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1.
Bioorg Med Chem ; 28(22): 115723, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-33007547

RESUMEN

Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Peroxidasa/antagonistas & inhibidores , Piridinas/farmacología , Triazoles/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Peroxidasa/metabolismo , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química
2.
Vet Pathol ; 55(2): 331-340, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29338616

RESUMEN

C-terminal Src kinase (Csk) is one of the critical negative regulators of the Src family of kinases. The Src family of kinases are nonreceptor tyrosine kinases that regulate inflammation, cell proliferation, motility, and adhesion. To investigate potential histologic lesions associated with systemic loss of Csk gene activity in adult mice, conditional Csk-knockout mice were examined. Cre-mediated systemic excision of Csk induced by tamoxifen treatment resulted in multiorgan inflammation. Specifically, induction of Csk gene excision with three days of tamoxifen treatment resulted in greater than 90% gene excision. Strikingly, these mice developed enteritis that ranged from minimal and suppurative to severe, fibrinonecrosuppurative and hemorrhagic. Other inflammatory lesions included suppurative pneumonia, gastritis, and myocarditis, and increased numbers of inflammatory cells within the hepatic parenchyma. When tamoxifen treatment was reduced from three days to one day in an effort to lower the level of Csk gene excision and limit lesion development, the mice developed severe suppurative to pyogranulomatous pneumonia and minimal to mild suppurative enteritis. Lesions observed secondary to Csk gene excision suggest important roles for Csk in downregulating the proinflammatory activity of the Src family of kinases and limiting neutrophil-mediated inflammation.


Asunto(s)
Inflamación/veterinaria , Ratones Noqueados/metabolismo , Supuración/veterinaria , Familia-src Quinasas/metabolismo , Animales , Southern Blotting , Proteína Tirosina Quinasa CSK , Femenino , Expresión Génica , Inflamación/metabolismo , Inflamación/patología , Masculino , Supuración/metabolismo , Supuración/patología
3.
J Pharmacol Exp Ther ; 352(2): 305-14, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25467132

RESUMEN

Liver X Receptors (LXRs) α and ß are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacology of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXRß selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC50 = 610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, respectively, with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are critical for RCT, were comparable. Increased liver triglyceride was observed after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS-779788, a partial LXRß selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRα activity.


Asunto(s)
Anticolesterolemiantes/farmacología , Imidazoles/farmacología , Hígado/efectos de los fármacos , Receptores Nucleares Huérfanos/agonistas , Sulfonas/farmacología , Transportadoras de Casetes de Unión a ATP/sangre , Transportadoras de Casetes de Unión a ATP/genética , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/sangre , Relación Dosis-Respuesta a Droga , Agonismo Parcial de Drogas , Imidazoles/administración & dosificación , Imidazoles/sangre , Lípidos/sangre , Lipogénesis/efectos de los fármacos , Hígado/metabolismo , Receptores X del Hígado , Macaca fascicularis , Masculino , Sulfonas/administración & dosificación , Sulfonas/sangre , Triglicéridos/metabolismo
4.
Bioorg Med Chem Lett ; 23(11): 3157-61, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23632269

RESUMEN

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.


Asunto(s)
Amidas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Indazoles/química , Quinolonas/química , Administración Intranasal , Amidas/farmacología , Amidas/uso terapéutico , Animales , Células CACO-2 , Callithrix , Vasos Coronarios/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Cara/irrigación sanguínea , Humanos , Indazoles/farmacología , Indazoles/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Quinolonas/farmacología , Quinolonas/uso terapéutico , Conejos , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/patología
5.
Am J Pathol ; 178(3): 1117-25, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21356363

RESUMEN

Chronic cholestatic liver injury induced by cholestasis in rodents is associated with hepatic fibrin deposition, and we found evidence of fibrin deposition in livers of patients with cholestasis. Key components of the fibrinolytic pathway modulate cholestatic liver injury by regulating activation of hepatocyte growth factor. However, the exact role of hepatic fibrin deposition in chronic cholestasis is not known. We tested the hypothesis that fibrinogen (Fbg) deficiency worsens liver injury induced by cholestasis. Fbg-deficient mice (Fbgα(-/-) mice) and heterozygous control mice (Fbgα(+/-) mice) were fed either the control diet or a diet containing 0.025% α-naphthylisothiocyanate (ANIT), which selectively injures bile duct epithelial cells in the liver, for 2 weeks. Hepatic fibrin and collagen deposits were evident in livers of heterozygous control mice fed the ANIT diet. Complete Fbg deficiency was associated with elevated serum bile acids, periportal necrosis, and increased serum alanine aminotransferase activity in mice fed the ANIT diet. Fbg deficiency was associated with enhanced hepatic expression of the transcription factor early growth response-1 (Egr-1) and enhanced induction of genes encoding the Egr-1-regulated proinflammatory chemokines monocyte chemotactic protein-1, KC growth-regulated protein, and macrophage inflammatory protein-2. Interestingly, peribiliary collagen deposition was not evident near necrotic areas in Fbg-deficient mice. The results suggest that in this model of chronic cholestasis, fibrin constrains the release of bile constituents from injured intrahepatic bile ducts, thereby limiting the progression of hepatic inflammation and hepatocellular injury.


Asunto(s)
Afibrinogenemia/complicaciones , Afibrinogenemia/metabolismo , Colestasis/complicaciones , Colestasis/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Fibrinógeno/metabolismo , Hígado/patología , 1-Naftilisotiocianato/administración & dosificación , Afibrinogenemia/patología , Anciano , Animales , Conductos Biliares/patología , Colestasis/inducido químicamente , Colestasis/patología , Enfermedad Crónica , Colágeno/metabolismo , Dieta , Modelos Animales de Enfermedad , Conducta Alimentaria , Femenino , Fibrina/deficiencia , Fibrina/metabolismo , Regulación de la Expresión Génica , Humanos , Hiperplasia , Inflamación/complicaciones , Inflamación/genética , Inflamación/patología , Hígado/metabolismo , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Ratones , Persona de Mediana Edad , Neutrófilos/metabolismo , Xenobióticos
6.
Toxicol Appl Pharmacol ; 250(3): 256-62, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21070799

RESUMEN

Cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) is provoked by injury to intrahepatic bile ducts and the progression of hepatic necrosis requires the procoagulant protein tissue factor (TF) and extrahepatic cells including neutrophils. Recent studies have shown that myeloid cell TF contributes to neutrophil activation. We tested the hypothesis that myeloid cell TF contributes to neutrophil activation in ANIT-treated mice. TF activity in liver homogenates increased significantly in TF(flox/flox) mice treated with ANIT, but not in TF(flox/flox)/LysMCre mice (TF(ΔMyeloid) mice), which have reduced TF expression in monocytes/macrophages and neutrophils. Myeloid cell-specific TF deficiency did not alter expression of the chemokines KC or MIP-2 but reduced hepatic neutrophil accumulation in ANIT-treated mice at 48 h as indicated by tissue myeloperoxidase (MPO) activity. Myeloid cell TF deficiency significantly reduced CD11b expression by blood neutrophils in ANIT-treated mice, and this was associated with reduced plasma MPO protein levels, an index of neutrophil degranulation. However, myeloid cell-specific TF deficiency had no effect on ANIT-induced coagulation cascade activation. The increase in serum ALT and ALP activities in ANIT-treated mice was reduced by myeloid cell TF deficiency (p<0.05), but the myeloid cell TF deficiency did not reduce hepatic necrosis at 48 h, as determined by histopathology and morphometry. The results suggest that myeloid cell TF contributes to neutrophil CD11b expression during cholestasis by a coagulation-independent pathway. However, the resultant reduction in neutrophil accumulation/activation is insufficient to substantially reduce ANIT hepatotoxicity, suggesting that myeloid cell TF is only one of many factors modulating hepatic necrosis during cholestasis.


Asunto(s)
1-Naftilisotiocianato/toxicidad , Antígeno CD11b/biosíntesis , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Neutrófilos/efectos de los fármacos , Tromboplastina/metabolismo , Xenobióticos/toxicidad , Animales , Coagulación Sanguínea/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Quimiocinas/biosíntesis , Colestasis/inducido químicamente , Colestasis/metabolismo , Molécula 1 de Adhesión Intercelular/biosíntesis , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Células Mieloides/metabolismo , Activación Neutrófila , Neutrófilos/metabolismo , Peroxidasa/metabolismo
7.
Xenobiotica ; 41(2): 144-54, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21043805

RESUMEN

2-Bromoethanamine (BEA) causes renal papillary necrosis (RPN) in rats after a single dose and has been widely used as a model compound for studying the lesion. Although the metabolism of BEA may be an important determinant of toxicity, the metabolic fate of the compound has not been fully elucidated. To date, the only identified BEA metabolites are aziridine, 2-oxazolidone and 5-hydroxy-2-oxazolidone. In this study, stable isotope labelling (SIL) of BEA analogs ((¹³C and ²H) were used to differentiate generated BEA metabolites from endogenous molecules which enabled the accurate liquid chromatography mass spectrometry detection of more than 180 novel metabolites. BEA metabolism was evaluated in rats after acute administration of a non-toxic dose (50 mg/kg) and a toxic dose (250 mg/kg) that caused frank RPN and polyuria. Newly identified metabolites include three carbamoylation products, two mercapturic acids and a group of amino acid conjugates. Overall, the results indicate that BEA metabolism is very complex, suggest the potential formation of reactive intermediates and establish that BEA is subject to conjugation with glutathione. The results also demonstrate the utility and sensitivity of the SIL approach for identification of metabolites from small, reactive compounds.


Asunto(s)
Carbamatos/metabolismo , Etilaminas/orina , Glutatión/metabolismo , Marcaje Isotópico/métodos , Aminoácidos/metabolismo , Animales , Etilaminas/química , Etilaminas/toxicidad , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
8.
J Proteome Res ; 9(1): 59-69, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19445528

RESUMEN

Tissue injury and repair are often overlapping consequences of disease or toxic exposure, but are not often considered as distinct processes in molecular studies. To establish the systemic metabolic response to liver regeneration, the partial hepatectomy (PH) model has been studied in the rat by an integrated metabonomics strategy, utilizing (1)H NMR spectroscopy of urine, liver and serum. Male Sprague-Dawley rats were subjected to either surgical removal of approximately two-thirds of the liver, sham operated (SO) surgery, or no treatment (n = 10/group) and samples collected over a 7 day period. A number of urinary metabolic perturbations were observed in PH rats compared with SO and control animals, including elevated levels of taurine, hypotaurine, creatine, guanidinoacetic acid, betaine, dimethylglycine and bile acids. Serum betaine and creatine were also elevated after PH, while levels of triglyceride were reduced. In the liver, triglycerides, cholesterol, alanine and betaine were elevated after PH, while choline and its derivatives were reduced. Upon examining the dynamic pattern of urinary response (the 'metabolic trajectory'), several metabolites could be categorized into groups likely to reflect perturbations to different processes such as dietary intake or hepatic 1-carbon metabolism. Several of the urinary perturbations observed during the regenerative phase of the PH model have also been observed after exposure to liver toxins, indicating that hepatic regeneration may make a contribution to the systemic alterations in metabolism associated with hepatotoxicity. The observed changes in 1-carbon and lipid metabolism are consistent with the proposed role of these pathways in the activation of a regenerative response and provide further evidence regarding the utility of urinary NMR profiles in the detection of liver-specific pathology. Biofluid (1)H NMR-based metabolic profiling provides new insight into the role of metabolism of liver regeneration, and suggests putative biomarkers for the noninvasive monitoring of the regeneration process.


Asunto(s)
Regeneración Hepática/fisiología , Hígado/fisiología , Metabolómica/métodos , Resonancia Magnética Nuclear Biomolecular/métodos , Animales , Biomarcadores/análisis , Análisis Químico de la Sangre , Peso Corporal , Hepatectomía , Histocitoquímica , Hígado/química , Hígado/metabolismo , Hígado/cirugía , Masculino , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley , Orina/química
9.
J Toxicol Environ Health A ; 73(1): 58-73, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-19953420

RESUMEN

Acetaminophen (APAP)-induced hepatotoxicity accounts for nearly half of acute liver failure cases in the United States. The doses that produce hepatotoxicity vary considerably and many risk factors have been proposed, including liver inflammation from viral hepatitis. Interestingly, inflammatory stress from another stimulus, bacterial endotoxin (lipopolysaccharide, LPS), renders the liver more sensitive to hepatotoxicity from numerous xenobiotic agents. The purpose of these studies was to test the hypothesis that inflammation induced by LPS or infection with reovirus increases sensitivity to APAP-induced liver injury. For LPS-induced inflammation, C57BL/6J mice were treated with either saline or LPS (44 x 10(6) EU/kg, ip) 2 h before treatment with APAP (100-400 mg/kg, ip) or saline. No elevation in serum alanine aminotransferase (ALT) activity was observed in mice that received vehicle or LPS alone. LPS co-treatment produced a leftward shift of the dose-response curve for APAP-induced hepatotoxicity and led to significantly greater tumor necrosis factor-alpha (TNF) production than APAP alone. Reovirus serotype 1 (10(8) PFU, iv) induced inflammation in Balb/c mice as evidenced by increases in hepatic mRNAs for macrophage inhibitory protein-2, interleukin-6, and TNF. Co-administration of reovirus and APAP at doses of 450 and 700 mg/kg (2 h after reovirus) led to increases in serum ALT activity, whereas neither reovirus nor APAP alone produced liver injury. Consistent with the increases in serum ALT activity, histopathologic examination revealed centrilobular necrosis with marked neutrophilic accumulation only in livers of mice treated with LPS/APAP or with reovirus/APAP. The results suggest that normally noninjurious doses of APAP are rendered hepatotoxic by modest inflammation, whether bacterial or viral in origin.


Asunto(s)
Acetaminofén/efectos adversos , Hígado/efectos de los fármacos , Infecciones por Reoviridae/inmunología , Animales , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Femenino , Glutatión/metabolismo , Inflamación/inducido químicamente , Inflamación/microbiología , Inflamación/virología , Lipopolisacáridos/farmacología , Hígado/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neutrófilos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesis
10.
J Proteome Res ; 8(11): 5175-87, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19821561

RESUMEN

The amino sugar galactosamine (galN) induces alterations in the hepatic uridine nucleotide pool and has been widely used as a model of human viral hepatitis. Histopathological and clinical chemistry analyses of a cohort of rats following administration of galN revealed extreme interindividual variability in the extent of the toxic response which enabled classification of 'responder' and 'non-responder' phenotypes. An integrative metabolic profiling approach was applied to characterize biomarkers of exposure to galN in urine, serum, feces and liver from responders and non-responders. The presence of N-acetylglucosamine and galN in the urine correlated with the occurrence and extent of toxic response. Conversely, the novel identification of galN-pyrazines in the feces of non-responders and their virtual absence in the feces of responders suggests an alternative means of distribution and metabolism of galN in non-responders. The absence of the UDP-hexosamines in the liver of non-responders further supports differential metabolism of galN and suggests an ability of non-responders to avoid UDP-glucose depletion. An observed disturbance of gut microbial derived metabolites in the urine and feces of non-responders may suggest a role of the microflora in reducing the effective dose of galN. This systems level metabonomic approach has provided new mechanistic insights into differential response to galN and is widely applicable to the study of interindividual variation in metabolism for any xenobiotic intervention.


Asunto(s)
Biomarcadores/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Galactosamina , Animales , Biomarcadores/química , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Heces/química , Galactosamina/metabolismo , Galactosamina/toxicidad , Humanos , Hígado/química , Hígado/metabolismo , Hígado/patología , Masculino , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fenotipo , Ratas , Ratas Sprague-Dawley , Orina/química
11.
Magn Reson Chem ; 47 Suppl 1: S26-35, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19639609

RESUMEN

The time-related metabolic effects of 1-cyano-2-hydroxy-3-butene (CHB, crambene), a naturally occurring nitrile and experimental model toxin causing exocrine pancreatitis, have been investigated in rats using high-resolution NMR spectroscopy of urine and serum in combination with pattern recognition analysis. Rats were administered CHB subcutaneously in two doses, 15 mg/kg dose (n = 10) and 150 mg/kg (n = 10), and conventional histopathology and clinical chemistry assessments were performed. Urine samples were collected at - 16 and 0, 8, 24, 48, 72, 96, 120, 144 and 168 h postdosing and serum samples were collected at 48 and 168 h postdosing; these were analyzed using a range of 1D and 2D NMR spectroscopic methods. The metabolic profile perturbations seen throughout the time-course of the study are described, and the application of the spectral correlation technique Statistical TOtal Correlation SpectroscopY (STOCSY) to detect both structural and novel toxicological connectivities between xenobiotic and endogenous metabolite signals is illustrated for the first time. As a result, it is suggested that the STOCSY approach may be of wider application in the identification of toxic versus nontoxic metabolites in drug metabolism studies.


Asunto(s)
Alquenos/envenenamiento , Metabolómica , Nitrilos/envenenamiento , Páncreas Exocrino , Pancreatitis/sangre , Pancreatitis/orina , Animales , Peso Corporal , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Tamaño de los Órganos , Páncreas Exocrino/patología , Ratas , Ratas Sprague-Dawley , Estándares de Referencia
12.
Artículo en Inglés | MEDLINE | ID: mdl-18472313

RESUMEN

Urinary metabolic perturbations associated with acute and chronic acetaminophen-induced hepatotoxicity were investigated using nuclear magnetic resonance (NMR) spectroscopy and ultra performance liquid chromatography/mass spectrometry (UPLC/MS) metabonomics approaches to determine biomarkers of hepatotoxicity. Acute and chronic doses of acetaminophen (APAP) were administered to male Sprague-Dawley rats. NMR and UPLC/MS were able to detect both drug metabolites and endogenous metabolites simultaneously. The principal component analysis (PCA) of NMR or UPLC/MS spectra showed that metabolic changes observed in both acute and chronic dosing of acetaminophen were similar. Histopathology and clinical chemistry studies were performed and correlated well with the PCA analysis and magnitude of metabolite changes. Depletion of antioxidants (e.g. ferulic acid), trigonelline, S-adenosyl-L-methionine, and energy-related metabolites indicated that oxidative stress was caused by acute and chronic acetaminophen administration. Similar patterns of metabolic changes in response to acute or chronic dosing suggest similar detoxification and recovery mechanisms following APAP administration.


Asunto(s)
Acetaminofén/envenenamiento , Enfermedad Hepática Inducida por Sustancias y Drogas , Cromatografía Líquida de Alta Presión/métodos , Biología Computacional/métodos , Hepatopatías/orina , Espectrometría de Masas/métodos , Metabolismo , Resonancia Magnética Nuclear Biomolecular/métodos , Ratas Sprague-Dawley/orina , Animales , Hígado/patología , Hepatopatías/patología , Masculino , Necrosis/patología , Necrosis/orina , Ratas
13.
J Am Vet Med Assoc ; 232(4): 564-73, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18279094

RESUMEN

OBJECTIVE: To describe the character and frequency of causes of death and associated lesions in long-distance racing sled dogs. DESIGN: Retrospective case series. ANIMALS: 23 dogs. PROCEDURES: Medical records of dogs that died during or soon after competition in the Iditarod Trail sled dog races (1994 through 2006) were examined for fi ndings of gross necropsy and histologic evaluation of tissue samples. From the data, descriptive and comparative statistics were obtained. RESULTS: Recognized causes of death included aspiration of gastric contents (n = 4), aspiration pneumonia (4), acute blood loss secondary to gastric ulceration (3), and sled dog myopathy (2). A cause of death was not established for 7 dogs. Prevalent lesions among the study population included rhabdomyolysis (n = 15), enteritis (10), gastritis (10), aspiration pneumonia (8), and gastric ulceration (8). All dogs with aspiration pneumonia had concurrent gastric mucosal lesions. Subjective biventricular cardiac hypertrophy was evident in most dogs; other lesions detected frequently included centrilobular hepatic fibrosis, gastric dilatation, and mild cardiac myodegeneration and necrosis. CONCLUSIONS AND CLINICAL RELEVANCE: Unexpected death is a rare event among conditioned sled dogs during competition in endurance races. Potentially life-threatening conditions of dogs that are associated with periods of long-distance physical exertion include aspiration pneumonia, gastric mucosal lesions, and severe rhabdomyolysis. Dogs that develop clinical signs suggestive of these conditions should be excluded from strenuous activities. Epidemiologic investigations are required to clarify the risk for death associated with these lesions in dogs competing in endurance races.


Asunto(s)
Enfermedades de los Perros/mortalidad , Mucosa Gástrica/patología , Condicionamiento Físico Animal/efectos adversos , Esfuerzo Físico/fisiología , Neumonía por Aspiración/veterinaria , Rabdomiólisis/veterinaria , Alaska , Animales , Causas de Muerte , Perros , Femenino , Gastritis/complicaciones , Gastritis/mortalidad , Gastritis/veterinaria , Masculino , Úlcera Péptica/complicaciones , Úlcera Péptica/mortalidad , Úlcera Péptica/veterinaria , Resistencia Física , Neumonía por Aspiración/complicaciones , Neumonía por Aspiración/mortalidad , Prevalencia , Estudios Retrospectivos , Rabdomiólisis/complicaciones , Rabdomiólisis/mortalidad
14.
Toxicol Sci ; 90(2): 569-85, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16415329

RESUMEN

Rats cotreated with lipopolysaccharide (LPS) and ranitidine (RAN) but not LPS and famotidine (FAM) develop hepatocellular injury in an animal model of idiosyncratic drug reactions. Evaluation of liver gene expression in rats given LPS and/or RAN led to confirmation that the hemostatic system, hypoxia, and neutrophils (PMNs) are critical mediators in LPS/RAN-induced liver injury. We tested the hypothesis that unique gene expression changes distinguish LPS/RAN-treated rats from rats given LPS or RAN alone and from those cotreated with LPS/FAM. Rats were treated with a nonhepatotoxic dose of LPS (44.4 x 10(6) endotoxin units/kg, iv) or its vehicle. Two hours thereafter they were given RAN (30 mg/kg, iv), FAM (either 6 mg/kg, a pharmacologically equi-efficacious dose, or 28.8 mg/kg, an equimolar dose, iv), or vehicle. They were killed 2 or 6 h after drug treatment for evaluation of hepatotoxicity (2 and 6 h) and liver gene expression (2 h only). At a time before the onset of hepatocellular injury, hierarchical clustering distinguished rats treated with LPS/RAN from those given LPS alone. 205 probesets were expressed differentially to a greater or lesser degree only in LPS/RAN-treated rats compared to LPS/FAM or LPS alone, which did not develop liver injury. These included VEGF, EGLN3, MAPKAPK-2, BNIP3, MIP-2, COX-2, EGR-1, PAI-1, IFN-gamma, and IL-6. Expression of these genes was confirmed by real-time PCR. Serum concentrations of MIP-2, PAI-1, IFN-gamma, and IL-6 correlated with their respective gene expression patterns. Overall, the expression of several gene products capable of controlling requisite mediators of injury (i.e., hemostasis, hypoxia, PMNs) in this model were enhanced in livers of LPS/RAN-treated rats. Furthermore, enhanced expression of MAPKAPK-2 in RAN-treated rats and its target genes in LPS/RAN-treated rats suggests that p38/MAPKAPK-2 signaling is a regulation point for enhancement of LPS-induced gene expression by RAN.


Asunto(s)
Famotidina/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Antagonistas de los Receptores H2 de la Histamina/toxicidad , Hígado/efectos de los fármacos , Ranitidina/toxicidad , Animales , Interacciones Farmacológicas , Ensayo de Inmunoadsorción Enzimática , Perfilación de la Expresión Génica , Lipopolisacáridos , Hígado/metabolismo , Hígado/patología , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley
15.
Cell Metab ; 24(2): 223-33, 2016 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-27508871

RESUMEN

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRß-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.


Asunto(s)
Movimiento Celular , Imidazoles/efectos adversos , Imidazoles/farmacología , Metabolismo de los Lípidos , Lipoproteínas/metabolismo , Receptores X del Hígado/agonistas , Neutrófilos/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Tejido Adiposo/metabolismo , Adolescente , Adulto , Animales , Movimiento Celular/efectos de los fármacos , Colesterol/sangre , Colesterol/metabolismo , Voluntarios Sanos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Imidazoles/uso terapéutico , Recuento de Leucocitos , Lipoproteínas/sangre , Macaca fascicularis , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Sistema Mononuclear Fagocítico/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Triglicéridos/sangre , Adulto Joven
16.
ACS Med Chem Lett ; 7(12): 1207-1212, 2016 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-27994765

RESUMEN

Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRß activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.

17.
Virus Res ; 90(1-2): 155-69, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12457971

RESUMEN

Bovine leukemia virus (BLV) causes persistent lymphocytosis, a preneoplastic, polyclonal expansion of B lymphocytes. The expansion increases viral transmission to new hosts, but the mechanisms of this expansion have not been determined. We hypothesized that BLV infection contributes to B-cell expansion by signaling initiated via viral transmembrane protein motifs undergoing tyrosine phosphorylation. Viral mimicry of host cell proteins is a well-demonstrated mechanism by which viruses may increase propagation or decrease recognition by the host immune system. The cytoplasmic tail of BLV transmembrane protein gp30 (TM) has multiple areas of homology to motifs of host cell signaling proteins, including two immunoreceptor tyrosine-based activation motifs (ITAMs) and two immunoreceptor tyrosine-based inhibition motifs (ITIMs), which are homologous to B-cell receptor and inhibitory co-receptor motifs. Signaling by these motifs in B cells typically relies on tyrosine phosphorylation, followed by interactions with Src-homology-2 (SH2) domains of nonreceptor protein tyrosine kinases or phosphatases. Phosphorylation of tyrosine residues in the cytoplasmic tail of TM was tested in four systems including ex vivo cultured peripheral blood mononuclear cells from BLV infected cows, BLV-expressing fetal lamb kidney cell and bat lung cell lines, and DT40 B cells transfected with a fusion of mouse extracellular CD8alpha and cytoplasmic TM. No phosphorylation of TM was detected in our experiments in any of the cell types utilized, or with various stimulation methods. Detection was attempted by immunoblotting for phosphotyrosines, or by metabolic labeling of cells. Thus BLV TM is not likely to modify host signal pathways through interactions between phosphorylated tyrosines of the ITAM or ITIM motifs and host-cell tyrosine kinases or phosphatases.


Asunto(s)
Linfocitos B/inmunología , Virus de la Leucemia Bovina/patogenicidad , Proteínas Oncogénicas de Retroviridae/metabolismo , Transducción de Señal , Tirosina/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Secuencia de Aminoácidos , Animales , Bovinos , Línea Celular , Leucosis Bovina Enzoótica/virología , Activación de Linfocitos , Ratones , Datos de Secuencia Molecular , Fosforilación , Receptores de Aminoácidos/química , Receptores de Aminoácidos/metabolismo , Receptores de Antígenos de Linfocitos B/química , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores Inmunológicos/química , Receptores Inmunológicos/metabolismo , Proteínas Oncogénicas de Retroviridae/química , Proteínas del Envoltorio Viral/química
18.
J Vet Intern Med ; 16(4): 426-32, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12141304

RESUMEN

Questions about pathogenesis and therapy for Helicobacter infections in dogs could be answered with a simple, noninvasive, sensitive, and specific diagnostic test. We hypothesized that a fecal polymerase chain reaction (PCR) assay would detect Helicobacter and could be useful for assessing therapeutic responses. Paired gastric biopsies and fecal samples were obtained from 39 random source dogs (group 1). Gastric biopsies from each of these dogs had histologic evidence of gastric spiral bacteria, and paired gastric tissue and fecal samples produced a 375-base pair (bp) product when amplified by PCR with Helicobacter-specific primers. Specificity of the PCR product was confirmed by detection of expected 60-, 119-, and 196-bp products following Hinfl digestion. Direct sequencing of amplicons from paired PCR products from gastric biopsy and fecal samples from 8 group I dogs showed that gastric products had the highest homologies with known gastric Helicobacter species, whereas fecal products had the highest homologies with intestinal species. Healthy mixed-breed dogs (group II; n = 8) with histologically confirmed spiral bacteria infection were treated with a 21-day course of metronidazole, amoxicillin, and famotidine. Fecal samples were collected from group II dogs twice before and within 3 days of completion of treatment. The PCR results correctly identified 15/16 pretreatment samples as positive: 1 pretreatment sample was negative. PCR results identified 8/8 posttreatment samples as Helicobacter negative. Fecal PCR is a useful test for detecting Helicobacter infection in dogs. This assay may be useful as a screening test for infection and could be used to address questions relevant to pathogenesis and therapy.


Asunto(s)
Enfermedades de los Perros/diagnóstico , Infecciones por Helicobacter/veterinaria , Helicobacter pylori/genética , Reacción en Cadena de la Polimerasa/veterinaria , ARN Ribosómico 16S/genética , Animales , Antibacterianos/uso terapéutico , Cruzamiento , Cartilla de ADN , Enfermedades de los Perros/tratamiento farmacológico , Perros , Heces/microbiología , Helicobacter/clasificación , Helicobacter/genética , Helicobacter/aislamiento & purificación , Infecciones por Helicobacter/diagnóstico , Helicobacter pylori/aislamiento & purificación , Reacción en Cadena de la Polimerasa/normas , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Estómago/microbiología , Estómago/patología
19.
J Am Vet Med Assoc ; 221(5): 659-61, 643-4, 2002 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-12216904

RESUMEN

A 9-year-old spayed female Golden Retriever was examined because of progressive hind limb lameness. Magnetic resonance imaging of the thoracic and lumbar portions of the vertebral column revealed a focal, contrast-enhancing, intramedullary spinal cord mass. The history, signalment, and magnetic resonance findings were suggestive of spinal cord neoplasia. A hemilaminectomy, durotomy, and longitudinal myelotomy were performed, and a 1 X 1-cm mass that contained numerous blood vessels was removed with blunt dissection. Results of histologic examination and immunohistochemical staining of the mass suggested that it was a hamartoma. The dog improved after surgery, with no evidence of a recurrence of clinical signs 14 months after surgery. Vascular malformations of the CNS in dogs include hamartomas, hemangiomas, angiomas, hemangioblastomas, meningocerebral hemangiomatosis, and arteriovenous malformations. A hamartoma is a non-neoplastic overgrowth of cells or an improper proportion of cells that are normally in the involved tissue. Although magnetic resonance imaging may be helpful in determining the extent of the lesion in dogs with vascular malforrmations, it cannot be used to distinguish neoplastic from non-neoplastic formations. Excision may result in a good outcome for dogs with an intramedullary spinal cord hamartoma.


Asunto(s)
Enfermedades de los Perros/cirugía , Hamartoma/veterinaria , Enfermedades de la Médula Espinal/veterinaria , Animales , Diagnóstico Diferencial , Enfermedades de los Perros/diagnóstico , Perros , Femenino , Hamartoma/diagnóstico , Hamartoma/cirugía , Imagen por Resonancia Magnética/veterinaria , Médula Espinal/patología , Médula Espinal/cirugía , Enfermedades de la Médula Espinal/diagnóstico , Enfermedades de la Médula Espinal/cirugía , Resultado del Tratamiento
20.
J Med Chem ; 57(5): 2013-32, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24521299

RESUMEN

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.


Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Antivirales/farmacocinética , Área Bajo la Curva , Carbamatos , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Hepacivirus/enzimología , Hepacivirus/fisiología , Imidazoles/química , Imidazoles/farmacocinética , Espectroscopía de Resonancia Magnética , Pirrolidinas , Ratas , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Valina/análogos & derivados
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