RESUMO
Most published reviews of preclinical toxicological clinical pathology focus on the fundamental aspects of hematology, clinical chemistry, coagulation, and urinalysis in routine toxicology animal species, for example, rats, mice, dogs, and nonhuman primates. The objective of this continuing education course was to present and discuss contemporary examples of nonroutine applications of clinical pathology endpoints used in the drug development setting. Area experts discussed bone turnover markers of laboratory animal species, clinical pathology of pregnant and growing laboratory animals, clinical pathology of nonroutine laboratory animal species, and unique applications of the Siemens Advia(®) hematology analyzer. This article is a summary based on a presentation given at the 31st Annual Symposium of the Society of Toxicologic Pathology, during the Continuing Education Course titled "Nontraditional Applications of Clinical Pathology in Drug Discovery and Preclinical Toxicology."
Assuntos
Avaliação Pré-Clínica de Medicamentos , Patologia Clínica/métodos , Animais , Biomarcadores/sangue , Osso e Ossos/metabolismo , Cricetinae , Modelos Animais de Doenças , Cães , Determinação de Ponto Final , Cobaias , Humanos , Camundongos , Primatas , Coelhos , RatosRESUMO
This manuscript is intended to provide a best practice approach to accurately and consistently assess toxicant-induced bone marrow effects of test articles. In nonclinical toxicity studies, complete blood count data in conjunction with the histological examination of the bone marrow are recommended as the foundation for assessing the effect of test articles on the hematopoietic system. This approach alone can be used successfully in many studies. However, in some situations it may be necessary to further characterize effects on the different hematopoietic lineages, either by cytological or flow cytometric evaluation of the bone marrow. Both modalities can be used successfully, and which one is selected will depend on the expertise, preference of the facility, and the nature of the change in the bone marrow. Other specialized techniques such as clonogenic assays or electron microscopy are used rarely to further characterize hematotoxicity. The indications and techniques to successfully employ histological, cytological, or flow cytometric evaluation as well as clonogenic assays and electron microscopy are reviewed.
Assuntos
Medula Óssea/patologia , Guias como Assunto , Hematopoese , Animais , Benchmarking , Biologia Celular/normas , Estudos de Avaliação como Assunto , Citometria de Fluxo/normas , Sistema Hematopoético , Histologia/normas , Humanos , Coloração e Rotulagem , Toxicologia/normasRESUMO
Toxicologic pathologists contribute significantly to the development of new biopharmaceuticals, yet there is often a lack of awareness of this specialized role. As the members of multidisciplinary teams, toxicologic pathologists participate in all aspects of the drug development process. This review is part of an initiative by the Society of Toxicologic Pathology to educate scientists about toxicologic pathology and to attract junior scientists, veterinary students, and veterinarians into the field. We describe the role of toxicologic pathologists in identifying candidate agents, elucidating bioactive pathways, and evaluating efficacy and toxicity in preclinical animal models. Educational and specialized training requirements and the challenges of working in a global environment are discussed. The biopharmaceutical industry provides diverse, challenging, and rewarding career opportunities in toxicologic pathology. We hope that this review promotes understanding of the important role the toxicologic pathologist plays in drug development and encourages exploration of an important career option.
Assuntos
Biotecnologia/métodos , Indústria Farmacêutica/educação , Patologia Clínica/educação , Toxicologia/educação , Médicos Veterinários , Animais , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/tendências , Humanos , Patologia Clínica/tendências , Medição de Risco , Estudantes , Toxicologia/tendênciasRESUMO
There is an international shortage of veterinary clinical pathologists in the workplace. Current trainees in veterinary clinical pathology may choose to pursue careers in academe, diagnostic laboratories, government health services, biopharmaceutical companies, or private practice. Academic training programs attempt to provide trainees with an exposure to several career choices. However, due to the proprietary nature of much of the work in the biopharmaceutical industry, trainees may not be fully informed regarding the nature of work for veterinary clinical pathologists and the myriad opportunities that await employment in the biopharmaceutical industry. The goals of this report are to provide trainees in veterinary clinical pathology and other laboratory personnel with an overview of the work-life of veterinary clinical pathologists employed in the biopharmaceutical industry, and to raise the profile of this career choice for those seeking to enter the workforce. Biographical sketches, job descriptions, and motivation for 3 successful veterinary clinical pathologists employed in the biopharmaceutical industry are provided. Current and past statistics for veterinary clinical pathologists employed in the biopharmaceutical industry are reviewed. An overview of the drug development process and involvement of veterinary clinical pathologists in the areas of discovery, lead optimization, and candidate evaluation are discussed. Additional duties for veterinary clinical pathologists employed in the biopharmaceutical industry include development of biomarkers and new technologies, service as scientific resources, diagnostic support services, and laboratory management responsibilities. There are numerous opportunities available for trainees in veterinary clinical pathology to pursue employment in the biopharmaceutical industry and enjoy challenging and rewarding careers.
Assuntos
Indústria Farmacêutica , Patologia Clínica , Médicos Veterinários/tendências , Biomarcadores , Ensaios Clínicos como Assunto , Desenho de Fármacos , Indústria Farmacêutica/tendências , Drogas em Investigação , Patologia Clínica/tendências , Fatores de Tempo , Recursos HumanosRESUMO
As part of the ICH process of harmonization of testing guidelines for immunotoxicity, the European Society of Toxicologic Pathology (ESTP) has contributed to the scientific discussion on methods and evaluation of immunotoxicity studies with technical and scientific recommendations on toxicologic pathology. The weighing and sampling of immune organs is discussed taking into consideration specifically the value of lymph node weighing and the selection of appropriate lymph nodes for the detection of local and systemic effects. The different techniques of bone marrow preparation are considered for routine and extended investigations. Criteria are given for the gross and histopathological detection of effects in Peyer's patches. For the histopathological evaluation it is strongly recommended that each compartment within the different lymphoid organs is investigated separately and semiquantitatively since this approach has shown to increase the sensitivity and specificity of immunohistopathology.
Assuntos
Sistema Imunitário/efeitos dos fármacos , Imunossupressores/toxicidade , Cooperação Internacional , Patologia Veterinária/métodos , Testes de Toxicidade/métodos , Xenobióticos/toxicidade , Animais , Sistema Imunitário/patologia , Patologia Veterinária/normas , Sociedades Científicas , Testes de Toxicidade/normasRESUMO
Bone marrow examination is an important part of the evaluation of the hematopoietic system. In pharmaceutical and toxicological research, bone marrow evaluation can help determine the potential hematotoxicity or effects of new compounds on hematopoietic cells. The rat is a common research animal, and bone marrow evaluation often is performed in this species. The goal of this review is to provide clinical pathologists and researchers with an updated overview of bone marrow evaluation in rats as well as practical guidelines for methods and microscopic evaluation. Indications for bone marrow collection in a research setting, methods of collection and smear preparation, and unique morphologic features of rat bone marrow cells are discussed. A summary of published cell differential percentages for bone marrow from healthy rats and possible explanations for discrepancies in these values also are provided.
Assuntos
Células da Medula Óssea/citologia , Técnicas Citológicas/veterinária , Ratos/anatomia & histologia , Coloração e Rotulagem/veterinária , Animais , Medula Óssea/anatomia & histologia , Células da Medula Óssea/fisiologia , Técnicas Citológicas/métodos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Guias de Prática Clínica como Assunto , Coloração e Rotulagem/métodosRESUMO
BACKGROUND: Increased serum parathyroid hormone-related peptide (PTHrP) concentration is used to diagnose humoral hypercalcemia of malignancy (HHM) in humans and animals. A commercially available assay for human PTHrP has diagnostic utility in the dog, but has not been assessed in cats. OBJECTIVE: The goals of this study were to determine serum or plasma levels of PTHrP in a population of hypercalcemic cats and to determine whether increased PTHrP concentration was associated with malignancy. In addition, we validated immunoradiometric assays (IRMAs) for intact parathormone (iPTH) and PTHrP for use with feline samples. METHODS: A retrospective analysis of iPTH and PTHrP results from 322 hypercalcemic cats (ionized calcium concentration > 1.4 mmol/L) was performed. Immunoassays for human iPTH and PTHrP (residues 1-84) were validated using standard methods, and reference intervals were calculated using values from 31 healthy adult cats. Hypercalcemic cats were classified as parathyroid-independent (iPTH < 2.3 pmol/L), equivocal (iPTH 2.3-4.6 pmol/L), or parathyroid-dependent (iPTH > 4.6 pmol/L). Seven cats with detectable or increased PTHrP concentrations were evaluated further for underlying disease. Formalin-fixed neoplastic tissues were immunohistochemically stained using rabbit antibody to human midregion PTHrP. RESULTS: Assays for iPTH and PTHrP showed acceptable precision for feline samples. The reference interval for iPTH was 0.8-4.6 pmol/L and for PTHrP was < 1.5 pmol/L. The majority of hypercalcemic cats (263/322, 81.7%) were parathyroid-independent, with fewer cats in the equivocal (32/322, 9.9%) and parathyroid-dependent (27/322, 8.4%) groups. In 31 (9.6%) cats, PTHrP concentration was > 1.5 pmol/L (range 1.5-26.6 pmol/L). All 7 cats for which follow-up information was available had HHM; 6 had carcinomas (4 lung carcinomas, 1 undifferentiated carcinoma, 1 thyroid carcinoma) and 1 had lymphoma. All tumors had mild to moderate positive staining for PTHrP; however, lung carcinomas from normocalcemic cats also stained positive. CONCLUSIONS: Human IRMA for PTHrP (1-84) can be used to measure PTHrP in cats. Malignancies, particularly carcinomas, appear to secrete PTHrP and induce HHM in this species. Immunohistochemistry alone cannot predict the occurrence of HHM in cats.
Assuntos
Carcinoma/veterinária , Doenças do Gato/diagnóstico , Hipercalcemia/veterinária , Ensaio Imunorradiométrico/veterinária , Hormônio Paratireóideo/metabolismo , Proteínas/metabolismo , Animais , Carcinoma/sangue , Carcinoma/fisiopatologia , Doenças do Gato/sangue , Gatos , Feminino , Hipercalcemia/sangue , Hipercalcemia/etiologia , Imuno-Histoquímica/veterinária , Ensaio Imunorradiométrico/métodos , Masculino , Hormônio Paratireóideo/análise , Proteína Relacionada ao Hormônio Paratireóideo , Proteínas/análise , Valores de Referência , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
The purpose of this paper by the Regulatory Affairs Committee (RAC) of the American Society for Veterinary Clinical Pathology (ASVCP) is to review the current regulatory guidances (eg, guidelines) and published recommendations for best practices in veterinary toxicologic clinical pathology, particularly in the pharmaceutical and biotechnology industries, and to utilize the combined experience of ASVCP RAC to provide updated recommendations. Discussion points include (1) instrumentation, validation, and sample collection, (2) routine laboratory variables, (3) cytologic laboratory variables, (4) data interpretation and reporting (including peer review, reference intervals and statistics), and (5) roles and responsibilities of clinical pathologists and laboratory personnel. Revision and improvement of current practices should be in alignment with evolving regulatory guidance documents, new technology, and expanding understanding and utility of clinical pathology. These recommendations provide a contemporary guide for the refinement of veterinary toxicologic clinical pathology best practices.
Assuntos
Biotecnologia/normas , Indústria Farmacêutica/normas , Laboratórios/normas , Pessoal de Laboratório Médico/normas , Patologia Clínica/normas , Patologia Veterinária/normas , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/veterinária , Guias de Prática Clínica como Assunto , Controle de Qualidade , Sociedades Científicas , Toxicologia , Estados UnidosRESUMO
This manuscript is intended to provide a best practice approach to accurately and consistently assess toxicant-induced bone marrow effects of test articles. In nonclinical toxicity studies, complete blood count data in conjunction with the histological examination of the bone marrow are recommended as the foundation for assessing the effect of test articles on the hematopoietic system. This approach alone can be used successfully in many studies. However, in some situations it may be necessary to further characterize effects on the different hematopoietic lineages, either by cytological or flow cytometric evaluation of the bone marrow. Both modalities can be used successfully, and which one is selected will depend on the expertise, preference of the facility, and the nature of the change in the bone marrow. Other specialized techniques such as clonogenic assays or electron microscopy are used rarely to further characterize hematotoxicity. The indications and techniques to successfully employ histological, cytological, or flow cytometric evaluation as well as clonogenic assays and electron microscopy are reviewed.