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This article highlights emerging roles for veterinary pathologists outside of traditional functions and in line with the translational research (TR) approach. Veterinary pathologists offer unique and valuable expertise toward addressing particular TR and associated translational pharmacology questions, identifying gaps and risks in biomarker and pathology strategies, and advancing TR team decision making. Veterinary pathologists' attributes that are integral to the TR approach include (i) well-developed understanding of comparative physiology, pathology, and disease; (ii) extensive experience in interpretation and integration of complex data sets on whole-body responses and utilizing this for deciphering pathogenesis and translating events between laboratory species and man; (iii) proficiency in recognizing differences in disease end points among individuals, animal species and strains, and assessing correlations between these differences and other investigative (including biomarker) findings; and (iv) strong background in a wide spectrum of research technologies that can address pathomechanistic questions and biomarker needs. Some of the more evident roles in which veterinary pathologists can offer their greatest contributions to address questions and strategies of TR and biomarker integration will be emphasized.
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Biomarcadores , Descubrimiento de Drogas , Patología Veterinaria , Investigación Biomédica Traslacional , Animales , Humanos , Patólogos , Medicina de PrecisiónRESUMEN
Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas nonallergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response. Consequently, drug allergies are DHRs for which an immunological mechanism, with antibody and/or T cell, is demonstrated. Despite decades of research, methods to predict the potential for a new chemical entity to cause DHRs or to correctly attribute DHRs to a specific mechanism and a specific molecule are not well-established. This review will focus on allergic reactions induced by systemically administered low-molecular weight drugs with an emphasis on drug- and patient-specific factors that could influence the development of DHRs. Strategies for predicting and diagnosing DHRs, including potential tools based on the current state of the science, will also be discussed.
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Hipersensibilidad a las Drogas , Humanos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/inmunologíaRESUMEN
The Health and Environmental Sciences Institute Cardiac Biomarkers Working Group surveyed the pharmaceutical development community to investigate practices in assessing hemostasis, including detection of hypocoagulable and hypercoagulable states. Scientists involved in discovery, preclinical, and clinical research were queried on laboratory evaluation of endothelium, platelets, coagulation, and fibrinolysis during safety assessment studies. Results indicated that laboratory assessment of hemostasis is inconsistent among institutions and not harmonized between preclinical and clinical studies. Hemostasis testing in preclinical drug safety studies primarily focuses on the risk of bleeding, whereas the clinical complication of thrombosis is seldom assessed. Our results reveal the need for broader utilization of biomarkers to detect altered hemostasis (e.g., endothelial and platelet activation) to improve preclinical safety assessments early in the drug development process. Survey respondents indicated a critical lack of validated markers of hypercoagulability and subclinical thrombosis in animal testing. Additional obstacles included limited blood volume, lack of cross-reacting antibodies for hemostasis testing in laboratory species, restricted availability of specialized hemostasis analyzers, and few centers of expertise in animal hemostasis testing. Establishment of translatable biomarkers of prothrombotic states in multiple species and strategic implementation of testing on an industry-wide basis are needed to better avert untoward drug complications in patient populations.
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Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Industria Farmacéutica/organización & administración , Hemostasis/efectos de los fármacos , Tromboembolia/inducido químicamente , Animales , Investigación Biomédica , Pruebas de Coagulación Sanguínea , Hemostasis/fisiología , Humanos , Proyectos de Investigación , Medición de Riesgo/métodos , Medición de Riesgo/normas , Encuestas y Cuestionarios , Tromboembolia/sangre , Tromboembolia/diagnósticoRESUMEN
Drug-induced cardiac toxicity is a recognized challenge in development and implementation of pharmacotherapy. Appropriate biomarkers are needed to detect these abnormalities early in development and to manage the risk of potentially cardiotoxic drugs or biologic agents. Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury. Although most commonly used to detect myonecrosis in the setting of ischemia, cTns are also elevated with other acute and chronic disease processes, including heart failure, renal failure, sepsis, pulmonary embolic disease, and many others. High-sensitivity assays for both cTnI and cTnT are now available that achieve acceptable imprecision (coefficient of variation <10%) at the 99th percentile of a normal reference population. Even more sensitive assays are being developed that detect cTn in ranges that are near the level of normal cellular turnover (apoptosis). These properties of cTn and the continuing evolution of highly sensitive assays position cTn as a potentially uniquely informative marker for early detection of cardiac toxicity. This article summarizes collaborative discussions among key stakeholders in the Cardiac Safety Research Consortium about the use of cTn monitoring in drug development.
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Investigación Biomédica , Fármacos Cardiovasculares/efectos adversos , Evaluación de Medicamentos , Cardiopatías/sangre , Corazón/efectos de los fármacos , Troponina/sangre , United States Food and Drug Administration , Animales , Fármacos Cardiovasculares/uso terapéutico , Educación Médica Continua , Cardiopatías/tratamiento farmacológico , Humanos , Estados UnidosRESUMEN
Assessments of respiratory response and animal activity are useful endpoints in drug pharmacology and safety research. We investigated whether continuous, direct monitoring of breathing rate and body motion in animals in the home cage using the Vum Digital Smart House can complement standard measurements in enabling more granular detection of the onset and severity of physiologic events related to lung injury in a well-established rodent model of paraquat (PQ) toxicity. In rats administered PQ, breathing rate was significantly elevated while body motion was significantly reduced following dosing and extending throughout the 14-day study duration for breathing rate and at least 5 days for both nighttime and daytime body motion. Time course differences in these endpoints in response to the potential ameliorative test article bardoxolone were also readily detected. More complete than standard in-life measurements, breathing rate and body motion tracked injury progression continuously over the full study time period and aligned with, and informed on interval changes in clinical pathology. In addition, breathing rates correlated with terminal pathology measurements, such as normalized lung weights and histologic alveolar damage and edema. This study is a preliminary evaluation of the technology; our results demonstrate that continuously measured breathing rate and body motion served as physiologically relevant readouts to assess lung injury progression and drug response in a respiratory injury animal model.
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Cardiac troponins (cTns) are established biomarkers of ischemic heart disease in humans. However, their value as biomarkers of cardiac injury from causes other than ischemic heart disease is now being explored, particularly in drug development. In a workshop sponsored by the Cardiac Troponin Biomarker Working Group of the Health and Environmental Sciences Institute, preclinical, clinical, and regulatory scientists discussed the application of cTns in their respective environments, issues in translating the preclinical application of cTn to clinical studies, and gaps in our understanding of cTn biology and pathobiology. Evidence indicates that cTns are sensitive and specific biomarkers of cardiac injury from varying causes in both animals and humans. Accordingly, monitoring cTns can help ensure patient safety during the clinical evaluation of new drugs. In addition, preclinical characterization of cardiac risk and cTns as biomarkers of that risk can guide relevant clinical application and interpretation. We summarize here the outcomes of the workshop which included consensus statements, recommendations for further research, and a proposal for a cross-disciplinary group of clinical, regulatory, and drug development scientists to collaborate in such research.
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Cardiomiopatías/inducido químicamente , Cardiomiopatías/diagnóstico , Troponina/sangre , Animales , Cardiomiopatías/sangre , Ensayos Clínicos como Asunto , Conducta Cooperativa , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Educación , Humanos , Comunicación Interdisciplinaria , Monitoreo Fisiológico , Valor Predictivo de las Pruebas , Medición de RiesgoRESUMEN
The outcome of perinatal low-level TCDD exposure on the T-cell-mediated contact hypersensitivity (CHS) response in adult F344 rats was investigated. Suppression of the 2,4-dinitrofluorobenzene (DNFB)-specific contact hypersensitivity reponse occurred in mature offspring of dams dosed by gavage with 1microg or 3microg TCDD/kg on gestation day (GD) 14. To determine if this effect was correlated with altered distribution or activation of major T-cell subtypes, cells of the auricular lymph node draining the hapten-treated skin were evaluated by flow cytometry for expressed phenotype, including activation markers, 24h after challenge. Six-month-old female offspring with significantly decreased CHS and born to dams given 3microg TCDD/kg, had significantly greater proportion of CD4(+) T cells expressing a naive phenotype marker, CD45RC(hi), in their draining nodes. The greater relative frequency of this CD4(+) subset in peripheral lymphoid tissues associated with a reduced CHS in these rats may be attributed to a reduction in the proportion of CD4(+) T cells maintaining or recruited into an activated state. The CHS proved to be a valuable bioassay for investigating long-term immunotoxic effects of perinatal TCDD exposure in rats.
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Contaminantes Ambientales/toxicidad , Feto/efectos de los fármacos , Hipersensibilidad Tardía/prevención & control , Exposición Materna , Dibenzodioxinas Policloradas/toxicidad , Efectos Tardíos de la Exposición Prenatal , Administración Oral , Animales , Contaminantes Ambientales/administración & dosificación , Femenino , Feto/anomalías , Citometría de Flujo , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/patología , Antígenos Comunes de Leucocito/metabolismo , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Masculino , Dibenzodioxinas Policloradas/administración & dosificación , Embarazo , Ratas , Ratas Endogámicas F344 , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patologíaRESUMEN
There has been a substantial increase in the number and efficacy of laboratory biomarkers for the evaluation of human cardiac injury over the last decade. The advantages of these over traditional laboratory tests have encouraged adoption of comparable markers in nonclinical studies for cardiac injury assessment. Of particular interest are markers that are not only more sensitive and/or specific than traditional parameters for cardiac injury, but also those that may directly bridge human and laboratory animal safety testing. However, a majority of recently developed markers are quantified through antibody-based assays, and cross-reactivity with the comparable analyte in nonhuman samples is difficult to predict and often species-variable. The utility of these novel biomarkers thus, depends upon adequate assay validation with each laboratory species of interest. In contrast, traditional laboratory parameters of cardiac injury lack the properties of an ideal biomarker, but are well established and have an extensive database in nonclinical safety assessment. The current status and utility of both recently developed and traditional biomarkers of cardiac injury in nonclinical testing, and considerations for validation of novel biomarkers of cardiac injury are reviewed.
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Técnicas de Diagnóstico Cardiovascular , Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Cardiopatías/diagnóstico , Pruebas de Toxicidad/métodos , Animales , Animales de Laboratorio , Biomarcadores/sangre , Cardiopatías/sangre , Cardiopatías/inducido químicamente , Preparaciones Farmacéuticas/clasificaciónRESUMEN
Percutaneous fine needle aspiration biopsy (FNAB) was used to diagnose a urinary bladder carcinoma in an aged cat. The cytologic appearance of specimens collected initially was similar to that reported for canine transitional cell carcinoma. However, impression smears of the tumor made at necropsy 7 weeks later consisted predominantly of atypical squamous epithelial cells compatible with squamous cell carcinoma. Histologically, the malignancy was noted to have intermixed areas of abnormal squamous and transitional cell proliferation. The neoplasia was interpreted as a transitional cell carcinoma with extensive transformation to squamous cell carcinoma. This report examines the use and limitations of FNAB in the diagnosis of feline urinary bladder carcinoma and the incidence and behavior of these tumors in the cat.