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In this study, we assessed the toxicity and toxicokinetics of racemic vigabatrin and its S- and R-enantiomers (vigabatrin consists of 50:50% of the two enantiomers) by administering doses of the three test articles to male Long Evans rats via oral gavage. The animals were housed under high-intensity light conditions and the study consisted of an escalating dose phase and a 21-day fixed-dose phase. Systemic toxicity of vigabatrin appears to be due to the Vig-S-enantiomer only, as increasing doses of Vig-S or Vig-RS caused body weight loss, decreased food consumption, and affected activity. Administration of the Vig-R-enantiomer did not cause any such effects. Systemic exposure to R- and S-enantiomers was approximately linear with dose. Compared to administration of the racemate, there appeared to be a tendency for animals to take up higher amounts of Vig-R and lower amounts of Vig-S when administered as enantiomer. Bilateral retinal atrophy was observed in the fixed-dose phase in rats receiving Vig-S (either alone or as part of Vig-RS) and was characterized by irregular thinning and disorganization of the outer nuclear layer and thinning of the photoreceptor layer. The administration of the R-enantiomer alone did not cause any microscopic retinal change.
Assuntos
Retina , Vigabatrina , Masculino , Ratos , Animais , Ratos Long-EvansRESUMO
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 nonhuman primate 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.
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The adult Göttingen Minipig is an acknowledged model for safety assessment of antisense oligonucleotide (ASO) drugs developed for adult indications. To assess whether the juvenile Göttingen Minipig is also a suitable nonclinical model for pediatric safety assessment of ASOs, we performed an 8-week repeat-dose toxicity study in different age groups of minipigs ranging from 1 to 50 days of age. The animals received a weekly dose of a phosphorothioated locked-nucleic-acid-based ASO that was assessed previously for toxicity in adult minipigs. The endpoints included toxicokinetic parameters, in-life monitoring, clinical pathology, and histopathology. Additionally, the ontogeny of key nucleases involved in ASO metabolism and pharmacologic activity was investigated using quantitative polymerase chain reaction and nuclease activity assays. Similar clinical chemistry and toxicity findings were observed; however, differences in plasma and tissue exposures as well as pharmacologic activity were seen in the juvenile minipigs when compared with the adult data. The ontogeny study revealed a differential nuclease expression and activity, which could affect the metabolic pathway and pharmacologic effect of ASOs in different tissues and age groups. These data indicate that the juvenile Göttingen Minipig is a promising nonclinical model for safety assessment of ASOs intended to treat disease in the human pediatric population.
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With advancements in whole slide imaging technology and improved understanding of the features of pathologist workstations required for digital slide evaluation, many institutions are investigating broad digital pathology adoption. The benefits of digital pathology evaluation include remote access to study or diagnostic case materials and integration of analysis and reporting tools. Diagnosis based on whole slide images is established in human medical pathology, and the use of digital pathology in toxicologic pathology is increasing. However, there has not been broad adoption in toxicologic pathology, particularly in the context of regulatory studies, due to lack of precedence. To address this topic, as well as practical aspects, the European Society of Toxicologic Pathology coordinated an expert international workshop to assess current applications and challenges and outline a set of minimal requirements needed to gain future regulatory acceptance for the use of digital toxicologic pathology workflows in research and development, so that toxicologic pathologists can benefit from digital slide technology.
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For pediatric indications requiring juvenile toxicity testing, the rat is the preferred species. However, for some drugs it might not be an appropriate model or regulatory agencies may also request a non-rodent species. Due to the relatively recent use of Göttingen minipigs, little background data are available. This shortage of historical data can raise concerns with respect to interpretation, thus potentially discouraging investigators. This article presents background data from 82 piglets collected at different ages. The data described show the normal variations and changes which are important in the interpretations of these studies. Age-related changes were observed for several cardiac and clinical pathology parameters and in the haematopoietic tissues. Therefore, all pigs were not considered equal. It can be concluded that these data can be used as guidance, to support the concurrent study control data but cannot completely replace them.
Assuntos
Envelhecimento/patologia , Modelos Animais , Porco Miniatura/fisiologia , Suínos/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Especificidade de Órgãos , Projetos Piloto , Especificidade da Espécie , Testes de ToxicidadeRESUMO
The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Toxicologia/normas , Animais , Guias como Assunto , Humanos , Medição de Risco , Fenômenos ToxicológicosRESUMO
Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Lesões do Sistema Vascular/induzido quimicamente , Animais , Modelos Animais de Doenças , HumanosRESUMO
Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Oligonucleotídeos Antissenso/efeitos adversos , Lesões do Sistema Vascular/induzido quimicamente , Animais , Modelos Animais de Doenças , HumanosRESUMO
The pups from 32 litters of SD rats were given 0, 1, 3 or 10mg/kg-d of cyclosporin by oral gavage from 4 to 28 days of age. 10mg/kg-d resulted in a persistent impairment of the primary antibody response at 10 weeks of age. Indications of systemic toxicity, including the death of 10/64 pups and severely depressed weight gain, were also observed at this dose level. Arteriopathy of the heart and tubular basophilia and edema in the cortico-medullary region of the kidney were observed at 3 and 10mg/kg-d. In conclusion, while pharmacological effects were seen at all dose levels, the adverse effects of cyclosporin on the development of the immune system in the rat only occurred at a dose level that also induced systemic toxicity.
Assuntos
Antibacterianos/toxicidade , Ciclosporina/toxicidade , Sistema Imunitário/efeitos dos fármacos , Testes de Toxicidade/métodos , Administração Oral , Animais , Animais Recém-Nascidos , Animais Lactentes , Formação de Anticorpos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Feminino , Coração/efeitos dos fármacos , Sistema Imunitário/crescimento & desenvolvimento , Rim/efeitos dos fármacos , Rim/patologia , Longevidade/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Maturidade Sexual/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Timo/efeitos dos fármacos , Timo/patologia , Tíbia/efeitos dos fármacos , Tíbia/crescimento & desenvolvimento , Suspensão de TratamentoRESUMO
Cell stress and death are linked in the neoplastic process, and heat shock proteins appear to play an important role by inhibiting apoptotic pathways. The apoptotic rates in 9 canine infundibular keratinizing acanthomas (IKAs) and 17 canine squamous cell carcinomas (SCCs) were correlated with the immunohistochemical expression of caspase-3 and the antiapoptotic heat shock proteins Hsp27, 72 and 73. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) method. The absence of a correlation between the TUNEL index and active-caspase-3 expression, a paucity of active-caspase-3-positive cells and Hsp72 over-expression were considered to be indicative of inhibition of apoptosis, and suggestive that inhibition of cell death plays a key role in oncogenesis and tumour growth of some canine skin neoplasms.
Assuntos
Acantoma/veterinária , Apoptose/fisiologia , Carcinoma de Células Escamosas/veterinária , Doenças do Cão/metabolismo , Proteínas de Choque Térmico/metabolismo , Acantoma/patologia , Animais , Apoptose/genética , Carcinoma de Células Escamosas/patologia , Cães , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Imuno-Histoquímica/veterinária , Marcação In Situ das Extremidades CortadasRESUMO
Ossification of the bladder wall, detected radiographically as a nonhomogeneous radiopaque area in the cranioventral part of the bladder in a puppy, is reported. We speculate that chronic inflammation due to the presence of uroliths in the lumen may have stimulated a metaplastic transformation of the cells.