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1.
Toxicol Pathol ; 44(7): 931-46, 2016 10.
Article in English | MEDLINE | ID: mdl-27663844

ABSTRACT

The toxicological profile of insulins is exclusively due to exaggerated pharmacology resulting in hypoglycemic findings. Insulin analogues displaying modifications and aimed at improving pharmacokinetics do not induce different toxicity. The main target is the brain displaying neuronal necrosis. Wallerian degeneration of nerves occurs rarely after severe hypoglycemia. These findings are of potential human relevance; nevertheless, these changes are induced in normoglycemic animals whereas diabetic patients suffer from hyperglycemia. Therefore, it is usually not difficult to achieve a therapeutic window for subsequent use in patients. Based upon this and in the absence of classical toxicity, there has been no scientific need for diabetic animal models. A greater challenge is the mitogenicity already inherent with regular insulin. Thus, the focus for preclinical safety evaluation of analogues is to demonstrate that modifications in regular insulin do not result in enhanced mitogenicity. The approaches used to assess the mitogenic potential of insulin analogues have changed over time driven by scientific progression and changes within the regulatory environment. Therefore, in vitro and in vivo evaluation of cell proliferation has become common practice, and to date there has been no evidence that the mitogenic potential of insulin analogues may be increased compared to regular insulin.


Subject(s)
Hypoglycemic Agents/toxicity , Insulins/toxicity , Toxicity Tests , Animals , Humans
2.
Toxicology ; 308: 50-9, 2013 Jun 07.
Article in English | MEDLINE | ID: mdl-23567313

ABSTRACT

Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine.


Subject(s)
Chloroquine/toxicity , Neurons/metabolism , Phospholipids/metabolism , Retina/metabolism , Synaptic Vesicles/metabolism , Animals , Biological Transport/drug effects , Biological Transport/physiology , Electroretinography/methods , Male , Neurons/drug effects , Neurons/pathology , Rats , Rats, Inbred BN , Rats, Sprague-Dawley , Retina/drug effects , Retina/pathology , Species Specificity , Synaptic Vesicles/drug effects , Synaptic Vesicles/pathology
3.
Toxicol Sci ; 103(1): 28-34, 2008 May.
Article in English | MEDLINE | ID: mdl-18281259

ABSTRACT

The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and the U.S. Food and Drug Administration, aimed at evaluating and qualifying biomarkers for a variety of toxicological endpoints. The Carcinogenicity Working Group of the Predictive Safety Testing Consortium has concentrated on sharing data to test the predictivity of two published hepatic gene expression signatures, including the signature by Fielden et al. (2007, Toxicol. Sci. 99, 90-100) for predicting nongenotoxic hepatocarcinogens, and the signature by Nie et al. (2006, Mol. Carcinog. 45, 914-933) for predicting nongenotoxic carcinogens. Although not a rigorous prospective validation exercise, the consortium approach created an opportunity to perform a meta-analysis to evaluate microarray data from short-term rat studies on over 150 compounds. Despite significant differences in study designs and microarray platforms between laboratories, the signatures proved to be relatively robust and more accurate than expected by chance. The accuracy of the Fielden et al. signature was between 63 and 69%, whereas the accuracy of the Nie et al. signature was between 55 and 64%. As expected, the predictivity was reduced relative to internal validation estimates reported under identical test conditions. Although the signatures were not deemed suitable for use in regulatory decision making, they were deemed worthwhile in the early assessment of drugs to aid decision making in drug development. These results have prompted additional efforts to rederive and evaluate a QPCR-based signature using these samples. When combined with a standardized test procedure and prospective interlaboratory validation, the accuracy and potential utility in preclinical applications can be ascertained.


Subject(s)
Carcinogenicity Tests/methods , Genomics , Animals , Gene Expression Profiling , Male , Rats , Rats, Sprague-Dawley
4.
Expert Rev Clin Pharmacol ; 1(6): 759-71, 2008 Nov.
Article in English | MEDLINE | ID: mdl-24410606

ABSTRACT

The screening of drug candidates to assess their carcinogenic potential has long been a challenge for drug development. While genotoxic compounds can be readily detected with a battery of standard tests, including short-term in vitro and in vivo assays, predicting nongenotoxic carcinogenicity remains a major challenge. The 2-year rodent bioassay has been held as the gold standard for the assessment of carcinogenic risk to humans. However, due primarily to the continuing doubt over their relevance to human risk assessment, there has been an increased demand for more efficient and accurate approaches to predict and understand human relevant risk of carcinogenicity. Novel biomarkers have helped to shed light on our understanding of the factors that lead to and are characteristic of the carcinogenic phenotypes. Tissue biomarkers of carcinogenicity identified to be concordant with drug exposures resulting in tumor outcome may assist the drug development process by resolving ambiguities, shortening timelines and enabling earlier decisions on compounds. This information could vastly improve the efficiency with which nongenotoxic carcinogens are identified and ensure earlier insight into the relevance for humans.

5.
Toxicol Pathol ; 35(5): 742-50, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17849357

ABSTRACT

The Society of Toxicologic Pathology convened a working group to evaluate current practices regarding organ weights in toxicology studies. A survey was distributed to pharmaceutical, veterinary, chemical, food/nutritional and consumer product companies in Europe, North America, and Japan. Responses were compiled to identify organs routinely weighed for various study types in rodent and non-rodent species, compare methods of organ weighing, provide perspectives on the value of organ weights and identify the scientist(s) responsible for organ weight data interpretation. Data were evaluated as a whole as well as by industry type and geographic location. Regulatory guidance documents describing organ weighing practices are generally available, however, they differ somewhat dependent on industry type and regulatory agency. While questionnaire respondents unanimously stated that organ weights were a good screening tool to identify treatment-related effects, opinions varied as to which organ weights are most valuable. The liver, kidneys, and testes were commonly weighed and most often considered useful by most respondents. Other organs that break were commonly weighed included brain, adrenal glands, ovaries, thyroid glands, uterus, heart, and spleen. Lungs, lymph nodes, and other sex organs were weighed infrequently in routine studies, but were often weighed in specialized studies such as inhalation, immunotoxicity, and reproduction studies. Organ-to-body weight ratios were commonly calculated and were considered more useful when body weights were affected. Organ to brain weight ratios were calculated by most North American companies, but rarely according to respondents representing veterinary product or European companies. Statistical analyses were generally performed by most respondents. Pathologists performed interpretation of organ weight data for the majority of the industries.


Subject(s)
Organ Size/drug effects , Toxicity Tests/methods , Animals , Body Weight/drug effects , Guidelines as Topic , Mice , Rats
6.
Toxicol Pathol ; 35(5): 751-5, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17849358

ABSTRACT

The evaluation of organ weights in toxicology studies is an integral component in the assessment of pharmaceuticals, chemicals, and medical devices. The Society of Toxicologic Pathology (STP) has created recommendations for weighing organs in GLP general toxicology studies lasting from 7 days to 1 year. The STP recommends that liver, heart, kidneys, brain, testes, and adrenal glands be weighed in all multidose general toxicology studies. Thyroid gland and pituitary gland weights are recommended for all species except mice. Spleen and thymus should be weighed in rodent studies and may be weighed in non-rodent studies. Weighing of reproductive organs is most valuable in sexually mature animals. Variability in age, sexual maturity, and stage of cycle in non-rodents and reproductive senescence in female rodents may complicate or limit interpretation of reproductive organ weights. The STP recommends that testes of all species be weighed in multidose general toxicology studies. Epididymides and prostate should be weighed in rat studies and may be weighed on a case-by-case basis in non-rodent and mouse studies. Weighing of other organs including female reproductive organs should be considered on a case-by-case basis. Organ weights are not recommended for any carcinogenicity studies including the alternative mouse bioassays. Regardless of the study type or organs evaluated, organ weight changes must be evaluated within the context of the compound class, mechanism of action, and the entire data set for that study.


Subject(s)
Organ Size/drug effects , Toxicity Tests/methods , Animals , Body Weight/drug effects
8.
Toxicol Pathol ; 32(2): 202-11, 2004.
Article in English | MEDLINE | ID: mdl-15200158

ABSTRACT

The topical administration of 7H-dibenzo[c,g]carbazole (7H-DBC) at very low but repeated doses causes genotoxic effects such as DNA adduct formation and produces hepatocellular apoptosis in mouse liver. The purpose of this work was to investigate the alterations in gene expression and protein levels of biomarkers associated with the p53 pathway in mouse liver after exposure to cumulative low doses of 7H-DBC by skin paint applications. The compound was administered topically at the dose of 13.35 microg per animal every 2 days to give either 6, 8, 10, or 12 applications. Animals were sacrificed 48 hours after the different treatments. The apoptotic index increased with the number of applications, with a major proportion of apoptotic cells in the periportal areas. A significant increase of Bax mRNA and protein expression was observed after the 8th application whereas the expression of mRNA levels of Fas and p53 did not show significant differences between treated and control animals. Nuclear staining of p53 was detected in hepatocyte nuclei showing the activation of this protein. Later in the apoptosis process we observed the up-regulation of TGF-beta1 in parenchymal cells. In addition to the induction of the p53 apoptosis pathway in vivo by 7H-DBC, we have observed molecular changes related to cell proliferation such as the overexpression of the antiapoptotic gene Bcl-2.


Subject(s)
Apoptosis/drug effects , Carbazoles/toxicity , Carcinogens/toxicity , Gene Expression Regulation, Neoplastic , Liver/drug effects , Proto-Oncogene Proteins c-bcl-2 , Administration, Topical , Animals , Apoptosis/genetics , Carbazoles/administration & dosage , Carcinogens/administration & dosage , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Nucleus/pathology , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , In Situ Nick-End Labeling , Liver/metabolism , Liver/pathology , Mice , Mice, Inbred DBA , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1 , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Up-Regulation , bcl-2-Associated X Protein
9.
J Pharmacol Exp Ther ; 309(1): 235-40, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14718579

ABSTRACT

SanOrg123781A is a synthetic hexadecasaccharide that displays antithrombin-dependent inhibition of factor Xa and thrombin and potent antithrombotic effects. The antithrombotic activity of SanOrg123781A has been studied in a new mouse model of arterial thrombosis, where thrombus formation was induced by the application of an electrical current to the adventitial surface of a carotid artery. In this model, antiplatelet agents such as the ADP-receptor antagonist clopidogrel (30 mg/kg, p.o. 2 h before stimulation) and the GpIIb/IIIa antagonist SR121566A [3-(N-[4-(4-[amino(imino)methyl]phenyl)-1,3-thiazol-2-yl]-N-[1-(carboxymethyl)piperidin-4-yl]amino)propionic acid, trihydrochloride] (0.3 mg/kg, i.v. 5 min before stimulation) strongly prolonged the time to occlusion (TTO) (761 and 473% increases, respectively), whereas aspirin was devoid of antithrombotic activity. Standard heparin (2 mg/kg, i.v.), the low molecular weight heparin enoxaparin (20 mg/kg, i.v.), and the synthetic, antithrombin-dependent inhibitor of factor Xa fondaparinux (10 mg/kg, i.v.) were also active in this model (742, 707, and 602% TTO increases, respectively). Interestingly, SanOrg123781A was active at much lower doses than the other oligosaccharides (554% increase in TTO at 0.3 mg/kg, i.v. 5 min before stimulation). Low doses of SanOrg123781A administered in combination with low doses of clopidogrel led to a marked increase in TTO, which was statistically more important than the additive effects of the two compounds given alone. These results indicate that SanOrg123781A exerts a potent antithrombotic activity in a mouse model of arterial thrombosis when compared with reference compounds and show that the combination of SanOrg123781A with clopidogrel leads to a marked synergistic antithrombotic effect.


Subject(s)
Carotid Artery Injuries/drug therapy , Carotid Artery Thrombosis/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Polysaccharides/therapeutic use , Ticlopidine/analogs & derivatives , Ticlopidine/therapeutic use , Animals , Clopidogrel , Drug Synergism , Electric Injuries , Male , Mice , Mice, Inbred BALB C , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Polysaccharides/pharmacology , Thrombosis/metabolism , Ticlopidine/pharmacology
10.
Altern Lab Anim ; 32 Suppl 1A: 113-6, 2004 Jun.
Article in English | MEDLINE | ID: mdl-23577442

ABSTRACT

Early toxicity screening of new drugs is performed to select candidates for development. Many cell models are used to assess basic cytotoxicity and to show a good correlation with acute toxicity. However, their correlation with chronic in vivo exposure is inadequate. The new hepatoma cell line (HBG BC2) possesses the capacities of being reversibly differentiated in vitro, and of maintaining a relatively higher metabolic rate when in the differentiated phase (3 weeks) as compared to Hep G2 cells. MTT reduction was used to evaluate the toxicity of propranolol, perhexiline, aspirin and paracetamol, after both single and repeated treatments (three times a week for 2 weeks). Under conditions of repeated treatment, cytotoxicity was observed at lower doses when compared with single administration. Moreover, the first non-toxic doses were in the same range as plasma concentrations measured in humans during therapeutic use. Our results suggest that the new human hepatoma HBG BC2 cell line may be of interest for the evaluation of cell toxicity under repeated treatment conditions.


Subject(s)
Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Toxicity Tests , Base Sequence , Biotransformation , Cell Differentiation , Cell Line, Tumor , DNA Primers , Gene Expression , Humans , Reverse Transcriptase Polymerase Chain Reaction
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