RESUMEN
Dogs have been often chosen as a nonrodent species for preclinical development of small molecule drugs mainly due to availability and relative ease of handling. Recently, focus has increased on the minipig as a potential alternative to the dog, based on either scientific rationale or public opinion concerns. There are, however, other factors influencing nonrodent choices, in particular drug amount and synthesis time, which differ between species and therefore may impact the milestones of a drug development program. To assess the magnitude of compound need, a retrospective internal survey was conducted on drug amounts used in dog studies which were translated into the requirements for minipigs. Compound need approximately doubles if minipigs are used. Costs of compound are accordingly higher, and synthesis times are slightly increased. In our company, the differences were not considered significant enough to preclude the use of minipigs if the later preclinical program might benefit from improved human risk prediction.
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Investigación Biomédica , Perros , Evaluación Preclínica de Medicamentos , Porcinos Enanos , Animales , Investigación Biomédica/economía , Investigación Biomédica/métodos , Investigación Biomédica/normas , Investigación Biomédica/estadística & datos numéricos , Evaluación Preclínica de Medicamentos/economía , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Femenino , Masculino , Modelos Animales , Proyectos de Investigación , Estudios Retrospectivos , PorcinosRESUMEN
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.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Toxicología/normas , Animales , Guías como Asunto , Humanos , Medición de Riesgo , Fenómenos ToxicológicosRESUMEN
Information about the incidence of spontaneously occurring, nonneoplastic background findings in Syrian hamsters is essential if Syrian hamsters are to be used for toxicity studies. Male and female Syrian hamsters of the strain Han:AURA from the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) breeding colony were maintained as control animals for carcinogenicity studies and were examined for the presence of nonneoplastic background findings either when they died or when the study was terminated. The nonneoplastic background lesions observed at an incidence of >50% (high), >25% (moderate), and >10% (low) in either male or female animals or in both sexes in one or more long-term studies are detailed. The results are compared to previous published reports of nonneoplastic, spontaneous background lesions in Syrian hamsters. Background information about the incidence of background lesions in Syrian hamsters on short- and long-term studies is useful to both toxicologists and toxicological pathologists.
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Enfermedades de los Animales/epidemiología , Enfermedades de los Animales/patología , Pruebas de Carcinogenicidad , Mesocricetus/fisiología , Patología/normas , Toxicología/normas , Enfermedades de los Animales/mortalidad , Animales , Cricetinae , Femenino , Incidencia , Masculino , Neoplasias/epidemiología , Neoplasias/patología , Estándares de ReferenciaRESUMEN
The global healthcare industry is undergoing substantial changes and adaptations to the constant decline of approved new medical entities. This decrease in internal research productivity is resulting in a major decline of patent-protected sales (patent cliff) of most of the pharmaceutical companies. Three major global adaptive trends as driving forces to cope with these challenges are evident: cut backs of internal research and development jobs in the western hemisphere (Europe and USA), following the market growth potential of Asia by building up internal or external research and development capabilities there and finally, 'early innovation hunting' with an increased focus on identifying and investing in very early innovation sources within academia and small start-up companies. Early innovation hunting can be done by different approaches: increased corporate funding, establishment of translational institutions to bridge innovation, increasing sponsored collaborations and formation of technology hunting groups for capturing very early scientific ideas and concepts. This emerging trend towards early innovation hunting demands special adaptations from both the pharmaceutical industry and basic researchers in academia to bridge the translation into new medicines which deliver innovative medicines that matters to the patient. This opinion article describes the different modalities of cross-fertilisation between basic university or publicly funded institutional research and the applied research and development activities within the pharmaceutical industry. Two key factors in this important translational bridge can be identified: preparation of both partnering organisations to open up for new and sometime disruptive ideas and creation of truly trust-based relationships between the different groups allowing long-term scientific collaborations while acknowledging that value-creating differences are an essential factor for successful collaboration building.
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Industria Farmacéutica/organización & administración , Sector de Atención de Salud/organización & administración , Comunicación Interdisciplinaria , Invenciones , Investigación Biomédica Traslacional/métodos , Investigación Biomédica/economía , Investigación Biomédica/organización & administración , Conducta Cooperativa , Aprobación de Drogas/legislación & jurisprudencia , Descubrimiento de Drogas/economía , Descubrimiento de Drogas/organización & administración , Humanos , Patentes como Asunto , Apoyo a la Investigación como Asunto , Investigación Biomédica Traslacional/organización & administración , Universidades/organización & administraciónRESUMEN
Male and female Syrian hamsters of the strain Han: AURA from the Fraunhofer Institute for Toxicology and Experimental Medicine breeding colony were maintained as control animals for five toxicity/carcinogenicity studies and were examined for the presence of neoplastic disease either when they died or when the study terminated. In total, 250 male animals and 250 female animals in three carcinogenicity studies were analyzed as well as the results of a 6-month study (fifty males and fifty females) and a 12-month study (fifty males and fifty females). In the 24-month studies, in the male animals, twenty-five organs were affected with malignant and benign tumors. In the female animals, twenty-four organs were affected with malignant and benign tumors. The most frequently affected tissue in the three 24-month studies was the adrenal gland where 141 cortical adenomas (56.4%) were noted in 250 male animals and 115 cortical adenomas (46%) noted in 250 female animals. In addition, a high incidence of squamous cell papilloma in the vagina was noted in female hamsters on the 24-month studies. A moderate incidence of squamous cell papilloma of the nonglandular forestomach, benign granulosa cell tumor of the ovary, lymphoma of the hemopoietic system, endometrial stromal polyp, and adenocarcinoma of the uterus and islet cell adenoma of the pancreas were also observed on the 24-month studies.
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Neoplasias Experimentales/patología , Animales , Pruebas de Carcinogenicidad , Grupos Control , Cricetinae , Modelos Animales de Enfermedad , Femenino , Técnicas Histológicas , Humanos , Masculino , Mesocricetus , Neoplasias Experimentales/químicaRESUMEN
Neoplasms of the nervous system, whether spontaneous or induced, are infrequent in laboratory rodents and very rare in other laboratory animal species. The morphology of neural tumors depends on the intrinsic functions and properties of the cell type, the interactions between the neoplasm and surrounding normal tissue, and regressive changes. The incidence of neural neoplasms varies with sex, location, and age of tumor onset. Although the onset of spontaneous tumor development cannot be established in routine oncogenicity studies, calculations using the time of diagnosis (day of death) have revealed significant differences in tumor biology among different rat strains. In the central nervous system, granular cell tumors (a meningioma variant), followed by glial tumors, are the most common neoplasms in rats, whereas glial cell tumors are observed most frequently in mice. Central nervous system tumors usually affect the brain rather than the spinal cord. Other than adrenal gland pheochromocytomas, the most common neoplasms of the peripheral nervous system are schwannomas. Neural tumors may develop in the central nervous system and peripheral nervous system from other cell lineages (including extraneural elements like adipose tissue and lymphocytes), but such lesions are very rare in laboratory animals.
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Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Periférico/clasificación , Neoplasias del Sistema Nervioso Periférico/patología , Animales , Encéfalo/patología , Carcinógenos/toxicidad , Neoplasias del Sistema Nervioso Central/inducido químicamente , Neoplasias del Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Humanos , Ratas , Roedores , Médula Espinal/patologíaRESUMEN
Protein 4.1B is a membrane skeletal protein expressed in various organs, and is associated with tumor suppressor in lung cancer-1 (TSLC1) in vitro. Although involvement of 4.1B in the intercellular junctions and tumor-suppression was suggested, some controversial results posed questions to the general tumor-suppressive function of 4.1B and its relation to TSLC1 in vivo. In this study, the expression of 4.1B and its interaction with TSLC1 were examined in rodent adrenal gland, and the involvement of 4.1B in tumorigenesis and the effect of 4.1B deficiency on TSLC1 distribution were also investigated using rodent pheochromocytoma and 4.1B-knockout mice. Although plasmalemmal immunolocalization of 4.1B was shown in chromaffin cells of rodent adrenal medulla, expression of 4.1B was maintained in developed pheochromocytoma, and morphological abnormality or pheochromocytoma generation could not be found in 4.1B-deficient mice. Furthermore, molecular interaction and colocalization of 4.1B and TSLC1 were observed in mouse adrenal gland, but the immunolocalization of TSLC1 along chromaffin cell membranes was not affected in the 4.1B-deficient mice. These results suggest that the function of 4.1B as tumor suppressor might significantly differ among organs and species, and that plasmalemmal retention of TSLC1 would be maintained by molecules other than 4.1B interacting in rodent chromaffin cells.
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Neoplasias de las Glándulas Suprarrenales/metabolismo , Médula Suprarrenal/metabolismo , Inmunoglobulinas/metabolismo , Proteínas de la Membrana/metabolismo , Feocromocitoma/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , Animales , Molécula 1 de Adhesión Celular , Moléculas de Adhesión Celular , Inmunoglobulinas/análisis , Hibridación in Situ , Proteínas de la Membrana/análisis , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Proteínas de Microfilamentos , Microscopía Electrónica , Feocromocitoma/patología , Proteínas Supresoras de Tumor/análisisRESUMEN
Specific regions in the rat larynx exhibit cellular changes in response to inhaled xenobiotics. These regions include the base of the epiglottis, ventral pouch, and medial surfaces of the vocal processes of the arytenoid cartilages. 1 , 2 In order to collect information on the usefulness of trimming techniques, the influence of different vehicles, the impact of different application routes in toxicity studies, and differences between induced vs. spontaneous lesions, the data obtained from a large number of inhalation and non-inhalation studies performed in Wistar RCCHan(TM): Wist rats at Harlan Laboratories Ltd Switzerland, all evaluated or reviewed by the same pathologist, were compiled for a detailed review. The value of different trimming techniques was deemed to be greatest for transverse and sagittolongitudinal section techniques, as compared to horizontolongitudinally section techniques. The comparison of lesions encountered in control rats of inhalation studies treated with different vehicles did not reveal differences in the type, distribution pattern, incidence and/or severity of spontaneous lesions. The types of lesions were also independent of different application routes in non-inhalation studies compared to inhalation studies. The pattern of spontaneous lesions in the rodent larynx was determined by degenerative and inflammatory lesions starting most often in the submucosal glands by desiccated secretion followed by mineralization and local inflammation or were induced by impacted foreign bodies. Squamous metaplasia was recorded in the respiratory epithelium overlaying the ventral gland as a spontaneous lesion in male Wistar rats from inhalation studies with a maxim of 20.0% in an inhalation oncogenicity study. Induced metaplastic changes recorded in the larynx were reversible. Other induced lesions in inhalation studies consisted of submucosal edema, necrosis, inflammation and/or granuloma. Induced lesions in non-inhalation studies were found to be exclusively related to reflux laryngitis or food impaction. It is concluded, that in rodents induced lesions of the larynx differ in type, distribution pattern, severity and incidence from spontaneous lesions.
RESUMEN
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.
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Sistema Inmunológico/efectos de los fármacos , Inmunosupresores/toxicidad , Cooperación Internacional , Patología Veterinaria/métodos , Pruebas de Toxicidad/métodos , Xenobióticos/toxicidad , Animales , Sistema Inmunológico/patología , Patología Veterinaria/normas , Sociedades Científicas , Pruebas de Toxicidad/normasRESUMEN
UNLABELLED: The effects of additional i.v. therapy with a cyclooxygenase-inhibitor Eltenac to a recombinant surfactant protein C (rSP-C) based surfactant were investigated in a rat lung lavage model of acute lung injury. Treatment was done at 60 min after the induction of acute lung injury by lavage. The influence of the different treatments were tested with regard to improving oxygenation, histopathological changes (hyaline membrane formation and alveolar influx of neutrophil leukocytes). These effects were further compared to a fixed combination of Eltenac with rSP-C surfactant which was administered intratracheally (i.tr.), 60 min after lavage. To prove that fibrinogen is involved in the formation of hyaline membranes in this animal model confocal microscopy was applied. Furthermore, for selected cases the influence of Eltenac or rSP-C surfactant on fibrinogen leakage was investigated by using confocal microscopy. Results of additional i.v. therapy exhibited an improved oxygenation with rSP-C surfactant, while a high dose of Eltenacalone did not influence oxygenation as compared to untreated controls. Addition of Eltenac lead to improved oxygenation using the low dose of rSP-C surfactant. The rSP-C surfactant prevented further hyaline membrane formation. Furthemore, addition of Eltenac to the low dose of rSP-C surfactant lead to improved hyaline membrane formation at a dose of 100 micromol/kg b.w. Results of combined i.tr. therapy confirmed the results of the additional therapy. Again, rSP-C surfactant improved oxygenation and further hyaline membrane formation, while even the high dose of i.tr. administered Eltenacalone only prevented further hyaline membrane formation. Using the low dose of rSP-C surfactant, combined treatment with Eltenac showed additional effects on oxygenation and inhibition of hyaline membrane formation. The maximum therapeutic effect of combined treatment was achieved at 0.3 mg Eltenac per kg b.w. which is equivalent to approximately 1 micromol. The inflammatory cell infiltration into the lung was not influenced by any of the therapeutic approaches. Confocal microscopy gave evidence that fibrinogen is involved in hyaline membrane formation in this animal model. Furthermore, as was shown by the explorative investigations with confocal microscopy, addition of the cyclooxygenase-inhibitor decreases the diffuse interstitial leakage of fibrinogen into the lung while surfactant monotherapy did not exhibit any influence on the fibrinogen influx into the alveoli. CONCLUSIONS: Confocal microscopy may be an effective method to investigate the connection between fibrinogen leakage and hyaline membrane formation. Effects of additional or combined treatment were superior when compared to each treatment alone leading to the conclusion that a rSP-C surfactant containing a cyclooxygenase-inhibitor, acts synergistically in this animal model of acute lung injury. Lower doses of Eltenac could be used to reach similar effects on oxygenation and prevention of hyaline membrane after combined i.tr. treatment than after additional i.v. treatment together with surfactant. This leads to the conclusion that a fixed combination of rSP-C surfactant and a cyclooxygenase-inhibitor may be an effective treatment. Further testing may be warranted to prove whether this is a promising treatment for patients with acute lung injury.
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Compuestos de Anilina/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Surfactantes Pulmonares/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Tiofenos/uso terapéutico , Enfermedad Aguda , Compuestos de Anilina/administración & dosificación , Animales , Análisis de los Gases de la Sangre , Lavado Broncoalveolar/métodos , Inhibidores de la Ciclooxigenasa/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Fibrinógeno/metabolismo , Inyecciones Intravenosas , Intubación Intratraqueal , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Microscopía Confocal , Surfactantes Pulmonares/administración & dosificación , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes , Síndrome de Dificultad Respiratoria/sangre , Tiofenos/administración & dosificaciónRESUMEN
UNLABELLED: The aim of the study was to determine the effects of a specific epithelial growth factor Receptor kinase inhibitor (EGFR-KI) and Taxol on tumor growth in a novel tumor model. MATERIAL & METHODS: A genetically engineered tumor model which uses "transgenic" organs in immune competent mice was used. NeuT-transfected immortalized HC11 epithelial cells and primary mouse mammary epithelial cells have been transplanted into the gland-free mammary fat pad of female BALB/c mice. Mammary tumors developed after a latency period of three to four weeks. The mice were thereafter daily orally treated over a 19 or 22-day period with 0, 38, 75, 2 x 75 mg/kg body weight (b.w.) EGFR-KI (n: 7-9 per group) or intravenously with 10 mg/kg b.w. Taxol. After necropsy the histopathological evaluation of the tumors was performed in a coded manner. The proliferation activity of tumor cells was analyzed by laser scanning cytometry (LSC) using anti-Ki67-antibodies. RESULTS: Oral Treatment with EGFR-KI in this transgenic organ model showed clear antitumor efficacy in a dose-dependent manner in the range between 38 and 75 mg/kg b.w. This antiproliferative effect appears to be minimally increased at 75 mg/kg/day twice per day. For all treatments a strong correlation between the biological behavior of the tumor, histopathology and cell proliferation could be established. In contrast, treatment with Taxol showed no significant reduction of tumor growth or cell proliferation in this model. This new transgenic organ model comprising histopathological evaluation and cell proliferation analysis appears to be a suitable test system for drug candidates that affect specific biochemical pathways. It may have greater predictive nature for clinical effects in humans as compared to conventional tumor models because of its c-erb B2 gene overexpression.
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Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Glándulas Mamarias Animales/trasplante , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Línea Celular Transformada , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales/métodos , Inhibidores Enzimáticos/administración & dosificación , Femenino , Citometría de Imagen , Inyecciones Intravenosas , Antígeno Ki-67/metabolismo , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Resultado del TratamientoRESUMEN
The nature of the pharmaceutical industry is such that the main driver for its growth is innovation. In view of the vast challenges that the industry has been facing for several years and, in particular, how to manage stagnating research and development (R&D) productivity, pharmaceutical companies have opened their R&D organizations to external innovation. Here, we identify and characterize four new types of open innovator, which we call 'knowledge creator', 'knowledge integrator', 'knowledge translator' and 'knowledge leverager', and which describe current open R&D models.
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Industria Farmacéutica/organización & administración , Eficiencia Organizacional , Investigación/organización & administración , Industria Farmacéutica/tendencias , Humanos , Conocimiento , Modelos Teóricos , Investigación/tendencias , Investigación Biomédica TraslacionalRESUMEN
Syrian golden hamsters (Mesocricetus auratus) are laboratory animals increasingly used for research and toxicological studies. Despite the need for an adequate knowledge of spontaneously occurring lesions, studies investigating the background pathology of different organ systems in hamsters are lacking. The aim of this study was to investigate the occurrence of spontaneous, age-dependent lesions in the central nervous system of this species. Multiple brain and spinal cord transverse sections of 520 hamsters of 1, 3, 6, 12, and 24 months of age were investigated using histology and immunohistochemistry. Vacuolation of grey matter neuropil and mineralisation especially in the brain stem were the most prominent findings. They gradually increased in severity and frequency with age. Vacuolation and mineralisation affected approximately 100% and 50% of 24-month-old hamsters, respectively. In addition, pigment deposition and mast cell infiltration were commonly detected. Whether vacuolation and mineralisation represent an incidental finding or are related to a cognitive dysfunction syndrome remains to be determined.
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Envejecimiento , Encéfalo/patología , Calcinosis/patología , Vacuolas/patología , Animales , Cricetinae , Femenino , Inmunohistoquímica , Masculino , MesocricetusRESUMEN
Syrian golden hamsters (Mesocricetus auratus) are facultative hibernators with a life expectancy of approximately 2 years. Previous investigations showed a hyperphosphorylation of the tau protein during hibernation and aging and raised hopes that Syrian hamsters might represent a useful animal model to study pathogenetic mechanisms of Alzheimer's disease. Brain and spinal cord transversal sections of 190 hamsters 1-36 months of age were investigated using histology and immunohistochemistry to detect neurofibrillary tangles and/or diffuse as well as neuritic plaques. Summarized, amyloid deposition, neurofibrillary tangles, and diffuse as well as neuritic plaques were absent indicating that the Syrian golden hamster does not develop changes characteristic of Alzheimer's disease even at advanced age and does not represent an appropriate animal model for this disease.
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Envejecimiento/patología , Encéfalo/patología , Mesocricetus/anatomía & histología , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Médula Espinal/patología , Animales , Cricetinae , Mesocricetus/crecimiento & desarrolloRESUMEN
In this paper, changes in serum levels of the cardiac biomarkers troponin I and the heart-type fatty acid-binding protein (H-FABP) following administration of a long-acting beta(2)-sympathicomimeticum (long-acting beta-agonist, LABA) to dogs were measured. We measured troponin I in dogs in a 4-week repeated-dose study with inhalative administration of formoterol (13microg/kgd) and a glucocorticoid/formoterol combination (143/16microg/kgd). The medians of troponin I increased within 3 days in both groups, far beyond the cut-off level (0.1microg/L), but returned to baseline levels on study day 9. The increase was more pronounced in the formoterol-only group (3.29microg/L) compared to the glucocorticoid/formoterol combination group (1.32microg/L). In a second study, we measured serum troponin I as well as serum H-FABP levels in several samples over 7 days in dogs, receiving a single inhalative dose of a glucocorticoid/formoterol combination (120/12mug/kgd). The median of the troponin I concentration increased above the cut-off level within 2h and that of H-FABP within 4h. The medians of both parameters were temporarily above the cut-off levels even on study day 7. Both studies were conducted according to national animal welfare guidelines. To our knowledge, this is the first report that shows a corresponding increase of troponin I and H-FABP in dogs treated with formoterol. Both parameters are more sensitive in detecting a drug-induced cardiac injury compared to total LDH, total CK as well as CK MB activity. However, it is recommended to take at least three blood samples per day to assess a temporary increase of troponin I.
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Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Etanolaminas/efectos adversos , Proteínas de Unión a Ácidos Grasos/sangre , Troponina I/sangre , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Animales , Biomarcadores/sangre , Ritmo Circadiano , Preparaciones de Acción Retardada , Perros , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Etanolaminas/administración & dosificación , Femenino , Fumarato de Formoterol , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Masculino , Isquemia Miocárdica/sangre , Isquemia Miocárdica/inducido químicamente , Factores de TiempoRESUMEN
Pathologists are uniquely qualified to play a central role in driving drug discovery and development programs by: 1) establishing disease models to assess potential therapies, 2) characterizing modifications in the disease state in response to therapies, 3) characterizing toxicologic mechanisms and responses to drug candidates, and 4) facilitating multidisciplinary efforts to monitor for the clinical occurrence, progression, and reversibility of adverse events. Such nontraditional deployment of resources must, to be viable, produce benefits to the pharmaceutical industry comparable to those of more conventional activities such as delivery of data in nonclinical safety studies. Additionally, benefits must be tangible from standpoints such as time savings or improved quality of research decisions, manifesting as either program acceleration or improved candidate survival.
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Patología/tendencias , 4-Quinolonas , Inhibidores de la Angiogénesis/farmacología , Animales , Antiinfecciosos/toxicidad , Anticuerpos/uso terapéutico , Modelos Animales de Enfermedad , Factores de Crecimiento Endotelial/inmunología , Haplorrinos , Humanos , Linfocinas/inmunología , Ratones , Patología/economía , Fenotipo , Ratas , Ratas Endogámicas BN , Investigación , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague-Dawley rats from carcinogenicity studies. Morphologically, benign pheochromocytomas were characterized by monomorphic, small, basophilic cells with almost absence of mitoses. Malignant pheochromocytomas presented a low grade of pleomorphism, higher rate of mitoses, necrosis, infiltrative growth and in 1 case metastases in the lung. Ganglioneuromas were characterized by ganglion and neuron-like cells embedded in an eosinophilic matrix containing neurites, Schwann cells, and scant fibrovascular elements. All pheochromocytomas were strongly immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Subpopulations of chromaffin cells expressed chromogranin A (CGA) positivity. Matrix and Schwann cells were positive for S-100 and for glial fibrillary acidic protein (GFAP). In focal areas of the tumors, ganglion cells and axons were positive for neurofilament proteins (NFP) and synaptophysin. Ganglion cells exhibited peripherin and beta-tubulin. Proliferative activity of the tumors was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67 and the proliferating cell nuclear antigen (PCNA). As expected, cell proliferation indices were much higher in malignant pheochromocytomas than in benign, yet ganglioneuromas remained immunonegative. Considering that Ki-67 antigen is more specific for cell proliferation, it should be regarded as marker of choice for supporting the differential diagnosis between benign and malignant pheochromocytomas.
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Neoplasias de las Glándulas Suprarrenales/patología , Envejecimiento/patología , Ganglioneuroma/patología , Feocromocitoma/patología , Neoplasias de las Glándulas Suprarrenales/química , Animales , Ganglioneuroma/química , Inmunohistoquímica , Antígeno Ki-67/análisis , Feocromocitoma/química , Antígeno Nuclear de Célula en Proliferación/análisis , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
One of the main concepts in toxicology and risk assessment is the identification of compounds with the least toxicity, gaining increased understanding of the underlying mechanisms of efficacy and toxicity so as to accelerate the early selection of compounds for development. For this purpose, "cutting-edge" technologies, such as flow cytometry (FC), laser scanning cytometry (LSC) and confocal laser scanning microscopy (CLSM), have proved to be valuable tools. FC, LSC and CLSM have been successfully applied in a wide range of areas within toxicology and research including genetics, reproduction, dermatology, pathology and target organ toxicity. The scope of this paper is to give a short overview of the usefulness of the different laser applications. Specific examples of the impact of these technologies will be presented or can be found in the references. Flow cytometry methods have been successfully applied in immunophenotyping, micronuclei scoring, polyploidy determination, apoptosis and cell cycle evaluation, cell proliferation and quantification. A three-parameter FC method for the analysis of testicular toxicity has also been established as an alternative to traditional histopathological methods. This method allows a large number of cells to be analysed in a short time and provides quantitative values to evaluate testicular damage in the rat. Laser scanning cytometry has been used in our unit for rat blood cell immunophenotyping, tumor proliferation, apoptosis and cell cycle analysis on minipig and rat skin and cardiac cells identification. The wide range of applications that can be applied with the LSC shows the enormous potential of this technology in research and development. Confocal laser scanning microscope was used in our laboratory, in collaboration with the research department, to investigate the mechanisms underlying hepatic lesions found in dogs, to detect fibrinogen influx into rat lung, to explore the mechanism of eye toxicity and to quantify dopaminergic fibers in brain sections. Integrating these technologies within discovery pathology allowed us to understand disease processes with respect to their development and subsequent consequences. It contributes to descriptive pathologic diagnostic and allows a productive interaction with research and development. These technologies offer a range of novel applications and have been shown to be useful tools in terms of specificity, sensitivity, reliability, rapidity and quantification. Expertise in cutting-edge technologies, pathology and cell and molecular biology is essential to a successful and flexible interaction across all therapeutic areas in drug discovery.