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1.
Toxicol Pathol ; 50(1): 153-157, 2022 01.
Article in English | MEDLINE | ID: mdl-34814786

ABSTRACT

Baclofen is a γ-aminobutyric acid-B receptor agonist used for control of spastic muscle activity and as a treatment for alcohol abuse. The review of the nonclinical database suggested a data gap for potential carcinogenicity following long-term use. Regulatory requirements for pharmaceutical safety testing of cancer-causing potential have historically included 2-year rodent studies in rats and mice. The availability of transgenic models with greater specificity and sensitivity to carcinogens provides safety testing alternatives that align with the 3Rs. The carcinogenicity of baclofen was evaluated in CB6F1-TgrasH2 transgenic mice following daily oral administration at 45, 90, and 180 mg/kg/d for 26 weeks, preceded by a 2-week drug-conditioning period. There were no treatment-related palpable masses or neoplastic findings, and survival rates were not affected by the baclofen treatment. In conclusion, baclofen was considered as noncarcinogenic in CB6F1-TgrasH2 mice, which is consistent with results previously obtained in a 2-year rat study.


Subject(s)
Baclofen , Carcinogens , Animals , Baclofen/toxicity , Carcinogenicity Tests/methods , Mice , Mice, Transgenic , Pharmaceutical Preparations , Rats
2.
Regul Toxicol Pharmacol ; 113: 104625, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32119974

ABSTRACT

Sequential intramuscular immunization with chimeric hemagglutinins (cHA) composed of the same conserved HA stalk domain and distinct HA heads is a proposed strategy to produce a supra-seasonal universal influenza vaccine. To evaluate the local tolerance and the local and systemic effects of this strategy, two studies were performed in rabbits. In the first study, two different split virion monovalent cHA vaccines, containing cH5/1N1 and cH8/1N1, with or without AS01 or AS03, were injected at a two-week interval. In the second study, animals were given these vaccines and two weeks later an additional dose of split virion monovalent cHA vaccine containing cH11/1N1, with or without AS01 or AS03. General health status, rectal temperature, local tolerance, ophthalmology, hematology, coagulation, and blood chemistry parameters were monitored. Macroscopic and microscopic evaluations were performed three days after the last dose and after a treatment-free recovery period. The treatment-related changes included body weight loss and food consumption decrease, increases in neutrophil count, C-reactive protein and fibrinogen levels. Microscopic signs of inflammation at the injection sites and immune stimulation of the draining lymph nodes and spleen were also noticed. Most post-injection findings could be linked to the transient inflammation due to the establishment of the desired vaccine-elicited immune response, and were mainly observed in the adjuvanted groups. In conclusion, the sequential administration of different cHA vaccines was locally and systemically well-tolerated in rabbits.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Hemagglutinins/immunology , Influenza Vaccines/immunology , Seasons , Adjuvants, Immunologic/adverse effects , Animals , Female , Hemagglutinins/administration & dosage , Hemagglutinins/adverse effects , Immunization Schedule , Influenza Vaccines/administration & dosage , Influenza Vaccines/adverse effects , Injections, Intramuscular , Male , Rabbits , Vaccination
3.
J Appl Toxicol ; 40(6): 748-762, 2020 06.
Article in English | MEDLINE | ID: mdl-31965598

ABSTRACT

ChAd3-EBO-Z is an investigational adenovirus-based vaccine for the prevention of Ebola virus disease. Two nonclinical studies were performed to evaluate the biodistribution, local tolerance and potential local and systemic toxic effects of this vaccine. In the biodistribution study, rats received a single intramuscular injection of either ChAd3-EBO-Z or saline. Enlargement of the draining lymph nodes, starting on day 2, was noticed in ChAd3-EBO-Z-treated rats, indicating that an immune response had taken place. Viral DNA was mainly found at the injection sites and in the draining lymph nodes, from where it progressively disappeared during the observation period, while it was found only transiently and occasionally in other organs. In the repeated-dose toxicity study, either ChAd3-EBO-Z or saline was administered intramuscularly to rabbits on two occasions with a 2-week interval. General health status, rectal temperature, local tolerance, ophthalmology, hematology, coagulation and blood chemistry parameters were monitored. Macroscopic and microscopic evaluations were performed. Treatment-related changes included a transient increase in neutrophil count, C-reactive protein and fibrinogen levels, and a transient decrease in platelet count. As expected, microscopic observations 3 days after the second injection were related to the elicited inflammatory reaction, and these inflammatory responses had almost completely disappeared 29 days after the second immunization. In conclusion, the vaccine was locally and systemically well-tolerated and the viral vector was partially or totally cleared from the organs where it disseminated, supporting the clinical development of the vaccine.


Subject(s)
Adenoviridae/genetics , Ebola Vaccines/pharmacokinetics , Ebolavirus/immunology , Genetic Vectors , Animals , Ebola Vaccines/administration & dosage , Ebola Vaccines/toxicity , Female , Immunization Schedule , Immunogenicity, Vaccine , Injections, Intramuscular , Male , Rabbits , Rats, Sprague-Dawley , Tissue Distribution , Vaccines, DNA/administration & dosage , Vaccines, DNA/pharmacokinetics , Vaccines, DNA/toxicity
4.
Toxicol Pathol ; 47(2): 190-195, 2019 02.
Article in English | MEDLINE | ID: mdl-30585127

ABSTRACT

We describe here an angiomyomatous hamartoma in the right axillary lymph node of a three-year-old male cynomolgus monkey ( Macaca fascicularis), used as a control subject in a short-term toxicity study. This is a very rare lesion that has been reported almost exclusively in inguinal lymph nodes, and to date only in human beings. In the present case, light microscopy revealed partial replacement of the lymph node parenchyma by a disorganized, irregular vascular network, sparsely distributed smooth muscle cells, and a fibro-adipocytic stroma. This was considered to be fortuitous given the age of the animal, with no clinical or toxicological significance. To the best of our knowledge, this is the first report of an intranodal angiomyomatous hamartoma in a nonhuman animal species.


Subject(s)
Hamartoma/veterinary , Lymph Nodes/pathology , Monkey Diseases/pathology , Animals , Macaca fascicularis , Male
5.
Regul Toxicol Pharmacol ; 92: 303-314, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29196029

ABSTRACT

The aim of the present work was to evaluate the effects of photo-activated toxicity induced after administration of two known melanin-binding phototoxic compounds, sparfloxacin (SPX) and 8-methoxypsoralen (8-MOP), followed or not by UVA/Vis exposure, in pigmented rats (Long Evans: LE) and albino rats (Sprague Dawley: SD). Groups of three rats were treated with SPX or 8-MOP by oral gavage for six consecutive days. Irradiated animals were submitted to a UVA/Vis light dose standardized to 10 J/cm2 UVA daily. Clinical signs, cutaneous reactions and body weight were monitored throughout the study period. Ear biopsy weight, lymph node weight and lymph node cell count were determined at necropsy. Ophthalmologic examinations were performed before the first treatment and on the day of sacrifice. Microscopic examinations were performed on skin biopsies and eyes. Phototoxicity was demonstrated for both SPX and 8-MOP in the pigmented and albino strains, in terms of auricular irritation, lymph node weight and proliferation index, cutaneous reactions and ocular histopathology. LE rats were less sensitive than SD rats, especially at the ocular level, supporting the notion that pigmentation may provide protection against photo-activation. The pigmented rat may be a more relevant model than the albino rat for human safety evaluation.


Subject(s)
Dermatitis, Phototoxic/etiology , Fluoroquinolones/adverse effects , Methoxsalen/adverse effects , Pigmentation/drug effects , Animals , Cell Proliferation/drug effects , Eye/drug effects , Female , Lymph Nodes/drug effects , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Skin/drug effects , Ultraviolet Rays/adverse effects
6.
Regul Toxicol Pharmacol ; 73(1): 401-12, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26232705

ABSTRACT

Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague-Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (-18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays.


Subject(s)
Carcinogens/toxicity , Enzyme Inhibitors/adverse effects , Neoplasms/chemically induced , Pyrrolidines/adverse effects , Animals , Body Weight/drug effects , Carcinogenicity Tests/methods , Carcinogens/administration & dosage , Enzyme Inhibitors/therapeutic use , Female , Gaucher Disease/drug therapy , Male , Mice , Mutagenicity Tests/methods , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley
7.
Mol Cell Biol ; 25(4): 1437-45, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15684394

ABSTRACT

The Notch signaling pathway controls several cell fate decisions during lymphocyte development, from T-cell lineage commitment to the peripheral differentiation of B and T lymphocytes. Deltex-1 is a RING finger ubiquitin ligase which is conserved from Drosophila to humans and has been proposed to be a regulator of Notch signaling. Its pattern of lymphoid expression as well as gain-of-function experiments suggest that Deltex-1 regulates both B-cell lineage and splenic marginal-zone B-cell commitment. Deltex-1 was also found to be highly expressed in germinal-center B cells. To investigate the physiological function of Deltex-1, we generated a mouse strain lacking the Deltex-1 RING finger domain, which is essential for its ubiquitin ligase activity. Deltex-1(Delta/Delta) mice were viable and fertile. A detailed histological analysis did not reveal any defects in major organs. T- and B-cell development was normal, as were humoral responses against T-dependent and T-independent antigens. These data indicate that the Deltex-1 ubiquitin ligase activity is dispensable for mouse development and immune function. Possible compensatory mechanisms, in particular those from a fourth Deltex gene identified during the course of this study, are also discussed.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/immunology , Antigens, T-Independent/immunology , B-Lymphocytes/immunology , DNA-Binding Proteins/immunology , T-Lymphocytes/immunology , Amino Acid Sequence , Animals , B-Lymphocytes/cytology , DNA-Binding Proteins/genetics , Flow Cytometry , Gene Expression Regulation, Developmental/immunology , Mice , Mice, Knockout , Molecular Sequence Data , Mutation/genetics , Mutation/immunology , Sequence Homology, Amino Acid , Spleen/cytology , Spleen/immunology , T-Lymphocytes/cytology , Ubiquitin-Protein Ligases
8.
PLoS One ; 12(9): e0183398, 2017.
Article in English | MEDLINE | ID: mdl-28886055

ABSTRACT

BACKGROUND: A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s) for nonclinical evaluation of sublingual immunotherapy products. With this aim, we studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species. METHODS: Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek) obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs) and non-rodents (i.e. rabbits, dogs, minipigs and monkeys) were characterized by histology and immunohistology in comparison with a human tongue. RESULTS: Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP) and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species. CONCLUSION: The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products.


Subject(s)
Mouth Mucosa/metabolism , Sublingual Immunotherapy/methods , Animals , Cricetinae , Dogs , Glycogen/metabolism , Guinea Pigs , Humans , Immunohistochemistry , Mice , Rabbits , Rats , Swine , Tongue/cytology , Tongue/metabolism
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