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1.
Toxicol Pathol ; 49(1): 110-228, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33393872

RESUMO

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the minipig used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.


Assuntos
Animais de Laboratório , Animais , Bases de Dados Factuais , Europa (Continente) , Japão , Suínos , Porco Miniatura
2.
Toxicol Pathol ; 49(5): 977-989, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33661059

RESUMO

The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article-related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.


Assuntos
Patologistas , Testes de Toxicidade , Animais , Documentação , Feminino , Humanos , Masculino , Políticas , Projetos de Pesquisa
3.
Toxicol Pathol ; 46(2): 121-130, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29471777

RESUMO

Arteritis/polyarteritis occurs spontaneously in many species used in preclinical toxicology studies. In Göttingen minipigs, arteritis/polyarteritis is an occasionally observed background change. In the minipig, this finding differs in frequency and nature from age-related polyarteritis nodosa in rats or monkeys, and Beagle pain syndrome in dogs. In minipigs, it can be present in a single small- or medium-sized artery of an organ or a few organs and is most commonly recorded in the cardiac and extracardiac blood vessels, vagina, oviduct, rectum, epididymis, spinal cord, pancreas, urinary bladder, kidneys, and stomach. The etiology is unknown although it has been considered in minipigs as well as in rats, dogs, and monkeys to be possibly immune mediated. This background change is important with respect to its nature and distribution in the minipig in order to distinguish it from drug-induced vascular changes, which might occur in similar locations and have similar morphologic features. This review summarizes the morphology, incidence, and predilection sites of arteritis as a spontaneously occurring background change and as a drug-induced vasculopathy in the minipig, and also describes the main aspects to consider when evaluating vascular changes in Göttingen minipig toxicity studies and their human relevance.


Assuntos
Arterite/etiologia , Arterite/patologia , Animais , Modelos Animais de Doenças , Poliarterite Nodosa/etiologia , Poliarterite Nodosa/patologia , Suínos , Porco Miniatura
4.
Toxicol Pathol ; 46(8): 865-897, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30282530

RESUMO

The 2018 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Indianapolis, Indiana, at the Society of Toxicologic Pathology's 37th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and other topics covered during the symposium included seminiferous tubule dysgenesis in rats, ameloblast and odontoblast degeneration/necrosis in a Sprague Dawley rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters, renal tubule cytoplasmic vacuolation with basophilic granules in mice treated swith antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque, and rete ovarii proliferative ovarian lesions in various aged rat strains. One particularly provocative lesion was a malignant neoplastic proliferation in the renal pelvic region of a cynomolgus macaque from a 21-day study. Additional challenging lesions included thyroid proliferative lesions in zebra fish and gross findings in fish larvae during routine chemical screening. The Rabbit and Minipig International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Groups also presented a series of challenging lesions.


Assuntos
Toxicologia , Animais
5.
Toxicol Pathol ; 44(4): 575-90, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27044377

RESUMO

Both a rodent and a nonrodent species are required for evaluation in nonclinical safety studies conducted to support human clinical trials. Historically, dogs and nonhuman primates have been the nonrodent species of choice. Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety as an alternate nonrodent species. The pig is an appropriate option for these toxicology studies based on metabolic pathways utilized in xenobiotic biotransformation. Both similarities and differences exist in phase I and phase II biotransformation pathways between humans and pigs. There are numerous breeds of pigs, yet only a few of these breeds are characterized with regard to both xenobiotic-metabolizing enzymes and background pathology findings. Some specific differences in these enzymes based on breed and sex are known. Although swine have been used extensively in biomedical research, there is also a paucity of information in the current literature detailing the incidence of background lesions and differences between commonly used breeds. Here, the xenobiotic-metabolizing enzymes are compared between humans and pigs, and minipig background pathology changes are reviewed with emphasis on breed differences.


Assuntos
Modelos Animais , Suínos/anatomia & histologia , Suínos/metabolismo , Toxicologia/métodos , Animais , Humanos , Testes de Toxicidade/métodos
6.
Toxicol Pathol ; 44(3): 325-37, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26534940

RESUMO

Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety assessment of small molecules, biopharmaceutical agents, and medical devices as an alternate nonrodent species. Although swine have been used extensively in biomedical research, there is a paucity of information in the current literature detailing the incidence of background lesions and differences in incidence between commonly used breeds. This article is a collaborative effort between multiple organizations to define and document lesions found in the common breeds of minipigs used for toxicological risk assessment in North America (NA) and the European Union (EU). We retrospectively assessed 10 years of historical control data from several institutions located in NA and EU, covering the period of 2004-2015. Here we report the background lesions with consideration of breed and geographical location. To our knowledge, this is the first report documenting spontaneous background lesions in commonly used breeds of swine in both NA and EU. This report serves as a resource to pathologists and will aid in interpretation of findings and differentiation of background from test article-related changes.


Assuntos
Pesquisa Biomédica , Doenças dos Suínos , Porco Miniatura , Animais , Pesquisa Biomédica/organização & administração , Pesquisa Biomédica/normas , Bases de Dados Factuais , Incidência , Suínos , Doenças dos Suínos/classificação , Doenças dos Suínos/epidemiologia , Doenças dos Suínos/patologia , Testes de Toxicidade/normas
7.
J Toxicol Pathol ; 25(4): 249-56, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23345927

RESUMO

Lymphoplasmacytic gastritis is a concern for toxicological pathologists reading preclinical, non-human primate toxicity studies because subtle gastric changes which could be treatment-related may be masked and gastritis lesions may be confused with treatment-related effects and thus a gastric finding may be incorrectly assigned as a treatment-related lesion. This paper discusses the incidence of lymphoplasmacytic gastritis in cynomolgus monkeys at a contract research organization. The incidence of lymphoplasmacytic gastritis in the fundus and antrum of control cynomolgus monkeys on 18 non-gastric compound studies, was scored. The average fundus score ranged from 0.3 to 1.5 and the average antral score ranged from 0.9 to 3.5 in the cynomolgus monkey stomachs examined. The number of affected control animals in a study ranged from 0 to 5 control animals. No correlation between the route of vehicle administration and the severity or incidence of the lesions was noted. The percentage incidence of affected animals ranged from 0 to 100%. An increased incidence lymphoplasmatic gastritis from 2000 to 2004 was noted. The implications of lymphoplasmacytic gastritis in cynomolgus monkeys used for acute toxicity studies are discussed.

8.
Int J Exp Pathol ; 89(2): 138-58, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18336531

RESUMO

Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.


Assuntos
Azatioprina/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Imunossupressores/toxicidade , Pancitopenia/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Azatioprina/administração & dosagem , Peso Corporal/efeitos dos fármacos , Células da Medula Óssea/patologia , Ensaio de Unidades Formadoras de Colônias , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Células Precursoras Eritroides/efeitos dos fármacos , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Imunossupressores/administração & dosagem , Camundongos , Camundongos Endogâmicos ICR
9.
Curr Drug Saf ; 8(2): 77-97, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23656453

RESUMO

Carcinogenic properties of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for the treatment of benign gynecological conditions such as uterine fibroids, were assessed in a 26-week carcinogenicity study in transgenic TgRasH2 mice and a 104-week study in Sprague Dawley rats. Dose levels used in the mouse study were 15, 45, or 130 mg/kg/day and for the ratstudy the doses used were 1, 3, or 10 mg/kg/day. Vehicle and water controls were part of both studies and a positive control, N-Nitroso-N-methylurea intraperitoneally, was included in the transgenic mouse assay. Survival at all dose levels was similar to vehicle controls in both sexes of both species and there was no evidence of any UPA-induced carcinogenicity in either species. Rats receiving UPA had decreased incidences of fibroadenomas and adenocarcinomas in the mammary gland in all treated groups. UPA exposure [AUC(0-24h)] at the highest dose in rats was 67 times human therapeutic exposure at 10 mg/day. In mice, no tumor of any type increased at UPA exposures up to 313 times of therapeutic exposure. UPA-related findings in mice were limited to organ weight changes in the liver, pituitary, thyroid/parathyroid glands, and epididymis as well as minimal panlobular hepatocellular hypertrophy in male and female mice receiving 130 mg/kg/day. Rats had UPA-related non-neoplastic findings in the reproductive system (mammary gland, ovary, uterus, vagina, seminal vesicle, prostate), endocrine system (adrenal, pituitary), thymus, muscle, liver, pancreas and lungs most of which are considered to be due to exaggerated pharmacological action of the compound.


Assuntos
Norpregnadienos/toxicidade , Receptores de Progesterona/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Sistema Endócrino/efeitos dos fármacos , Feminino , Masculino , Metilnitrosoureia/farmacologia , Camundongos , Camundongos Transgênicos , Norpregnadienos/administração & dosagem , Norpregnadienos/farmacocinética , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/metabolismo , Fenômenos Reprodutivos Fisiológicos/efeitos dos fármacos , Especificidade da Espécie
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