-COOH generate significant reactive superoxide species at a higher concentration (25 μg/mL), while reduced graphene oxide does not initiate reactive species in human sperm. Further, we demonstrate that exposure to these nanomaterials does not hinder the sperm sorting process, and microfluidic sorting systems can select the sperm that show low oxidative stress post-exposure.

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

    PubMed Central

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

    2015-01-01

    Faced with the novelty of a 212Pb-labeled monoclonal antibody (mAb) for clinical translation, concerns were expressed by the Food and Drug Administration (FDA) regarding 212Pb prematurely released from the mAb-chelate conjugate. The objective of this study was to simulate the worst case scenario of such a failure. Groups of Balb/c mice (n = 9–20) were administered 212Pb by intraperitoneal (0.0925–1.85 MBq) or intravenous (0.0925–1.11 MBq) injection and then euthanized at 7 or 90 days to assess acute or chronic effects. Weights were recorded prior to injection of the 212Pb and at the end of the observation periods. Blood samples were collected for clinical chemistry and blood cell analysis. Thirty tissues were harvested and formalin fixed for histopathological examination. Treatment related effects of the 212Pb were observed in the bone marrow, spleen, kidneys and the liver. Histological alterations in these organs were considered mild to moderate, indicating low grade toxicity, and not considered severe enough to affect function. This data was presented to the FDA and determined to be acceptable. The clinical trial with 212Pb-TCMC-trastuzumab was approved in January 2011 and the trial opened at the University of Alabama at Birmingham (UAB) in July. PMID:26213947

  5. Toxicological studies for some agricultural waste extracts on mosquito larvae and experimental animals

    PubMed Central

    El-Maghraby, Somia; Nawwar, Galal A; Bakr, Reda FA; Helmy, Nadia; Kamel, Omnia MHM

    2012-01-01

    Objective To evaluate some agricultural waste extracts as insecticide and their effects on enzyme activities in liver and kidney of male mice. Methods The insecticidal activity of five tested compounds (one crude extract and 4 waste compounds) was bioassay against the 3rd instars of the Culex pipiens (Cx. pipiens) larvae in the laboratory. The LC50 values of eucalyptol, apricot kernel, Rice bran, corn, black liquor and white liquor are 91.45, 1 166.1, 1 203.3, 21 449.65, 4 025.78 and 6 343.18 ppm, respectively. Selection of the compounds for the subsequent studies was not only dependent on LC50 values but also on the persistence of these wastes products on large scale. Results White and black liquor did not produce any gross effect at 200 mg/Kg body weight. No apparent toxic symptoms were observed in tested animals during the whole period of the experiment which run out for 14 days. No statistically significance was observed in the enzyme cholinesterase activity, the activities of liver enzymes and kidney function in treated mice with black and white liquors. While, no and slight inhibition was observed after the 2 weeks of treatment period with deltamethrin and fenitrothion reached to about 24% in plasma cholinesterase enzyme activity. Significantly increase in the activities of liver enzymes and kidney function in treated mice with deltamethrin and fenitrothion. Conclusions Black liquor can be used efficiently to control Cx. pipiens larvae under laboratory condition. Environmental problem caused by rice straw can be solved by converting the waste material to beneficial natural selective insecticide. PMID:23569971

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

    PubMed

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

    2015-12-01

    Emulsions are gaining increasing interest to be applied as drug delivery systems. The main goal of this work was the formulation of an oil/water nutraceutical emulsion (NE) for oral administration, enriched in omega 3 (ω3) and omega 6 (ω6), and able to encapsulate risperidone (RISP), an antipsychotic drug widely used in the treatment of autism spectrum disorders (ASD). RISP has low solubility in aqueous medium and poor bioavailability because of its metabolism and high protein binding. Coadministration of ω3, ω3, and vitamin E complexed with RISP might increase its bioavailability and induce a synergistic effect on the treatment of ASD. Here, we developed an easy and quick method to obtain NEs and then optimized them. The best formulation was chosen after characterization by particle size, defects of the oil-in-water interface, zeta potential (ZP), and in vitro drug release. The formulation selected was stable over time, with a particle size of around 3 μm, a ZP lower than -20 mV and controlled drug release. To better understand the biochemical properties of the formulation obtained, we studied in vitro toxicity in the Caco-2 cell line. After 4 h of treatment, an increase in cellular metabolism was observed for all RISP concentrations, but emulsions did not change their metabolic rate, except at the highest concentration without drug (25 μg/mL), which showed a significant reduction in metabolism respect to the control. Additionally, locomotor activity and heart rate in zebrafish were measured as parameters of in vivo toxicity. Only the highest concentration (0.625 μg/mL) showed a cardiotoxic effect, which corresponds to the decrease in spontaneous movement observed previously. As all the materials contained in the formulations were US FDA approved, the NE selected would be good candidate for clinical trials.

  7. Metformin's performance in in vitro and in vivo genetic toxicology studies.

    PubMed

    Sant'Anna, Juliane R; Yajima, Joana Paula R S; Rosada, Lúcia J; Franco, Claudinéia C S; Prioli, Alberto J; Della-Rosa, Valter A; Mathias, Paulo Cezar F; Castro-Prado, Marialba A A

    2013-07-01

    Metformin is a hypoglycemiant drug prescribed for the treatment and control of the type 2 diabetes mellitus. Recently, the potential efficacy of this antidiabetic drug as an anticancer agent has been demonstrated in various mammalian cancer cells. This report evaluates the mutagenic as well as the recombinogenic potentials of the metformin drug in therapeutically relevant plasma concentrations (12.5 µM, 25.0 µM or 50.0 µM). Since the loss of heterozygosity is a process associated with carcinogenesis, the recombinogenic potential of such a drug was evaluated by the homozygotization assay using a heterozygous diploid strain of Aspergillus nidulans. The homozigotization indices (HI) for the genetic markers from the metformin-treated diploids were not statistically different from the negative control (non-treated diploids). For the first time, this indicated a lack of recombinogenic activity of the antidiabetic drug. The mutagenic potential of the metformin drug was evaluated by the chromosome aberrations and the micronuclei tests in human lymphocytes cultures. The metformin drug did not show any significant increase either in the numerical or in the structural chromosome aberrations and did not affect significantly the mitotic index when compared to the negative control. In the in vitro micronucleus test, the drug did not increase the number of micronuclei or nuclear buds when compared with the negative control. The data in this study suggest that the metformin drug is not a secondary cancer inducer, since it has neither showed recombinogenic nor mutagenic activities when used in pharmacological concentrations.

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

    PubMed

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

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

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

    PubMed Central

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

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

  10. Toxicological significance of dihydrodiol metabolites

    SciTech Connect

    Hsia, M.T.

    1982-01-01

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

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

    SciTech Connect

    DeNardo, S.J.

    1995-12-31

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

  12. Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.

    PubMed

    Luthra, Pratibha Mehta; Barodia, Sandeep Kumar; Raghubir, Ram

    2009-04-15

    Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD.

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

    PubMed Central

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

    2015-01-01

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

  14. Validating animal models for preclinical research: a scientific and ethical discussion.

    PubMed

    Varga, Orsolya E; Hansen, Axel K; Sandøe, Peter; Olsson, I Anna S

    2010-06-01

    The use of animals to model humans in biomedical research relies on the notion that basic processes are sufficiently similar across species to allow extrapolation. Animal model validity is discussed in terms of the similarity between the model and the human condition it is intended to model, but no formal validation of models is applied. There is a stark contrast here with the use of non-animal alternatives in toxicology and safety studies, for which an extensive validation is required. We discuss both the potential and the limitations of validating preclinical animal models for proof-of-concept studies, by using an approach similar to that applied to alternative non-animal methods in toxicology and safety testing. A major challenge in devising a validation system for animal models is the lack of a clear gold standard with which to compare results. While a complete adoption of the validation approach for alternative methods is probably inappropriate for research animal models, key features, such as making data available for external validation and defining a strategy to run experiments in a way that permits meaningful retrospective analysis, remain highly relevant.

  15. Pre-clinical studies of toxin-specific nanobodies: evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming.

    PubMed

    Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Lahoutte, Tony

    2012-10-15

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

  16. A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment.

    PubMed

    Kerbel, Robert S

    2015-01-01

    The clinical circumstance of treating spontaneous metastatic disease, after resection of primary tumors, whether advanced/overt or microscopic in nature, is seldom modeled in mice and may be a major factor in explaining the frequent discordance between preclinical and clinical therapeutic outcomes where the trend is "overprediction" of positive results in preclinical mouse model studies. To evaluate this hypothesis, a research program was initiated a decade ago to develop multiple models of metastasis in mice, using variants of human tumor cell lines selected in vivo for enhanced spontaneous metastatic aggressiveness after surgical resection of established orthotopic primary tumors. These models have included breast, renal, and colorectal carcinomas; ovarian cancer (but without prior surgery); and malignant melanoma. They have been used primarily for experimental therapeutic investigations involving various antiangiogenic drugs alone or with chemotherapy, especially "metronomic" low-dose chemotherapy. The various translational studies undertaken have revealed a number of clinically relevant findings. These include the following: (i) the potential of metronomic chemotherapy, especially when combined with a vascular endothelial growth factor pathway targeting drug to successfully treat advanced metastatic disease; (ii) the development of relapsed spontaneous brain metastases in mice with melanoma or breast cancer whose systemic metastatic disease is successfully controlled for a period with a given therapy; (iii) foreshadowing the failure of adjuvant antiangiogenic drug-based phase III trials; (iv) recapitulating the failure of oral antiangiogenic tyrosine kinase inhibitors plus standard chemotherapy in contrast to the modest successes of antiangiogenic antibodies plus chemotherapy in metastatic breast cancer; and (v) revealing "vessel co-option" and absence of angiogenesis as a determinant of intrinsic resistance or minimal responsiveness to antiangiogenic therapy

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

    PubMed Central

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

    2015-01-01

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

  18. The Economics of Reproducibility in Preclinical Research

    PubMed Central

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

    2015-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

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

  20. Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy.

    PubMed

    de Moraes, Luciana V; Dechavanne, Sebastien; Sousa, Patrícia M; Barateiro, André; Cunha, Sónia F; Nunes-Silva, Sofia; Lima, Flávia A; Murillo, Oscar; Marinho, Claudio R F; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A; Janse, Chris J; Gamain, Benoit; Franke-Fayard, Blandine; Penha-Gonçalves, Carlos

    2016-06-01

    Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 10(4) P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei At doses of 10(5) and 10(6) IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6-EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA. PMID:27045035

  1. Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy.

    PubMed

    de Moraes, Luciana V; Dechavanne, Sebastien; Sousa, Patrícia M; Barateiro, André; Cunha, Sónia F; Nunes-Silva, Sofia; Lima, Flávia A; Murillo, Oscar; Marinho, Claudio R F; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A; Janse, Chris J; Gamain, Benoit; Franke-Fayard, Blandine; Penha-Gonçalves, Carlos

    2016-06-01

    Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 10(4) P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei At doses of 10(5) and 10(6) IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6-EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA.

  2. Advanced urine toxicology testing.

    PubMed

    Tenore, Peter L

    2010-10-01

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

  3. American College of Medical Toxicology

    MedlinePlus

    ... NACCT Board Review Course Chemical Agents of Opportunity: TICs and TIMs Seminars in Forensic Toxicology Clandestine Meth ... City Center Reservations 2016 Chemical Agents of Opportunity: TICs and TIMs Syllabus Seminars in Forensic Toxicology 2013 ...

  4. Oral-toxicology

    PubMed Central

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

    2014-01-01

    Forensic toxicology deals with the investigation of toxic substances, poisonous products or with the environmental chemicals. This field of science helps to identify poison substance and hazardous chemicals. Forensic toxicology deals with the way that substances are absorbed, distributed or eliminated in the body – the metabolism of substances. This paper reviews the manifestations that each poisonous substance presents concentrating toward the commonly used poisonous substance especially in India. It also explains the Indian Penal Code, which is main criminal code intended to cover all substantive aspects of criminal law regarding poison. PMID:24696586

  5. Shuttle Lesson Learned - Toxicology

    NASA Technical Reports Server (NTRS)

    James, John T.

    2010-01-01

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

  6. Clinical Traumatic Brain Injury in the Preclinical Setting.

    PubMed

    Berkner, Justin; Mannix, Rebekah; Qiu, Jianhua

    2016-01-01

    Traumatic brain injury (TBI) is the leading cause of death and disability for people under 45 years of age. Clinical TBI is often the result of disparate forces resulting in heterogeneous injuries. Preclinical modeling of TBI is a vital tool for studying the complex cascade of metabolic, cellular, and molecular post-TBI events collectively termed secondary injury. Preclinical models also provide an important platform for studying therapeutic interventions. However, modeling TBI in the preclinical setting is challenging, and most models replicate only certain aspects of clinical TBI. This chapter details the most widely used models of preclinical TBI, including the controlled cortical impact, fluid percussion, blast, and closed head models. Each of these models replicates particular critical aspects of clinical TBI. Prior to selecting a preclinical TBI model, it is important to address what aspect of human TBI is being sought to evaluate. PMID:27604710

  7. Advancing Risk Assessment through the Application of Systems Toxicology.

    PubMed

    Sauer, John Michael; Kleensang, André; Peitsch, Manuel C; Hayes, A Wallace

    2016-01-01

    Risk assessment is the process of quantifying the probability of a harmful effect to individuals or populations from human activities. Mechanistic approaches to risk assessment have been generally referred to as systems toxicology. Systems toxicology makes use of advanced analytical and computational tools to integrate classical toxicology and quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Three presentations including two case studies involving both in vitro and in vivo approaches described the current state of systems toxicology and the potential for its future application in chemical risk assessment. PMID:26977253

  8. Advancing Risk Assessment through the Application of Systems Toxicology

    PubMed Central

    Sauer, John Michael; Kleensang, André; Peitsch, Manuel C.; Hayes, A. Wallace

    2016-01-01

    Risk assessment is the process of quantifying the probability of a harmful effect to individuals or populations from human activities. Mechanistic approaches to risk assessment have been generally referred to as systems toxicology. Systems toxicology makes use of advanced analytical and computational tools to integrate classical toxicology and quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Three presentations including two case studies involving both in vitro and in vivo approaches described the current state of systems toxicology and the potential for its future application in chemical risk assessment. PMID:26977253

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

    PubMed

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

    2004-08-01

    Studies are described on the metabolism and the toxicologic analysis of the nonopioid cough suppressant dropropizine [R,S-3-(4-phenyl-1-piperazinyl)1,2-propandiol, DRO] in human urine using gas chromatography-mass spectrometry (GC-MS). The metabolism studies showed that DRO was metabolized in humans mainly by hydroxylation of the aromatic ring, by N-dealkylation of the parent drug and of the hydroxyl-metabolite to the corresponding N-phenylpiperazines, and by degradation of the piperazine moiety. The authors' systematic toxicologic analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction, and microwave-assisted acetylation allowed the unambiguous detection of DRO and its above-mentioned metabolites in human urine up to about 32 hours after intake of a single common therapeutic dose. The target analytes were found to be the parent compound DRO (earlier phase of excretion) and the hydroxylated metabolite para-hydroxy-DRO (later phase of excretion). Both allowed unambiguous detection of an intake of DRO and also differentiation from other phenylpiperazine derivatives.

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

    PubMed

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

    2004-08-01

    Studies are described on the metabolism and the toxicologic analysis of the nonopioid cough suppressant dropropizine [R,S-3-(4-phenyl-1-piperazinyl)1,2-propandiol, DRO] in human urine using gas chromatography-mass spectrometry (GC-MS). The metabolism studies showed that DRO was metabolized in humans mainly by hydroxylation of the aromatic ring, by N-dealkylation of the parent drug and of the hydroxyl-metabolite to the corresponding N-phenylpiperazines, and by degradation of the piperazine moiety. The authors' systematic toxicologic analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction, and microwave-assisted acetylation allowed the unambiguous detection of DRO and its above-mentioned metabolites in human urine up to about 32 hours after intake of a single common therapeutic dose. The target analytes were found to be the parent compound DRO (earlier phase of excretion) and the hydroxylated metabolite para-hydroxy-DRO (later phase of excretion). Both allowed unambiguous detection of an intake of DRO and also differentiation from other phenylpiperazine derivatives. PMID:15257075

  11. Reform in teaching preclinical pathophysiology.

    PubMed

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

    2015-12-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools.

  12. Preclinical assessment of infant formula.

    PubMed

    Lönnerdal, Bo

    2012-01-01

    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.

  13. Toxicology of chlorofluorocarbon replacements.

    PubMed Central

    Dekant, W

    1996-01-01

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

  14. Toxicology of chlorofluorocarbon replacements.

    PubMed

    Dekant, W

    1996-03-01

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

  15. NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethoxybenzidine Dihydrochloride (CAS No. 20325-40-0) in F344/N Rats (Drinking Water Studies).

    PubMed

    1990-01-01

    3,3'-Dimethoxybenzidine dihydrochloride is an off-white powder with a melting point of 274 degrees C. 3,3'-Dimethoxybenzidine is used principally as an intermediate in the production of commercial bisazobiphenyl dyes for coloring textiles, paper, plastic, rubber, and leather. In the synthesis of the bisazobiphenyl dyes, the amine groups of 3,3'-dimethoxybenzidine are chemically linked with other aromatic amines. A small quantity of 3,3'-dimethoxybenzidine is also used as an intermediate in the production of o-dianisidine diisocyanate, which is used in isocyanate-based adhesive systems and as a component of polyurethane elastomers. 3,3'-Dimethoxybenzidine dihydrochloride was evaluated in toxicity and carcinogenicity studies as part of the National Toxicology Program's Benzidine Dye Initiative. This Initiative was designed to evaluate the representative benzidine congeners and benzidine congener-derived and benzidine-derived dyes. 3,3'-Dimethoxybenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. NTP Toxicology and Carcinogenesis studies were conducted by administering 3,3'-dimethoxybenzidine dihydrochloride (greater than 97.5% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, 9 months, or 21-months. The 21-month studies were intended to last 24 months but were terminated early because of rapidly declining survival due to neoplasia. Studies were performed only in rats because similar studies are being performed in mice at the National Center for Toxicology Research. Genetic toxicology studies were conducted with Salmonella typhimurium, Chinese hamster over (CHO) cells, and Drosophila melanogaster. Fourteen-Day Studies: All rats receiving drinking water concentrations up to 4,500 ppm lived to the end of the studies. Rats that received water containing 4,500 ppm 3

  16. In silico toxicology for the pharmaceutical sciences.

    PubMed

    Valerio, Luis G

    2009-12-15

    The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical

  17. In silico toxicology for the pharmaceutical sciences

    SciTech Connect

    Valerio, Luis G.

    2009-12-15

    The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical

  18. Toxicology and Chemical Safety.

    ERIC Educational Resources Information Center

    Hall, Stephen K.

    1983-01-01

    Topics addressed in this discussion of toxicology and chemical safety include routes of exposure, dose/response relationships, action of toxic substances, and effects of exposure to chemicals. Specific examples are used to illustrate the principles discussed. Suggests prudence in handling any chemicals, whether or not toxicity is known. (JN)

  19. Toxicology, an STS Approach.

    ERIC Educational Resources Information Center

    Wagner, Richard

    1990-01-01

    Presented are activities suggested through Project L.A.B.S. that involve the topic of toxicology. Activities include suggested research, the risk benefit seesaw, human-made compounds, legislation, a historical perspective, and health. A suggested readings list is provided. (KR)

  20. Synthetic cathinone pharmacokinetics, analytical methods, and toxicological findings from human performance and postmortem cases.

    PubMed

    Ellefsen, Kayla N; Concheiro, Marta; Huestis, Marilyn A

    2016-05-01

    Synthetic cathinones are commonly abused novel psychoactive substances (NPS). We present a comprehensive systematic review addressing in vitro and in vivo synthetic cathinone pharmacokinetics, analytical methods for detection and quantification in biological matrices, and toxicological findings from human performance and postmortem toxicology cases. Few preclinical administration studies examined synthetic cathinone pharmacokinetic profiles (absorption, distribution, metabolism, and excretion), and only one investigated metabolite pharmacokinetics. Synthetic cathinone metabolic profiling studies, primarily with human liver microsomes, elucidated metabolite structures and identified suitable biomarkers to extend detection windows beyond those provided by parent compounds. Generally, cathinone derivatives underwent ketone reduction, carbonylation of the pyrrolidine ring, and oxidative reactions, with phase II metabolites also detected. Reliable analytical methods are necessary for cathinone identification in biological matrices to document intake and link adverse events to specific compounds and concentrations. NPS analytical methods are constrained in their ability to detect new emerging synthetic cathinones due to limited commercially available reference standards and continuous development of new analogs. Immunoassay screening methods are especially affected, but also gas-chromatography and liquid-chromatography mass spectrometry confirmation methods. Non-targeted high-resolution-mass spectrometry screening methods are advantageous, as they allow for retrospective data analysis and easier addition of new synthetic cathinones to existing methods. Lack of controlled administration studies in humans complicate interpretation of synthetic cathinones in biological matrices, as dosing information is typically unknown. Furthermore, antemortem and postmortem concentrations often overlap and the presence of other psychoactive substances are typically found in combination

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

    PubMed Central

    Kasai, Kazue; Nakashima, Hiroshi; Liu, Fang; Kerr, Samantha; Wang, Jiang; Phelps, Mitch; Potter, Philip M; Goins, William B; Fernandez, Soledad A; Chiocca, E Antonio

    2013-01-01

    MGH2.1 is a herpes simplex virus type 1 (HSV1) oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA)-activating cytochrome P4502B1 (CYP2B1) and the CPT11-activating secreted human intestinal carboxylesterase (shiCE). Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 ± prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p.) administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 108 pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 108 pfus in the absence of prodrugs and at 106 pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas. PMID:23922029

  2. From quantal counts to mechanisms and systems: the past, present, and future of biometrics in environmental toxicology.

    PubMed

    Bailer, A J; Piegorsch, W W

    2000-06-01

    As appreciation for human impact on the environment has developed, so have the experimental systems and associated statistical tools that quantify this impact. Toxicological study in particular has grown in its complexity and its need for advanced statistical support. Within this perspective, we describe statistical practice in environmental toxicology and risk assessment. We present two case studies, one from mammalian toxicology and one from aquatic toxicology, that highlight the evolution of statistical practice in environmental toxicology.

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

    SciTech Connect

    Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Lahoutte, Tony

    2012-10-15

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

  4. Preclinical Molecular Imaging of Tumor Angiogenesis

    PubMed Central

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

    2010-01-01

    Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging technologies accelerate the translation of preclinical research to the clinic. In oncology, various imaging modalities are widely applied to drug development, tumor early detection and therapy response monitoring. So far, several angiogenesis related imaging agents are promising in cancer diagnosis. However, more effective imaging agents with less side-effect still need to be pursued to visualize angiogenesis process non-invasively. The main purpose of this review is to summarize the recent progresses in preclinical molecular imaging of angiogenesis and to discuss the potential of the current preclinical probes specific to various angiogenesis targets including vascular endothelial growth factor and its receptors (VEGF/VEGFRs), integrin αvβ3 and matrix metalloproteinases (MMPs). It is predicable that related investigations in the field will benefit cancer research and quicken the anti-angiogenic drug development. PMID:20639815

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

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

    SciTech Connect

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

    2014-05-15

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

  7. Emerging Approaches in Predictive Toxicology

    PubMed Central

    Zhang, Luoping; McHale, Cliona M.; Greene, Nigel; Snyder, Ronald D.; Rich, Ivan N.; Aardema, Marilyn J.; Roy, Shambhu; Pfuhler, Stefan; Venkatactahalam, Sundaresan

    2016-01-01

    Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. PMID:25044351

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

    PubMed

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

    2015-07-01

    Benznidazole (BNZ) and nifurtimox are the only drugs available for treating Chagas disease. In this work, we validated a bioanalytical method for the quantification of BNZ in plasma aimed at improving sensitivity and time of analysis compared with the assays already published. Furthermore, we demonstrated the application of the method in a preclinical pharmacokinetic study after administration of a single oral dose of BNZ in Wistar rats. A Waters® Acquity UHPLC system equipped with a UV-vis detector was employed. The method was established using an Acquity® UHPLC HSS SB C18 protected by an Acquity® UHPLC HSS SB C18 VanGuard guard column and detection at 324 nm. The mobile phase consisted of ultrapure water-acetonitrile (65:35), and elution was isocratic. The mobile phase flow rate was 0.55 mL/min, the volume of injection was 1 μL, 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.

  9. Review, discussion, and summary: toxicology.

    PubMed

    Graham, J A

    1989-02-01

    The research presented in the toxicology session of the Symposium on the Health Effects of Acid Aerosols significantly advances our understanding of the health effects of acid aerosols and clearly illustrates the importance of animal inhalation toxicology to risk assessment. The description of the effects of acid on airway mucus buffering capacity and viscosity helps explain some of the mechanisms responsible for the effects of sulfuric acid on mucociliary clearance and pulmonary function observed in man and animals. Several of the papers illustrate that other pollutants interact with sulfuric acid (H2SO4), causing concern about exposure risks and helping in elucidating the effects observed in epidemiology studies that have not yet been duplicated in a laboratory. For example, H2SO4 absorbed in zinc oxide (ZnO) particles appears to be about a log more potent than H2SO4 alone in causing pulmonary function decrements. Low levels of H2SO4 and O3 were found to be synergistic in increasing collagen synthesis, implying a risk in development of lung fibrosis. More complex mixtures containing H2SO4 cause a variety of interactions, depending upon the end points examined and the chemistry of the mixture. Other reports indicate that dose rate and length of exposure issues are critical to toxicological outcomes. Animal data on mucociliary clearance, which parallels that of human data, was extended to show that concentration of exposure was more important than time of exposure in eliciting a response, although time played a significant role. A recent chronic study showed that H2SO4 caused effects that also can occur in the development of chronic bronchitis.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Nanosilver: application and novel aspects of toxicology.

    PubMed

    Schluesener, Jan K; Schluesener, Hermann J

    2013-04-01

    Nanomaterials are a challenge to toxicology. The high diversity of novel materials and products will require extensive expertize for evaluation and regulatory efforts. Nanomaterials are of substantial scientific and economic potential. Here, we will focus on nanosilver, a material not only with medical applications, but a rapidly increasing use in surprisingly many products. Consequently, toxicological evaluation has to cover an increasing range of complex topics. The toxicology of nanosilver is advancing rapidly; regulatory efforts by Federal Drug Agency and European Environment Protection Agencies are substantial. Current toxicological data, ranging from in vitro studies with cell lines to rodent experiments and ecological evaluation, are numerous, and many groups are providing continuously new data. However, standard classification based on nanosize only is neglecting nanoshape, which adds another level of complexity to the analysis of biological effects. A surprising neglect in nanosilver toxicology so far is the analysis of effects of nanosilver on amyloidosis. Amyloid diseases are widespread in humans and a severe health hazard. The known potential of silver to stimulate amyloidosis in rodents will require a timely and balanced evaluation of nanosilvers.

  11. Toxicologic methods: controlled human exposures.

    PubMed Central

    Utell, M J; Frampton, M W

    2000-01-01

    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

  12. 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...

  13. Chemical and mechanistic toxicology evaluation of exon skipping phosphorodiamidate morpholino oligomers in mdx mice.

    PubMed

    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane; Nelson, Keith; Shrewsbury, And Stephen B

    2011-05-01

    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) designed to induce skipping of dystrophin exon 51 and restore its expression in patients with Duchenne muscular dystrophy (DMD). Preclinically, restoration of dystrophin in the dystrophic mdx mouse model requires skipping of exon 23, achieved with the mouse-specific PMO, AVI-4225. Herein, we report the potential toxicological consequences of exon skipping and dystrophin restoration in mdx mice using AVI-4225. We also evaluated the toxicological effects of AVI-4658 in both mdx and wild-type mice. In both studies, animals were dosed once weekly for 12 weeks up to the maximum feasible dose of 960 mg/kg per injection. Both AVI-4658 and AVI-4225 were well-tolerated at all doses. Findings in AVI-4225-treated animals were generally limited to mild renal tubular basophilia/vacuolation, without any significant changes in renal function and with evidence of reversing. No toxicity associated with the mechanism of action of AVI-4225 in a dystrophic animal was observed.

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

    PubMed Central

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

    2013-01-01

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

  15. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model.

    PubMed

    Nassar, Inthisham; Pasupati, Thanikachalam; Judson, John Paul; Segarra, Ignacio

    2010-06-01

    Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

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

    NASA Astrophysics Data System (ADS)

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

    2014-08-01

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

  17. Uruguay eHealth initiative: preliminary studies regarding an integrated approach to evaluate vascular age and preclinical atherosclerosis (CUiiDARTE project).

    PubMed

    Armentano, Ricardo L; Bia, Daniel; Zócalo, Yanina; Torrado, Juan; Farro, Ignacio; Farro, Federico; Florio, Lucía; Olascoaga, Alicia; Alallon, Walter; Negreira, Carlos; Lluberas, Ricardo

    2011-01-01

    In this work we present an initiative to develop a national (Uruguayan) program to evaluate vascular age and to detect pre-clinical atherosclerosis using: gold-standard technologies; complimentary and integrative approaches to asses arterial functional and structural indexes; data bases systems to process, analyze and determine normal and reference values and to identify the most sensitive markers of vascular changes for different ages. We evaluated, in a Uruguayan population complementary structural and functional vascular parameters that associate aging-related changes and are considered markers of sub-clinical atherosclerosis. Traditional CV risk factors were assessed. The subjects (n=281) were submitted to non-invasive vascular studies to evaluate: 1) Common carotid artery (CCA) intima-media thickness and diameter waveforms, 2) CCA stiffness, 3) aortic stiffness (pulse wave velocity) and 4) peripheral and central pressure pulse wave derived parameters. Age groups: 21-30, 31-40, 41-50, 51-60, and 61-70 years-old. Age-related profiles were obtained for the different vascular parameters, and their utility to assess vascular changes in young, middle-aged and old subjects was evaluated. The work has the strength of being the first that uses, in Latin-America an integrative approach to characterize vascular aging-related changes.

  18. In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice.

    PubMed

    Duret, Christophe; Wauthoz, Nathalie; Merlos, Romain; Goole, Jonathan; Maris, Calliope; Roland, Isabelle; Sebti, Thami; Vanderbist, Francis; Amighi, Karim

    2012-08-01

    The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ∼1 mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation. PMID:22538097

  19. Universal Hand-held Three-dimensional Optoacoustic Imaging Probe for Deep Tissue Human Angiography and Functional Preclinical Studies in Real Time

    PubMed Central

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

    2014-01-01

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

  20. NTP Toxicology and Carcinogenesis Studies of Benzaldehyde (CAS No. 100-52-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1990-03-01

    Benzaldehyde is an aromatic aldehyde used in the food, beverage, pharmaceutical, perfume, soap, and dyestuff industries. NTP Toxicology and Carcinogenesis studies were conducted by administering benzaldehyde (99% pure) in corn oil 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, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Sixteen-Day Studies: All rats that received 1,600 mg/kg died by day 2, and 2/5 males and 2/5 females that received 800 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of the 800 mg/kg groups, in which males were 14% lighter and females were 11% lighter than vehicle controls. All mice that received 1,600 or 3,200 mg/kg died by day 3. Final mean body weights of dosed and vehicle control mice were similar. No gross lesions attributable to benzaldehyde were detected upon necropsy. Thirteen-Week Studies: Six of 10 male rats and 3/10 female rats that received 800 mg/kg and 1/10 female rats that received 400 mg/kg died near the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of male rats receiving 800 mg/kg, which were 26% lighter than vehicle controls. Compound-related lesions seen in rats receiving 800 mg/kg, but not in those receiving 400 mg/kg, included degeneration and necrosis in the cerebellum, necrosis in the hippocampus, hyperplasia and/or hyperkeratosis in the forestomach, and degeneration or necrosis of the liver and of the tubular epithelium in the kidney. Nine of 10 male mice and 1/10 female mice that received 1,200 mg/kg benzaldehyde died by the end of the first week. Compound-related renal tubule degeneration and/or necrosis and reduction in final body weight were observed in the 600 mg/kg group of male mice. No reductions in body weight

  1. Veterinary Forensic Toxicology.

    PubMed

    Gwaltney-Brant, S M

    2016-09-01

    Veterinary pathologists working in diagnostic laboratories are sometimes presented with cases involving animal poisonings that become the object of criminal or civil litigation. Forensic veterinary toxicology cases can include cases involving animal cruelty (malicious poisoning), regulatory issues (eg, contamination of the food supply), insurance litigation, or poisoning of wildlife. An understanding of the appropriate approach to these types of cases, including proper sample collection, handling, and transport, is essential so that chain of custody rules are followed and proper samples are obtained for toxicological analysis. Consultation with veterinary toxicologists at the diagnostic laboratory that will be processing the samples before, during, and after the forensic necropsy can help to ensure that the analytical tests performed are appropriate for the circumstances and findings surrounding the individual case. PMID:27090769

  2. 20 years of toxicology.

    PubMed Central

    Fisher, B E

    1998-01-01

    With over 80,000 chemicals being used in commerce worldwide, it is important to identify the human health effects of these chemicals and the levels of exposure at which they are harmful to humans. In order to address this need, the National Toxicology Program (NTP) was established in 1978; since then, the NTP has become the world's leader in designing, conducting, and interpreting various types of toxicity assays. PMID:9755149

  3. Toxicology - A primer on toxicology principles and applications

    SciTech Connect

    Kamrin, M.A.

    1988-01-01

    As the use of synthetic chemicals increased dramatically after World War II, concern about the possible adverse health and environmental effects of such use grew. The book opens with a discussion of the general principles of toxicology and how these general principles are applied in assessing the acute, subacute and chronic effects of chemicals. Both qualitative and quantitative measures of toxicity are addressed and the protocols for the various tests are described. Emphasis is placed on both the strengths and limitations of the techniques which are in current use. This is then followed by a discussion of risk assessment and risk management. Risk assessment deals with both the toxic potential of a chemical and the exposure likely to occur in specific situations. Risk management includes the steps taken to reduce or eliminate risks identified in the assessment process. The components of risk assessment are described in relation to a variety of possible toxic effects and exposure scenarios. The last part of the book provides a description and analysis of four case studies, each dealing with a different substance. These include the food additives, cyclamate and saccharin; asbestos; formaldehyde; and benzene. The basic toxicological information regarding each, and the different regulations to which they have been subject, provide the basis for exploring how the principles introduced in the first part of the book are applied in practice.

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

    SciTech Connect

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

    1989-07-15

    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.

  5. Preclinical safety evaluation of low molecular weight heparin-deoxycholate conjugates as an oral anticoagulant.

    PubMed

    Kim, Ji-young; Jeon, Ok-Cheol; Moon, Hyun Tae; Hwang, Seung Rim; Byun, Youngro

    2016-01-01

    The preclinical safety of a newly developed oral anticoagulant, the low molecular weight heparin-deoxycholate conjugate (OH09208), was evaluated by a comprehensive evaluating program in compliance with standard guidelines. The single dose oral toxicity study in rats receiving 2000 and 5000 mg kg(-1) of OH09208 did not reveal any mortality, unusual body weight changes or necropsy findings. The results of the 4-week oral toxicity study with a 4-week recovery program in rats receiving OH09208 in doses of 100, 300 and 1000 mg kg(-1) day(-1) did not reveal any mortality, or indicate any unusual clinical signs, or show any toxicokinetic relationships to the administration of OH09208. Although the increase in liver enzymes in one male dog treated with 300 mg kg(-1) day(-1) and one female dog treated with 1000 mg kg(-1) day(-1) could not be excluded from the effect of the test substance, no other toxicologically significant changes were observed in the 4-week oral toxicity study with a 4-week recovery in beagle dogs. Thus, while the no-observed-adverse-effect level value from the 4-week study in both male and female rats was 1000 mg kg(-1) day(-1), those from the 4-week study in male and female beagle dogs were 300 and 1000 mg kg(-1) day(-1), respectively. Furthermore, OH09208 did not induce anaphylactic reactions in guinea pigs, micronucleated bone marrow cells in male ICR mice, chromosomal aberration in Chinese hamster lung cell lines, bacterial reverse mutation, and any abnormalities in hERG current assay, mouse central nervous system and dog cardiovascular studies. Overall, there were no unexpected toxicities in this preclinical study that might have precluded the safe administration of OH09208 to humans.

  6. A 90-day toxicology study of high-amylose transgenic rice grain in Sprague-Dawley rats.

    PubMed

    Zhou, Xing Hua; Dong, Ying; Xiao, Xiang; Wang, Yun; Xu, Yong; Xu, Bin; Shi, Wei Dong; Zhang, Yi; Zhu, Li Jia; Liu, Qiao Quan

    2011-12-01

    A transgenic rice line (TRS) with high amylose level has been developed by antisense RNA inhibition of starch branching enzymes. Compositional analysis of TRS demonstrated that the content of resistant starch (RS) was significantly higher compared to conventional non-transgenic rice. High level of RS is an important raw material in food industry and has various physiological effects for human health. In order to provide the reliable theory basis for field release of TRS rice, we evaluated the potential health effects of long-term consumption of the TRS. The 90-day toxicology feeding experiment was conducted in Sprague-Dawley rats fed with diets containing 70% of either TRS rice flour, its near-isogenic rice flour or the control diet. The clinical performance variables (body weight, body weight gain and food consumption) were measured and pathological responses (hematological parameters and serum chemistry at the midterm and the completion of the experiment, urinalysis profile and serum sex hormone response at the completion of the experiment) were performed. Besides, clinical signs, relative organ weights and microscopic observations were also compared between TRS group and its near-isogenic rice group. The combined data indicates that high-amylose TRS grain is as safe as the conventional non-transgenic rice for rat consumption.

  7. A 90-day toxicology study of transgenic lysine-rich maize grain (Y642) in Sprague-Dawley rats.

    PubMed

    He, Xiao Yun; Tang, Mao Zhi; Luo, Yun Bo; Li, Xin; Cao, Si Shuo; Yu, Jing Juan; Delaney, Bryan; Huang, Kun Lun

    2009-02-01

    The gene for a lysine-rich protein (sb401) obtained from potatoes (Solanum berthaultii) was inserted into maize seed to produce Y642 transgenic maize. Compositional analysis of Y642 grain demonstrated that the concentrations of lysine and total protein were higher than those observed in maize grain from a near-isogenic non-genetically modified (non-GM) commercially available control quality protein maize (Nongda 108). The safety of Y642 maize grain was assessed by comparison of toxicology response variables in Sprague-Dawley (SD) rats consuming diets containing Y642 maize grain with those containing Nongda 108 maize grain. Maize grains from Y642 or Nongda 108 were incorporated into rodent diets at low (30%) or high concentrations (76%) and administered to SD rats (n=10/sex/group) for 90 days. An additional group of negative control group of rats (n=10/sex/group) were fed AIN93G diets. No adverse diet-related differences in body weights, feed consumption/utilization, clinical chemistry, hematology, absolute and relative organ weights were observed. Further, no differences in gross or microscopic pathology were observed between rats consuming diets with Y642 maize grain compared with rats consuming diets containing Nongda 108 maize grain. These results demonstrated that Y642 lysine-rich maize is as safe and nutritious as conventional quality protein maize.

  8. Studies of the toxicological potential of capsinoids: VIII. A 13-week toxicity study of commercial-grade dihydrocapsiate in rats.

    PubMed

    Watanabe, Eri; Kodama, Terutaka; Masuyama, Takeshi; Tsubuku, Shoji; Otabe, Akira; Mochizuki, Masahiro; Bernard, Bruce K

    2008-01-01

    Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnona- noate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses < or = 300 mg/kg or in females at any of the doses tested (< or = 1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study. PMID:19037802

  9. Effects of intratracheally instilled laser printer-emitted engineered nanoparticles in a mouse model: A case study of toxicological implications from nanomaterials released during consumer use

    PubMed Central

    Pirela, Sandra V.; Lu, Xiaoyan; Miousse, Isabelle; Sisler, Jennifer D.; Qian, Yong; Guo, Nancy; Koturbash, Igor; Castranova, Vincent; Thomas, Treye; Godleski, John; Demokritou, Philip

    2016-01-01

    Incorporation of engineered nanomaterials (ENMs) into toners used in laser printers has led to countless quality and performance improvements. However, the release of ENMs during printing (consumer use) has raised concerns about their potential adverse health effects. The aim of this study was to use “real world” printer-emitted particles (PEPs), rather than raw toner powder, and assess the pulmonary responses following exposure by intratracheal instillation. Nine-week old male Balb/c mice were exposed to various doses of PEPs (0.5, 2.5 and 5 mg/kg body weight) by intratracheal instillation. These exposure doses are comparable to real world human inhalation exposures ranging from 13.7 to 141.9 h of printing. Toxicological parameters reflecting distinct mechanisms of action were evaluated, including lung membrane integrity, inflammation and regulation of DNA methylation patterns. Results from this in vivo toxicological analysis showed that while intratracheal instillation of PEPs caused no changes in the lung membrane integrity, there was a pulmonary immune response, indicated by an elevation in neutrophil and macrophage percentage over the vehicle control and low dose PEPs groups. Additionally, exposure to PEPs upregulated expression of the Ccl5 (Rantes), Nos1 and Ucp2 genes in the murine lung tissue and modified components of the DNA methylation machinery (Dnmt3a) and expression of transposable element (TE) LINE-1 compared to the control group. These genes are involved in both the repair process from oxidative damage and the initiation of immune responses to foreign pathogens. The results are in agreement with findings from previous in vitro cellular studies and suggest that PEPs may cause immune responses in addition to modifications in gene expression in the murine lung at doses that can be comparable to real world exposure scenarios, thereby raising concerns of deleterious health effects. PMID:26989787

  10. Toxicological Benchmarks for Wildlife

    SciTech Connect

    Sample, B.E. Opresko, D.M. Suter, G.W.

    1993-01-01

    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, food, etc.). While exceedance of these benchmarks does not indicate any particular level or type of risk, concentrations below the benchmarks should not result in significant effects. In practice, when contaminant concentrations in food or water resources are less than these toxicological benchmarks, the contaminants may be excluded from further consideration. However, if the concentration of a contaminant exceeds a benchmark, that contaminant should be retained as a contaminant of potential concern (COPC) and investigated further. The second tier in ecological risk assessment, the baseline ecological risk assessment, may use toxicological benchmarks as part of a weight-of-evidence approach (Suter 1993). Under this approach, based toxicological benchmarks are one of several lines of evidence used to support or refute the presence of ecological effects. Other sources of evidence include media toxicity tests, surveys of biota (abundance and diversity), measures of contaminant body burdens, and biomarkers. This report presents NOAEL- and lowest observed adverse effects level (LOAEL)-based toxicological benchmarks for assessment of effects of 85 chemicals on 9 representative mammalian wildlife species (short-tailed shrew, little brown bat, meadow vole, white-footed mouse, cottontail rabbit, mink, red fox, and whitetail deer) or 11 avian wildlife species (American robin, rough-winged swallow, American woodcock, wild turkey, belted kingfisher, great blue heron, barred owl, barn owl, Cooper's hawk, and red-tailed hawk

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

    SciTech Connect

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

    1988-08-01

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

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

    PubMed

    Mishra, Awanish; Goel, Rajesh Kumar

    2014-12-01

    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.

  13. Mouse models for studies of HLA-G functions in basic science and pre-clinical research.

    PubMed

    Nguyen-Lefebvre, Anh Thu; Ajith, Ashwin; Portik-Dobos, Vera; Horuzsko, Daniel D; Mulloy, Laura L; Horuzsko, Anatolij

    2016-09-01

    HLA-G was described originally as a tolerogenic molecule that allows the semiallogeneic fetus to escape from recognition by the maternal immune response. This review will discuss different steps in the study of HLA-G expression and functions in vivo, starting with analyses of expression of the HLA-G gene and its receptors in transgenic mice, and continuing with applications of HLA-G and its receptors in prevention of allograft rejection, transplantation tolerance, and controlling the development of infection. Humanized mouse models have been discussed for developing in vivo studies of HLA-G in physiological and pathological conditions. Collectively, animal models provide an opportunity to evaluate the importance of the interaction between HLA-G and its receptors in terms of its ability to regulate immune responses during maternal-fetal tolerance, survival of allografts, tumor-escape mechanisms, and development of infections when both HLA-G and its receptors are expressed. In addition, in vivo studies on HLA-G also offer novel approaches to achieve a reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.

  14. Quantile Regression with a Change-point Model for Longitudinal Data: An Application to the Study of Cognitive Changes in Preclinical Alzheimer’s Disease

    PubMed Central

    Li, Chenxi; Dowling, N. Maritza; Chappell, Rick

    2015-01-01

    Summary Progressive and insidious cognitive decline that interferes with daily life is the defining characteristic of Alzheimer’s disease (AD). Epidemiological studies have found that the pathological process of AD begins years before a clinical diagnosis is made and can be highly variable within a given population. Characterizing cognitive decline in the preclinical phase of AD is critical for the development of early intervention strategies when disease-modifying therapies may be most effective. In the last decade, there has been an increased interest in the application of change-point models to longitudinal cognitive outcomes prior to and after diagnosis. Most of the proposed statistical methodology for describing decline relies upon distributional assumptions that may not hold. In this paper, we introduce a quantile regression with a change-point model for longitudinal data of cognitive function in persons bound to develop AD. A change-point in our model reflects the transition from the cognitive decline due to normal aging to the accelerated decline due to disease progression. Quantile regression avoids common distributional assumptions on cognitive outcomes and allows the covariate effects and the change-point to vary for different quantiles of the response. We provided an approach for estimating the model parameters, including the change-point, and presented inferential procedures based on the asymptotic properties of the estimators. A simulation study showed that the estimation and inferential procedures perform reasonably well in finite samples. The practical use of our model was illustrated by an application to longitudinal episodic memory outcomes from two cohort studies of aging and AD. PMID:25892034

  15. Generation, characterization and preclinical studies of a human anti-L1CAM monoclonal antibody that cross-reacts with rodent L1CAM.

    PubMed

    Cho, Seulki; Park, Insoo; Kim, Haejung; Jeong, Mun Sik; Lim, Mooney; Lee, Eung Suk; Kim, Jin Hong; Kim, Semi; Hong, Hyo Jeong

    2016-01-01

    L1 cell adhesion molecule (L1CAM) is aberrantly expressed in malignant tumors and plays important roles in tumor progression. Thus, L1CAM could serve as a therapeutic target and anti-L1CAM antibodies may have potential as anticancer agents. However, L1CAM is expressed in neural cells and the druggability of anti-L1AM antibody must be validated at the earliest stages of preclinical study. Here, we generated a human monoclonal antibody that is cross-reactive with mouse L1CAM and evaluated its pharmacokinetic properties and anti-tumor efficacy in rodent models. First, we selected an antibody (Ab4) that binds human and mouse L1CAM from the human naïve Fab library using phage display, then increased its affinity 45-fold through mutation of 3 residues in the complementarity-determining regions (CDRs) to generate Ab4M. Next, the affinity of Ab4M was increased 1.8-fold by yeast display of single-chain variable fragment containing randomly mutated light chain CDR3 to generate Ab417. The affinities (KD) of Ab417 for human and mouse L1CAM were 0.24 nM and 79.16 pM, respectively. Ab417 specifically bound the Ig5 domain of L1CAM and did not exhibit off-target activity, but bound to the peripheral nerves embedded in normal human tissues as expected in immunohistochemical analysis. In a pharmacokinetics study, the mean half-life of Ab417 was 114.49 h when a single dose (10 mg/kg) was intravenously in