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1.
Biomark Med ; 4(3): 475-83, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20550481

RESUMO

Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase)--the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance create dilemmas regarding which standard(s) indicates true injury. Concordance amongst a broader set of biomarker injury signals in a qualification paradigm will increase confidence, leading to accepted and integrated translational biomarker signals during safety assessment processes across the pharmaceutical industry, with academia, in government and in contractor laboratories.


Assuntos
Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diagnóstico Precoce , Glutamato Desidrogenase/metabolismo , Humanos , L-Iditol 2-Desidrogenase/sangue , Valor Preditivo dos Testes
2.
Regul Toxicol Pharmacol ; 56(3): 237-46, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19903504

RESUMO

Drug-induced liver injury (DILI) is the most frequent cause of discontinuation of new chemical entities during development. DILI can either be intrinsic/predictable or an idiosyncratic type. These two forms of DILI are contrasted in their manifestation and diagnosis. Even with regulatory guidance (FDA, 2009), there is still a gap in our ability to identify predictable DILI, both specifically and sensitively. Alanine aminotransferase (ALT) is the principal reference standard biomarker to diagnose DILI, yet its current application in preclinical to clinical translation for decision-making purposes has imperfections: (1) analytical ALT assay uniformity across industry would be aided by common analytical processes; (2) assessment of ALT toxicological performance in a large preclinical analysis would help to establish a true threshold of elevation for predictable DILI and improve translational use across various stages of pharmaceutical development and finally, (3) clinical evaluation of ALT elevations prospectively and retrospectively is recommended to define and manage variations in clinical study subjects including rising body mass index (BMI) range and ALT upper limit of normal (ULN) in the broader population over time. The emergence of new hepatotoxicity biomarkers necessitates a parallel and equivalent assessment to the aminotransferases in a regulatory qualification model.


Assuntos
Alanina Transaminase/normas , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Alanina Transaminase/metabolismo , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Humanos , Padrões de Referência
3.
Toxicol Pathol ; 37(1): 28-33, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19171926

RESUMO

Recently, in early clinical development, a few biologics and small molecules intended as antitumor or anti-inflammatory agents have caused a severe adverse pro-inflammatory systemic reaction also known as systemic inflammatory response syndrome (SIRS). This toxicity could result from expected pharmacological effects of a therapeutic antibody and/or from interaction with antigens expressed on cells/tissues other than the intended target. Clinical monitoring of SIRS is challenging because of the narrow diagnostic window to institute a successful intervening therapeutic strategy prior to acute circulatory collapse. Furthermore, for these classes of therapeutic agents, studies in animals have low predictive ability to identify potential human hazards. In vitro screens with human cells, though promising, need further development. Therefore, identification of improved preclinical diagnostic markers of SIRS will enable clinicians to select applicable markers for clinical testing and avoid potentially catastrophic events. There is limited preclinical toxicology data describing the interspecies performance of acute-phase proteins because the response time, type, and duration of major acute-phase proteins vary significantly between species. This review will attempt to address this intellectual gap, as well as the use and applicability of acute-phase proteins as preclinical to clinical translational biomarkers of SIRS.


Assuntos
Proteínas de Fase Aguda/metabolismo , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Testes de Toxicidade/métodos , Animais , Modelos Animais de Doenças , Cães , Humanos , Camundongos , Ratos , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Xenobióticos/toxicidade
4.
Res Vet Sci ; 83(3): 318-21, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17367831

RESUMO

The objective of this study was to determine the relationship between the number of transferable embryos (TE) and various blood chemistry parameters as a reflection of the metabolic state of cows after superovulatory treatment. Forty-nine Holstein cows were subjected to superovulatory treatment for commercial embryo production. At the time of embryo harvest, individual blood samples were taken from cows for biochemical analysis. All embryos including dead ones as well as non-fertilized oocytes were counted in uterine lavage. Feed samples collected daily for a period of two weeks before embryo harvest, were analyzed for mycotoxins: vomitoxin, zearalenone and T-2 toxin. On average, cows produced 9.45+/-5.60 embryos and oocytes of which 5.27+/-4.20 were TE, 0.37+/-0.80 were dead embryos and 3.82+/-3.78 were non-fertilized oocytes. Higher concentrations of Mg and K were associated with a higher production of TE (p=0.005 and p=0.043, respectively) and higher activity of creatinine kinase was associated with a lower production of TE (p=0.011).


Assuntos
Bovinos/sangue , Bovinos/embriologia , Embrião de Mamíferos , Superovulação/sangue , Administração Intravaginal , Animais , Creatina Quinase/sangue , Transferência Embrionária/veterinária , Estradiol/farmacologia , Feminino , Magnésio/sangue , Indução da Ovulação , Potássio/sangue , Progesterona/administração & dosagem , Progesterona/farmacologia , Superovulação/efeitos dos fármacos
5.
Vet Clin Pathol ; 34(4): 417-20, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16270272

RESUMO

A 16-year-old, male, neutered cat had a 2.5 X 1.5 cm mass on the medial aspect of the right carpus. Cytologic examination of a fine-needle aspirate of the mass indicated a markedly pleomorphic population of plasmacytoid to histiocytic-appearing cells. The cytologic diagnosis was malignant neoplasia of probable mesenchymal or round cell origin. The right forelimb was surgically removed and the scapular, axillary, and prescapular lymph nodes were excised. Malignant fibrous histiocytoma was tentatively diagnosed histologically; however, the tumor cells subsequently were found to be negative for histiocytic (MAC 387, antitrypsin), T-cell (CD3), and B-lymphocyte (immunoglobulin light chains, Ly 5/CD45R) markers, and positive for glial fibrillary acidic protein, vimentin, and S-100. Based on the immunohistochemical results, the diagnosis was modified to malignant peripheral nerve sheath tumor (PNST). Six months after surgery, the cat was reported to be well and had no evidence of metastasis. PNSTs are rare tumors in cats, and are considered as synonymous with schwannomas, neurofibrosarcomas, and hemangiopericytomas. In this cat, the plasmacytoid and pleomorphic appearance of the PNSTcells in cytologic and histologic specimens was unusual, and made it difficult to reach an accurate diagnosis without immunocytochemistry.


Assuntos
Doenças do Gato/diagnóstico , Membro Anterior , Neoplasias de Bainha Neural/veterinária , Tela Subcutânea/patologia , Animais , Biópsia por Agulha Fina/métodos , Biópsia por Agulha Fina/veterinária , Doenças do Gato/metabolismo , Doenças do Gato/patologia , Gatos , Diagnóstico Diferencial , Proteína Glial Fibrilar Ácida/análise , Histiocitoma Fibroso Maligno/química , Histiocitoma Fibroso Maligno/diagnóstico , Histiocitoma Fibroso Maligno/patologia , Histiocitoma Fibroso Maligno/veterinária , Imuno-Histoquímica/métodos , Imuno-Histoquímica/veterinária , Coxeadura Animal , Masculino , Neoplasias de Bainha Neural/química , Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/patologia , Neurilemoma/química , Neurilemoma/diagnóstico , Neurilemoma/patologia , Neurilemoma/veterinária , Proteínas S100/análise , Tela Subcutânea/química , Vimentina/análise
9.
Vet Clin Pathol ; 25(1): 10-13, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-12660981

RESUMO

Canine serum was used to compare seven chemistry analytes on two tabletop clinical dry chemistry analyzers, Boehringer's Reflotron and Kodak's Ektachem. Results were compared to those obtained on a wet chemistry reference analyzer, Roche Diagnostic's Cobas Mira. Analytes measured were urea nitrogen (BUN), creatinine, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol and bilirubin. Nine to 12 canine sera with values in the low, normal, and high range were evaluated. The correlations were acceptable for all comparisons with correlation coefficients greater than 0.98 for all analytes. Regression analysis resulted in significant differences for both tabletop analyzers when compared to the reference analyzer for cholesterol and bilirubin, and for glucose and AST on the Kodak Ektachem. Differences appeared to result from proportional systematic error occurring at high analyte concentrations.

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