52 results on '"Evan B. Janovitz"'
Search Results
2. Discovery Toxicology and Discovery Pathology
- Author
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Glenn H. Cantor, Evan B. Janovitz, and René Meisner
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- 2023
3. Contributors
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Basel T. Assaf, Adam D. Aulbach, Virunya Bhat, Brad Bolon, William M. Bracken, Alys E. Bradley, Glenn H. Cantor, Kevin B. Donnelly, Elodie Drevon-Gaillot, Stephen K. Durham, Jeffery A. Engelhardt, Daniela Ennulat, James Fikes, John Reginald Foster, Kathleen Funk, Sibylle Gröters, Magali R. Guffroy, Silvia Guionaud, Katherine Hammerman, Carole Harbison, Claudia Harper, Christopher Hurst, Evan B. Janovitz, Kevin Keane, Stephanie Klein, Rebecca Kohnken, Michael W. Leach, Xiantang Li, René Meisner, Keith Nelson, Thomas Nolte, Arun R. Pandiri, Jonathan A. Phillips, Colin G. Rousseaux, Daniel G. Rudmann, Keegan C. Rudmann, Aaron M. Sargeant, JoAnn C.L. Schuh, A. Eric Schultze, Rani S. Sellers, James A. Swenberg, Eric Tien, John L. Vahle, Lyn M. Wancket, and Charles E. Wood
- Published
- 2023
4. Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1
- Author
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Yan, Shi, Ying, Wang, Wei, Meng, Robert P, Brigance, Denis E, Ryono, Scott, Bolton, Hao, Zhang, Sean, Chen, Rebecca, Smirk, Shiwei, Tao, Joseph A, Tino, Kristin N, Williams, Richard, Sulsky, Laura, Nielsen, Bruce, Ellsworth, Michael K Y, Wong, Jung-Hui, Sun, Leslie W, Leith, Dawn, Sun, Dauh-Rurng, Wu, Anuradha, Gupta, Richard, Rampulla, Arvind, Mathur, Bang-Chi, Chen, Aiying, Wang, Helen G, Fuentes-Catanio, Lori, Kunselman, Michael, Cap, Jacob, Zalaznick, Xiaohui, Ma, Heng, Liu, Joseph R, Taylor, Rachel, Zebo, Beverly, Jones, Stephen, Kalinowski, Joann, Swartz, Ada, Staal, Kevin, O'Malley, Lisa, Kopcho, Jodi K, Muckelbauer, Stanley R, Krystek, Steven A, Spronk, Jovita, Marcinkeviciene, Gerry, Everlof, Xue-Qing, Chen, Carrie, Xu, Yi-Xin, Li, Robert A, Langish, Yanou, Yang, Qi, Wang, Kamelia, Behnia, Aberra, Fura, Evan B, Janovitz, Nicola, Pannacciulli, Steven, Griffen, Bradley A, Zinker, John, Krupinski, Mark, Kirby, Jean, Whaley, Robert, Zahler, Joel C, Barrish, Jeffrey A, Robl, and Peter T W, Cheng
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Diabetes Mellitus, Type 2 ,Glucokinase ,Organophosphonates ,Azetidines ,Humans ,Hypoglycemic Agents ,Hypoglycemia - Abstract
Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator"
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- 2022
5. Contributors
- Author
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Rick Adler, Famke Aeffner, Laura E. Armstrong, Dmitri Artemov, Adam D. Aulbach, Bindu M. Bennet, Eric A. Blomme, Brad Bolon, Christopher J. Bowman, Molly Boyle, Alys Bradley, Dino Bradley, Danielle Brown, Pierre R. Bushel, Ellen Cannady, Mark F. Cesta, Curtis Chan, Jennifer A. Chilton, Peter J.M. Clements, Torrie A. Crabbs, Myrtle A. Davis, Sandy Eldridge, Daniela Ennulat, Jeffrey Everitt, Isabel Figueroa, James D. Fikes, Thomas Forest, Catherine A. Foss, John R. Foster, Kathleen Gabrielson, Shayne C. Gad, Kapil Gadkar, Jinping Gan, David Garcia-Tapia, Frank J. Geoly, Wendy G. Halpern, Jerry F. Hardisty, Wanda M. Haschek, Kathleen Marie Heinz-Taheny, Kristi Helke, Lauren E. Himmel, Mark J. Hoenerhoff, Jennifer L. Ingram–Ross, Armando R. Irizarry Rovira, Evan B. Janovitz, Kishore Katyayan, Charlotte M. Keenan, Angela King-Herbert, Steven T. Laing, Lois D. Lehman-McKeeman, Na Li, Calvert Louden, Claire Lyons, Kevin McDorman, Elizabeth McInnes, Lyn Miller Wancket, Sheroy Minocherhomji, Sébastien Monette, James Morrison, Vasanthi Mowat, Sydney Mukaratirwa, Keith Nelson, Arun R. Pandiri, Tracey Papenfuss, Nita Patel, Daniel J. Patrick, Shari A. Price, Deepa B. Rao, James T. Raymond, Jennifer Rojko, Colin G. Rousseaux, Sara F. Santagostino, Aaron Sargeant, Christina Satterwhite, A. Eric Schultze, Vanessa Schumacher, Cheryl Scudamore, Keith R. Shockley, Bhanu P. Singh, David M. Stresser, Polina Sysa-Shah, Debra A. Tokarz, Terry Van Vleet, Matthew A. Wallig, Jin Wang, Cynthia J. Willson, Kristin Lewis Wilson, Christopher T. Winkelmann, Jeffrey C. Wolf, Charles Wood, Daniela Bumbaca Yadav, and Mark Zarella
- Published
- 2022
6. Morphologic Manifestations of Toxic Cell Injury
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Matthew A. Wallig and Evan B. Janovitz
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- 2022
7. Assessing the risk of drug crystallization in vivo
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Yang Wu, Dieter M. Drexler, Joseph B. Santella, Thomas Brodie, Janet DiPiero, Stefan Ruepp, Umesh Hanumegowda, Brian Gemzik, Ching-Chiang Su, Evan B. Janovitz, Randy White, Michael J. Hageman, Julie Carman, John Hynes, Duohai Pan, and John R. Megill
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Male ,Risk ,Drug ,Duodenum ,Pyridines ,media_common.quotation_subject ,Primary Cell Culture ,Biological Availability ,Spectrum Analysis, Raman ,Toxicology ,law.invention ,Rats, Sprague-Dawley ,In vivo ,law ,Drug Discovery ,Macrophages, Alveolar ,Microscopy ,Animals ,Crystallization ,media_common ,Pharmacology ,Polarized light microscopy ,Chemistry ,Rats ,Bioavailability ,Interleukin-1 Receptor-Associated Kinases ,Solubility ,Drug development ,Tolerability ,Pyrazoles ,Female ,Biomedical engineering - Abstract
Introduction Low intrinsic solubility leading to poor oral bioavailability is a common challenge in drug discovery that can often be overcome by formulation strategies, however, it remains a potential limitation that can pose challenges for early risk assessment and represent a significant obstacle to drug development. We identified a selective inhibitor (BMS-986126) of the IL-1 receptor–associated kinase 4 (IRAK4) with favorable properties as a lead candidate, but with unusually low intrinsic solubility of Methods Conventional histopathology identified the issue of crystal formation in vivo. Subsequent investigative work included confocal Raman micro-spectroscopy, MALDI-MS, polarized light microscopy of fresh wet-mount tissue scrapings and transmission electron microscopy. Results BMS-986126 was advanced into a 2-week toxicology study in rats. The main finding in this study was minimal granulomatous inflammation in the duodenum, associated with the presence of birefringent crystals at the highest dosage of 100 mg/kg/day. Considering the safety margin, and the single location of the lesion, BMS-986126 was further progressed into IND-enabling toxicology studies where tolerability deteriorated with increasing dosing duration. Birefringent crystals and granulomatous inflammation were detected in multiple organs at dosages ≥20 mg/kg/day. Raman spectroscopy confirmed the identity of the crystals as BMS-986126. Therefore, follow up investigations were conducted to further characterize drug crystallization and to evaluate detection methods for their potential to reliably detect in vivo crystallization early. Discussion The purpose of our efforts was to identify critical factors influencing in vivo drug crystallization and to provide a preliminary assessment (based on one compound) which method would be best suited for identifying crystals. Results indicated a combination of methods was required to provide a complete assessment of drug crystallization and that a simple technique, scraping of freshly collected tissue followed by evaluation under polarizing light was suitable for detecting crystals. However, dosing for 2 weeks was required for crystals to grow to a clearly detectable size.
- Published
- 2019
8. From the Cover: Investigative Nonclinical Cardiovascular Safety and Toxicology Studies with BMS-986094, an NS5b RNA-Dependent RNA Polymerase Inhibitor
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James Hennan, Michael Gill, John R. Megill, Marc H. Davies, Shawn P. Clark, Michael J. Graziano, Denise Bounous, Randy White, Kristen Horn, Evan B. Janovitz, and Thomas P. Sanderson
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Male ,0301 basic medicine ,medicine.medical_specialty ,Guanosine Monophosphate ,Hemodynamics ,Viral Nonstructural Proteins ,Kidney ,Toxicology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,Ejection fraction ,Proteinuria ,business.industry ,Beta-2 microglobulin ,Skeletal muscle ,Heart ,Stroke volume ,Hepatitis C, Chronic ,RNA-Dependent RNA Polymerase ,medicine.disease ,Molecular biology ,Toxicokinetics ,Macaca fascicularis ,Mitochondrial toxicity ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,business - Abstract
BMS-986094, a 2'-C-methylguanosine prodrug that was in development for treatment of chronic hepatitis C infection was withdrawn from Phase 2 clinical trials because of unexpected cardiac and renal adverse events. Investigative nonclinical studies were conducted to extend the understanding of these findings using more comprehensive endpoints. BMS-986094 was given orally to female CD-1 mice (25 and 150 mg/kg/d) for 2 weeks (53/group) and to cynomolgus monkeys (15 and 30 mg/kg/d) for up to 6 weeks (2-3/sex/group for cardiovascular safety, and 5/sex/group for toxicology). Endpoints included toxicokinetics; echocardiography, telemetric hemodynamics and electrocardiography, and tissue injury biomarkers (monkey); and light and ultrastructural pathology of heart, kidney, and skeletal muscle (mouse/monkey). Dose-related and time-dependent findings included: severe toxicity in mice at 150 mg/kg/d and monkeys at 30 mg/kg/d; decreased left ventricular (LV) ejection fraction, fractional shortening, stroke volume, and dP/dt; LV dilatation, increased QTc interval, and T-wave flattening/inversion (monkeys at ≥ 15 mg/kg/d); cardiomyocyte degeneration (mice at 150 mg/kg/d and monkeys at ≥ 15 mg/kg/d) with myofilament lysis/myofbril disassembly; time-dependent proteinuria and increased urine β-2 microglobulin, calbindin, clusterin; kidney pallor macroscopically; and tubular dilatation (monkeys); tubular regeneration (mice 150 mg/kg/d); and acute proximal tubule degeneration ultrastructurally (mice/monkeys); and skeletal muscle degeneration with increased urine myoglobin and serum sTnI. These studies identified changes not described previously in studies of BMS-986094 including premonitory cardiovascular functional changes as well as additional biomarkers for muscle and renal toxicities. Although the mechanism of potential toxicities observed in BMS-986094 studies was not established, there was no evidence for direct mitochondrial toxicity.
- Published
- 2016
9. Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor
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Jeffrey A. Robl, Michael Thomas, Mary Ann Pelleymounter, Brian Gemzik, Anthony V. Azzara, Brian J. Murphy, Sharon N. Bisaha, Helen E. Godonis, Daniel Longhi, Neil Flynn, William N. Washburn, Kenneth W. Rohrbach, Khehyong Ngu, Saleem Ahmad, Susan Harvey, Christine Huang, Evan B. Janovitz, Andres S. Hernandez, James Devenny, Hongwei Zhang, Lisa Zhang, Susan Glick, Suzanne Rooney, and Wei Wang
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010405 organic chemistry ,Stereochemistry ,Chemistry ,Antagonist ,Halogenation ,Pharmacology ,010402 general chemistry ,01 natural sciences ,In vitro ,0104 chemical sciences ,Melanin-concentrating hormone receptor ,Pharmacokinetics ,In vivo ,Drug Discovery ,Molecular Medicine ,Structure–activity relationship ,Receptor - Abstract
The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.
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- 2016
10. Evaluation of Uracil, Sodium Ascorbate, and Rosiglitazone as Promoters of Urinary Bladder Transitional Cell Carcinomas in Male Sprague-Dawley Rats
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Michael J. Graziano, Solomon Haile, John R. Foster, Bassem Attalla, Magnus Söderberg, Evan B. Janovitz, Shen-Jue Chen, Karen Granaldi, Yunling Song, Mark Tirmenstein, Martin Billger, Thomas Dorr, Raja Mangipudy, Kristina D. Chadwick, Ann-Marie Bergholm, and Melissa Czajkowski
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0301 basic medicine ,Sodium ascorbate ,Male ,medicine.medical_specialty ,Urinary system ,Urinary Bladder ,Urology ,Ascorbic Acid ,Toxicology ,Pathology and Forensic Medicine ,Urothelial Hyperplasia ,Rats, Sprague-Dawley ,Rosiglitazone ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Uracil ,Molecular Biology ,Carcinoma, Transitional Cell ,Urinary bladder ,business.industry ,Incidence (epidemiology) ,Cell Biology ,Rats ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Carcinogens ,Histopathology ,business ,medicine.drug - Abstract
The purpose of this study was to establish a 2-stage model of urinary bladder carcinogenesis in male Sprague-Dawley rats to identify tumor promoters. In phase 1 of the study, rats ( n = 170) were administered 100 mg/kg of the tumor initiator, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), twice weekly by oral gavage (po) for a period of 6 weeks. Phase 2 consisted of dividing rats into 4 groups ( n = 40 per group) and administering one of the following for 26 weeks to identify putative tumor promoters: (1) vehicle po, (2) 25 mg/kg/day rosiglitazone po, (3) 5% dietary sodium l-ascorbate, and (4) 3% dietary uracil. Rats were necropsied after 7.5 months, and urinary bladders were evaluated by histopathology. BBN/vehicle treatments induced the development of urothelial hyperplasia (83%) and papillomas (15%) but no transitional cell carcinomas (TCCs). Rosiglitazone increased the incidence and severity of papillomas (93%) and resulted in TCC in 10% of treated rats. Uracil was the most effective tumor promoter in our study and increased the incidence of papillomas (90%) and TCC (74%). Sodium ascorbate decreased the incidence of urothelial hyperplasia (63%) and did not increase the incidence of urothelial papillomas or TCC. These data confirm the capacity of our 2-stage model to identify urinary bladder tumor promoters.
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- 2018
11. Systemic Loss of C-terminal Src Kinase Expression Elicits Spontaneous Suppurative Inflammation in Conditional Knockout Mice
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Evan B. Janovitz, Lisa Berman-Booty, Glenn H. Cantor, Rukiye Eraslan, Beverly K. Jones, Michael Hayward, Denise Bounous, Umesh Hanumegowda, Olesia Buiakova, and Susan Wee
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0301 basic medicine ,Male ,Gene Expression ,Inflammation ,Proinflammatory cytokine ,Enteritis ,Lesion ,CSK Tyrosine-Protein Kinase ,03 medical and health sciences ,Conditional gene knockout ,Medicine ,Animals ,Mice, Knockout ,Suppuration ,General Veterinary ,business.industry ,Kinase ,medicine.disease ,Blotting, Southern ,030104 developmental biology ,src-Family Kinases ,Cancer research ,Female ,medicine.symptom ,business ,Tyrosine kinase ,Proto-oncogene tyrosine-protein kinase Src - Abstract
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.
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- 2018
12. Morphologic Manifestations of Toxic Cell Injury
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Evan B. Janovitz and Matthew A. Wallig
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Programmed cell death ,Necrosis ,040301 veterinary sciences ,Biology ,0403 veterinary science ,Pathogenesis ,chemistry.chemical_compound ,03 medical and health sciences ,Liquefactive necrosis ,Atrophy ,Fibrosis ,Metaplasia ,medicine ,business.industry ,04 agricultural and veterinary sciences ,Hyperplasia ,medicine.disease ,Coagulative necrosis ,030104 developmental biology ,chemistry ,Etiology ,medicine.symptom ,business ,Toxicant - Abstract
Whatever causes injury to a cell – toxicant, toxin, infectious agent, or otherwise – the result is a simple or complex biochemical shift that generally results in a morphologic change which can be observed in some form. The pathologist must be able to recognize that such changes in morphology reflect a significant alteration in the cell’s homeostasis and then must decide whether or not this finding indicates reversible injury, irreversible injury, or adaptation to the new situation. Visible manifestations of disrupted function, whether ultrastructural, microscopic, or macroscopic, are lesions by definition, and lesions are still the primary means by which a toxicologic pathologist arrives at a diagnosis, hopefully one that includes the etiology as well as a description of the underlying morphologic alterations and a plausible pathogenesis of how the lesions came about. This chapter will serve as an overview of the basic histologic and ultrastructural features that reflect cell injury and cell death as well as the sequelae to such processes.
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- 2018
13. Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities
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John C. Kozlosky, Michael J. Graziano, Thomas Dorr, Joseph Horvath, Timothy P. Reilly, Raja Mangipudy, Laura Patrone, Mark S. Kirby, Victor Wang, Karyn Colman, Peter T. W. Cheng, Bradley A. Zinker, Mark Tirmenstein, and Evan B. Janovitz
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Blood Glucose ,Male ,medicine.medical_specialty ,endocrine system diseases ,Enzyme Activators ,Type 2 diabetes ,Hypoglycemia ,Toxicology ,Pathology and Forensic Medicine ,Eating ,Dogs ,Species Specificity ,Diabetes mellitus ,Internal medicine ,Glucokinase ,Diabetes Mellitus ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Glucose homeostasis ,Glycolysis ,Adverse effect ,Molecular Biology ,business.industry ,Body Weight ,nutritional and metabolic diseases ,Cell Biology ,medicine.disease ,Rats ,Rats, Zucker ,Toxicokinetics ,Endocrinology ,Toxicity ,Insulin Resistance ,business - Abstract
Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.
- Published
- 2015
14. Identification of a Nonbasic Melanin Hormone Receptor 1 Antagonist as an Antiobesity Clinical Candidate
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Jeffrey A. Robl, Guohua Zhao, Joel C. Barrish, Bei Wang, Brad D. Maxwell, Christian Caporuscio, Hongwei Zhang, James Devenny, Mary F. Grubb, Zhenghua Wang, Suzanne Rooney, James Mignone, Lisa Zhang, Brian J. Murphy, Wei Wang, Daniel Longhi, William N. Washburn, Kenneth W. Rohrbach, Evan B. Janovitz, Mark C. Manfredi, Mary Ann Pelleymounter, Michael Thomas, Hong Yang, Paul Stetsko, Saleem Ahmad, Atsu Apedo, Mary Jane Cullen, Brian Gemzik, Ning Huang, Chris Freeden, Susan Harvey, Anthony V. Azzara, Khehyong Ngu, Christine Huang, Rulin Zhao, Susan Glick, Neil Flynn, Pratik Devasthale, Andres S. Hernandez, and Helen E. Godonis
- Subjects
Male ,ERG1 Potassium Channel ,biology ,Drug discovery ,Chemistry ,hERG ,Antagonist ,Pharmacology ,Ether-A-Go-Go Potassium Channels ,Rats ,Clinical trial ,Melanin ,Dogs ,Hormone receptor ,Drug Discovery ,biology.protein ,Animals ,Humans ,Molecular Medicine ,Identification (biology) ,Anti-Obesity Agents ,Obesity ,Receptors, Somatostatin ,Receptor - Abstract
Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).
- Published
- 2014
15. Occurrence of Spontaneous Pancreatic Lesions in Normal and Diabetic Rats: A Potential Confounding Factor in the Nonclinical Assessment of GLP-1–Based Therapies
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Raja Mangipudy, Kristina D. Chadwick, Anthony M. Fletcher, Timothy P. Reilly, Susan Bonner-Weir, Evan B. Janovitz, Michael J. Graziano, M. Cecilia M. Parrula, and Denis Roy
- Subjects
geography ,medicine.medical_specialty ,geography.geographical_feature_category ,Amyloid ,business.industry ,Endocrinology, Diabetes and Metabolism ,Inflammation ,Type 2 diabetes ,medicine.disease ,Islet ,Atrophy ,Endocrinology ,Internal medicine ,Pancreatic cancer ,Internal Medicine ,Medicine ,Pancreatitis ,medicine.symptom ,business ,Glycemic - Abstract
Glucagon-like peptide 1–based therapies, collectively described as incretins, produce glycemic benefits in the treatment of type 2 diabetes. Recent publications raised concern for a potential increased risk of pancreatitis and pancreatic cancer with incretins based in part on findings from a small number of rodents. However, extensive toxicology assessments in a substantial number of animals dosed up to 2 years at high multiples of human exposure do not support these concerns. We hypothesized that the lesions being attributed to incretins are commonly observed background findings and endeavored to characterize the incidence of spontaneous pancreatic lesions in three rat strains (Sprague-Dawley [S-D] rats, Zucker diabetic fatty [ZDF] rats, and rats expressing human islet amyloid polypeptide [HIP]; n = 36/group) on a normal or high-fat diet over 4 months. Pancreatic findings in all groups included focal exocrine degeneration, atrophy, inflammation, ductular cell proliferation, and/or observations in large pancreatic ducts similar to those described in the literature, with an incidence of exocrine atrophy/inflammation seen in S-D (42–72%), HIP (39%), and ZDF (6%) rats. These data indicate that the pancreatic findings attributed to incretins are common background findings, observed without drug treatment and independent of diet or glycemic status, suggesting a need to exercise caution when interpreting the relevance of some recent reports regarding human safety.
- Published
- 2014
16. Mechanisms for Hepatobiliary Toxicity in Rats Treated with an Antagonist of Melanin Concentrating Hormone Receptor 1 (MCHR1)
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Monicah A. Otieno, Evan B. Janovitz, Yimer Callejas, Lois D. Lehman-McKeeman, William B. Foster, Vasanthi Bhaskaran, William N. Washburn, John R. Megill, and Brian Gemzik
- Subjects
0301 basic medicine ,Male ,Metabolite ,education ,Pharmacology ,Toxicology ,Heterocyclic Compounds, 2-Ring ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cholestasis ,Microscopy, Electron, Transmission ,medicine ,Animals ,Receptors, Somatostatin ,Progenitor cell ,Biliary Tract ,Dose-Response Relationship, Drug ,Chemistry ,Gene Expression Profiling ,digestive, oral, and skin physiology ,Transporter ,Hyperplasia ,medicine.disease ,Melanin-concentrating hormone receptor ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,030220 oncology & carcinogenesis ,Hepatocyte ,Toxicity - Abstract
The objective of this work was to investigate the mechanisms of hepatobiliary toxicity caused by thienopyrimidone MCHR1 antagonists using BMS-773174 as a tool molecule. Co-administration of the pan CYP inhibitor 1-aminobenzotriazole with BMS-773174 prevented hepatobiliary damage, and direct delivery of the diol metabolite BMS-769750 caused hepatobiliary toxicity, identifying the diol and possibly its downstream hydroxyacid (BMS-800754) metabolite as the toxic species. Rat liver gene expression revealed treatment-related changes in hepatic transporters and induction of oval cell-specific genes including deleted malignant tumor 1 (Dmbt1). The metabolites did not alter hepatic transporter activities, suggesting that transporter-mediated cholestasis was not involved. Because injury to biliary epithelium can result in adaptive hyperplasia, rat biliary epithelial cells (BECs) were isolated and exposed to the oxidative metabolites. BMS-769750 was cytotoxic to BECs, but not rat hepatocytes, suggesting a role of the diol in biliary epithelial injury. BMS-800754 was cytotoxic to rat hepatocytes therefore its contribution to hepatocyte injury in rats is a possibility. Induction of Dmbt1 in rat BECs was investigated because of its role in hepatic progenitor cell differentiation/proliferation during injury. Dmbt1 mRNA was induced by BMS-769750, but not BMS-800754 in BECs; this induction and cellular injury was confirmed with diol metabolites formed by other compounds with the same hepatobiliary liability. In conclusion, hepatobiliary injury by thienopyrimidinone MCHR1 antagonists was driven through a CYP-mediated bioactivation pathway. Induction of Dmbt1 mRNA coupled with cellular injury suggests that injury of biliary epithelium may be the first step toward an adaptive proliferative response causing BDH by these compounds.
- Published
- 2016
17. Application of ultrasound‐guided cholecystocentesis to the evaluation of the metabolite profiling in bile of dogs and cynomolgus monkeys
- Author
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R. Marcus Fancher, Elizabeth A. Dierks, Jamus MacGuire, Chiuwa E. Luk, James Smalley, Kimberly A. Foster, Evan B. Janovitz, Qin Sun, Hong Cai, and Maxine Fox
- Subjects
Metabolite ,Atorvastatin ,Pharmacology ,biliary excretion ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,Biliary excretion ,Dogs ,Glucuronides ,0302 clinical medicine ,medicine ,Animals ,Bile ,Metabolomics ,General Pharmacology, Toxicology and Pharmaceutics ,Chromatography, High Pressure Liquid ,Ultrasonography, Interventional ,Bile duct ,Original Articles ,preclinical models ,drug metabolism ,Ultrasound guided ,Macaca fascicularis ,Oxidative Stress ,medicine.anatomical_structure ,Neurology ,chemistry ,030220 oncology & carcinogenesis ,Metabolite profiling ,Original Article ,Bile Ducts ,Glucuronide ,Drug metabolism ,medicine.drug - Abstract
In this study, we describe a novel approach for collecting bile from dogs and cynomolgus monkeys for metabolite profiling, ultrasound‐guided cholecystocentesis (UCC). Sampling bile by UCC twice within 24 hours was well tolerated by dogs and monkeys. In studies with atorvastatin (ATV) the metabolite profiles were similar in bile obtained through UCC and from bile duct‐cannulated (BDC) dogs. Similar results were observed in UCC and BDC monkeys as well. In both monkey and dog, the primary metabolic pathway observed for ATV was oxidative metabolism. The 2‐hydroxy‐ and 4‐hydroxyatorvastatin metabolites were the major oxidation products, which is consistent with previously published metabolite profiles. S‐cysteine and glucuronide conjugates were also observed. UCC offers a viable alternative to bile duct cannulation for collection of bile for metabolite profiling of compounds that undergo biliary excretion, given the similar metabolite profiles in bile obtained via each method. Use of UCC for metabolite profiling may reduce the need for studies using BDC animals, a resource‐intensive model.
- Published
- 2019
18. Nonclinical Toxicology Assessments Support the Chronic Safety of Dapagliflozin, a First-in-Class Sodium-Glucose Cotransporter 2 Inhibitor
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Michael J. Graziano, Joelle M. Onorato, Timothy P. Reilly, Lynn M. Abell, Jean M. Whaley, Thomas Dorr, Evan B. Janovitz, Deborah Hagan, and Mark Tirmenstein
- Subjects
Male ,medicine.medical_specialty ,Urinary system ,Metabolite ,Drug Evaluation, Preclinical ,CHO Cells ,Type 2 diabetes ,Pharmacology ,Toxicology ,Rats, Sprague-Dawley ,Excretion ,Mice ,chemistry.chemical_compound ,Cricetulus ,Dogs ,Glucosides ,Sodium-Glucose Transporter 2 ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Benzhydryl Compounds ,Dapagliflozin ,Adverse effect ,Sodium-Glucose Transporter 2 Inhibitors ,Mice, Knockout ,Calcium metabolism ,Mice, Inbred ICR ,Dose-Response Relationship, Drug ,business.industry ,medicine.disease ,Rats ,Endocrinology ,chemistry ,Female ,business - Abstract
Dapagliflozin, a first-in-class, selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), promotes urinary glucose excretion to reduce hyperglycemia for the treatment of type 2 diabetes. A series of nonclinical studies were undertaken to evaluate dapagliflozin in species where it was shown to have pharmacologic activity comparable with that in humans at doses that resulted in supratherapeutic exposures. In vitro screening (>300 targets; 10 μmol/L) indicated no significant off-target activities for dapagliflozin or its primary human metabolite. Once daily, orally administered dapagliflozin was evaluated in Sprague-Dawley rats (≤6 months) and in beagle dogs (≤1 year) at exposures >5000-fold those observed at the maximum recommended human clinical dose (MRHD; 10 mg). Anticipated, pharmacologically mediated effects of glucosuria, osmotic diuresis, and mild electrolyte loss were observed, but there were no adverse effects at clinically relevant exposures, including in the kidneys or urogenital tract. The SGLT2−/− mice, which show chronic glucosuria, and dapagliflozin-treated, wild-type mice exhibited similar safety profiles. In rats but not dogs, dapagliflozin at >2000-fold MRHD exposures resulted in tissue mineralization and trabecular bone accretion. Investigative studies suggested that the effect was not relevant to human safety, since it was partially related to off-target inhibition of SGLT1, which was observed only at high doses of dapagliflozin and resulted in intestinal glucose malabsorption and increased intestinal calcium absorption. The rigorous assessment of supra- and off-target dapagliflozin pharmacology in nonclinical species allowed for a thorough evaluation of potential toxicity, providing us with confidence in its safety in patients with diabetes.
- Published
- 2013
19. Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor
- Author
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Saleem, Ahmad, William N, Washburn, Andres S, Hernandez, Sharon, Bisaha, Khehyong, Ngu, Wei, Wang, Mary Ann, Pelleymounter, Daniel, Longhi, Neil, Flynn, Anthony V, Azzara, Kenneth, Rohrbach, James, Devenny, Suzanne, Rooney, Michael, Thomas, Susan, Glick, Helen, Godonis, Susan, Harvey, Hongwei, Zhang, Brian, Gemzik, Evan B, Janovitz, Christine, Huang, Lisa, Zhang, Jeffrey A, Robl, and Brian J, Murphy
- Subjects
Male ,Macaca fascicularis ,Mice ,Structure-Activity Relationship ,Dogs ,Pyrimidines ,Halogenation ,Animals ,Humans ,Anti-Obesity Agents ,Obesity ,Receptors, Somatostatin ,Rats - Abstract
The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.
- Published
- 2016
20. Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Novel Pharmaceuticals
- Author
-
Allison Vitsky, Chandikumar S. Elangbam, Tanja S. Zabka, Evan B. Janovitz, Shawn Berens, Laura Conour, and Sherry J. Morgan
- Subjects
medicine.medical_specialty ,Drug Evaluation, Preclinical ,Disease ,Pharmacology ,Toxicology ,Risk Assessment ,Pathology and Forensic Medicine ,Mice ,Human disease ,Animal model ,Toxicity Tests ,Animals ,Humans ,Medicine ,Intensive care medicine ,Molecular Biology ,business.industry ,Disease expression ,Mechanism (biology) ,Nonclinical safety ,Cell Biology ,Rats ,Disease Models, Animal ,Drug development ,Risk assessment ,business - Abstract
Animal models of human disease are commonly utilized to gain insight into the potential efficacy and mode of action of novel pharmaceuticals. However, conventional (healthy) rodent and nonrodent models are generally utilized in nonclinical safety testing. Animal models of human disease may be helpful in understanding safety risks of compounds in nonclinical or clinical development, with their greatest value being in targeted or hypothesis-driven studies to help understand the mechanism of a particular toxicity. Limitations of animal models of disease in nonclinical safety testing include a lack of historical control, heterogeneity in disease expression, a limited life span, and confounding effects of the disease. In most instances, animal models of human disease should not be utilized to supplant testing in conventional animal models. While of potential benefit, testing in an animal model of human disease should only be taken after adequate consideration of relevance along with benefits and limitations of the proposed model.
- Published
- 2012
21. Identification of 1- and 3-methylhistidine as biomarkers of skeletal muscle toxicity by nuclear magnetic resonance-based metabolic profiling
- Author
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Steve Stryker, John A. Rathmacher, Jun Dai, Evan B. Janovitz, Nelly Aranibar, Michael D. Reily, Lois D. Lehman-McKeeman, Jeffrey D. Vassallo, Yingru Zhang, Linda J. Lowe-Krentz, and Don Robertson
- Subjects
Male ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Time Factors ,Pyridines ,Urinary system ,Biophysics ,Urine ,Biochemistry ,Muscle hypertrophy ,Rats, Sprague-Dawley ,Nuclear magnetic resonance ,Muscular Diseases ,Internal medicine ,medicine ,Animals ,Metabolomics ,Muscle, Skeletal ,Myopathy ,Molecular Biology ,Dose-Response Relationship, Drug ,Chemistry ,Skeletal muscle ,Cerivastatin ,Cell Biology ,Creatine ,Methylhistidines ,Rats ,Dose–response relationship ,Endocrinology ,medicine.anatomical_structure ,Toxicity ,Female ,medicine.symptom ,Biomarkers ,medicine.drug - Abstract
Nuclear magnetic resonance (NMR)-based metabolomic profiling identified urinary 1- and 3-methylhistidine (1- and 3-MH) as potential biomarkers of skeletal muscle toxicity in Sprague-Dawley rats following 7 and 14 daily doses of 0.5 or 1mg/kg cerivastatin. These metabolites were highly correlated to sex-, dose- and time-dependent development of cerivastatin-induced myotoxicity. Subsequently, the distribution and concentration of 1- and 3-MH were quantified in 18 tissues by gas chromatography-mass spectrometry. The methylhistidine isomers were most abundant in skeletal muscle with no fiber or sex differences observed; however, 3-MH was also present in cardiac and smooth muscle. In a second study, rats receiving 14 daily doses of 1mg/kg cerivastatin (a myotoxic dose) had 6- and 2-fold elevations in 1- and 3-MH in urine and had 11- and 3-fold increases in 1- and 3-MH in serum, respectively. Selectivity of these potential biomarkers was tested by dosing rats with the cardiotoxicant isoproterenol (0.5mg/kg), and a 2-fold decrease in urinary 1- and 3-MH was observed and attributed to the anabolic effect on skeletal muscle. These findings indicate that 1- and 3-MH may be useful urine and serum biomarkers of drug-induced skeletal muscle toxicity and hypertrophy in the rat, and further investigation into their use and limitations is warranted.
- Published
- 2011
22. Use of Cardiovascular Telemetry to Elucidate the Pathogenesis of Drug-Induced Exacerbation of Atrial Thrombosis in Mice with Isoproterenol-Induced Cardiomyopathy
- Author
-
Evan B. Janovitz, Karen Granaldi, Julia Li, Paul Levesque, Lei Zhao, Lisa Berman-Booty, John Krupinski, James K. Hennan, Paul G. Sleph, and Michael Basso
- Subjects
Pharmacology ,Drug ,medicine.medical_specialty ,Exacerbation ,business.industry ,media_common.quotation_subject ,Cardiomyopathy ,Toxicology ,medicine.disease ,Atrial thrombosis ,Pathogenesis ,Internal medicine ,Cardiology ,Medicine ,business ,media_common - Published
- 2017
23. (3R,5S,E)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential
- Author
-
Doree F. Sitkoff, Ming Chang, Carolyn A Cuff, Bang-Chi Chen, Cort S. Madsen, Xiaohong Yin, Saleem Ahmad, Evan B. Janovitz, Richard A. Reeves, Thomas Harrity, Lawrence J. Kennedy, Carol S. Ryan, Hossain Monshizadegan, Van Nguyen-Tran, Tong Li, Robert Zahler, Michael A. Blanar, Khehyong Ngu, Philip D. Stein, Rongan Zhang, Sharon N. Bisaha, Christine Huang, Joel C. Barrish, Eileen Bird, Debra Search, Celia D’Arienzo, Mary Giancarli, Robert Setters, Rulin Zhao, Jeffrey A. Robl, Xing Chen, and Shaobin Zhuang
- Subjects
Models, Molecular ,Guinea Pigs ,Administration, Oral ,Biological Availability ,In Vitro Techniques ,Reductase ,Crystallography, X-Ray ,Chemical synthesis ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Dogs ,Oral administration ,In vivo ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,chemistry.chemical_classification ,Muscle Cells ,biology ,Chemistry ,Stereoisomerism ,Haplorhini ,Triazoles ,Hydroxymethylglutaryl-CoA reductase ,Rats ,Cholesterol ,Pyrimidines ,Enzyme ,Liver ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Female ,Hydroxymethylglutaryl CoA Reductases ,Chemical and Drug Induced Liver Injury ,Hydroxymethylglutaryl-CoA Reductase Inhibitors - Abstract
3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
- Published
- 2008
24. Discovery of (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a Selective, Orally Active Agonist of the 5-HT2C Receptor
- Author
-
Evan B. Janovitz, Mary Ann Pelleymounter, Mary F. Malley, Eva Zuvich, Jeffrey G. Varnes, Xueying Cao, Chen-Pin Hung, Karen A. Rossi, Mary Jane Cullen, Thao Ung, William J. Keim, Sarah E. Malmstrom, Michael Thomas, Keith J. Miller, Ginger Wu, Kenneth W. Rohrbach, Ge Zhang, Rangaraj Narayanan, Qinling Qu, Lois D. Lehman-McKeeman, Jeffrey A. Robl, James Devenny, and Dean A. Wacker
- Subjects
Male ,Agonist ,Indoles ,medicine.drug_class ,Stereochemistry ,Administration, Oral ,Isoindoles ,Pharmacology ,Weight Gain ,Chemical synthesis ,Cell Line ,Rats, Sprague-Dawley ,Mice ,Necrosis ,Radioligand Assay ,Parietal Cells, Gastric ,Pharmacokinetics ,Oral administration ,In vivo ,Drug Discovery ,medicine ,Functional selectivity ,Animals ,Humans ,Chemistry ,Antagonist ,Stereoisomerism ,Feeding Behavior ,Rats ,5-HT2C receptor ,Blood-Brain Barrier ,Pyrazines ,Conditioning, Operant ,Molecular Medicine ,Anti-Obesity Agents ,Serotonin 5-HT2 Receptor Agonists - Abstract
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
- Published
- 2007
25. Choroid Plexus Papilloma in a Scottish Highland Cow
- Author
-
José A. Ramos-Vara, Matti Kiupel, M. J. Hoenerhoff, and Evan B. Janovitz
- Subjects
Ependymoma ,Choroid Plexus Neoplasms ,Pathology ,medicine.medical_specialty ,Cattle Diseases ,Biology ,Cell junction ,Pathology and Forensic Medicine ,Adherens junction ,medicine ,Animals ,Third ventricle ,General Veterinary ,S100 Proteins ,Anatomy ,medicine.disease ,Choroid plexus papilloma ,eye diseases ,Gene Expression Regulation, Neoplastic ,Intercellular Junctions ,medicine.anatomical_structure ,Choroid Plexus ,Keratins ,Papilloma ,Immunohistochemistry ,Cattle ,Female ,Papilloma, Choroid Plexus ,Choroid plexus ,sense organs - Abstract
Choroid plexus papilloma, a rare tumour in bovids, arising from the roof of the third ventricle was diagnosed at necropsy in a 4-year-old Scottish Highland cow. The animal presented with a 2-month history of progressive ataxia, ventromedial strabismus, and hyperaesthesia. Neoplastic epithelial cells were positive immunohistochemically for pancytokeratin and S-100, and negative for GFAP. Ultrastructurally, epithelial cells were characterized by intercellular junctions, zonulae adherens, and zonulae occludens. Neither cilia nor basal bodies were identified. The gross, microscopical, immunohistochemical and ultrastructural findings were consistent with those of a choroid plexus papilloma.
- Published
- 2006
26. Avian Pox in Sanderlings from Florida
- Author
-
Dennis B. DeNicola, Armando R. Irizarry-Rovira, Christine Kreuder, Evan B. Janovitz, and P. J. Deitschel
- Subjects
medicine.medical_specialty ,food.ingredient ,Ecology ,Bird Diseases ,viruses ,Beak ,Virion ,virus diseases ,Poxviridae Infections ,Feathers ,Biology ,Virology ,Avipoxvirus ,Birds ,Microscopy, Electron ,Calidris ,food ,Tongue ,Cytology ,Florida ,medicine ,Animals ,Wings, Animal ,Histopathology ,Ecology, Evolution, Behavior and Systematics - Abstract
Asian pox was diagnosed in three sanderlings (Calidris alba) on Sanibel Island, Florida (USA) in February 1997. All three cases had large tumor-like lesions which contributed significantly to their mortality. Poxvirus infection was confirmed by cytology, histopathology, and electron microscopy. This is the first report of poxvirus infection in sanderlings.
- Published
- 1999
27. Discovery Toxicology and Pathology
- Author
-
Glenn H. Cantor and Evan B. Janovitz
- Subjects
Toxicology ,Pathology ,medicine.medical_specialty ,Genetically engineered ,business.industry ,Drug discovery ,medicine ,Disease ,Biology ,business ,Pharmaceutical industry ,Target expression - Abstract
Pathologists play a key role in discovery pathology and discovery toxicology in the pharmaceutical industry. Discovery pathologists function as well-rounded whole-body biologists. Their unique skill set provides critical perspectives on a wide variety of issues for the successful development of a new pharmaceutical candidate. These include identifying, characterizing, and validating animal models of disease and efficacy, phenotyping genetically engineered rodents, designing experiments to assess whether exaggerated pharmacology results in toxicity, and determining whether target expression in animals is representative of what is known in humans. These skills can be practiced as part of a discovery toxicology group, in which classical toxicologists work together with pathologists, in vitro biologists, cell and molecular biologists, genotoxicologists, cardiologists, electrophysiologists, bioinformaticians and genomicists, reproductive biologists, immunologists, and others. This multidisciplinary approach can often identify toxicologic liabilities at an early stage of drug discovery or development and provide insight into how to avoid or manage these liabilities.
- Published
- 2013
28. Contributors
- Author
-
E. Terence Adams, Rick Adler, Carl L. Alden, Phillip M. Bartholomew, Joydeep Basu, Val R. Beasley, Brian R. Berridge, Timothy A. Bertram, Hyo-eun Bhang, Hugh E. Black, Brad Bolon, Gary A. Boorman, Denise I. Bounous, Rogely Waite Boyce, William M. Bracken, Amy E. Brix, Danielle Brown, Mark T. Butt, Glenn H. Cantor, Bruce D. Car, Vincent Castranova, Russell C. Cattley, Curtis Chan, Robert E. Chapin, Samuel M. Cohen, Steve Colegate, Daniel Cook, Paul S. Cooke, Torrie A. Crabbs, Dianne M. Creasy, James W. Crissman, John M. Cullen, Dimitry M. Danilenko, Barbara Davis, Myrtle A. Davis, T. Zane Davis, Ronald A. DeLellis, Nancy D. Denslow, Kelly L. Diegel, David C. Dorman, Richard R. Dubielzig, Stephen K. Durham, Sandy Eldridge, Susan A. Elmore, Jeffrey I. Everitt, Suzanne Fenton, Duncan C. Ferguson, Reuel Field, George L. Foley, William R. Foster, Jerry D. Frantz, Kathy Gabrielson, Shayne C. Gad, Elizabeth J. Galbreath, Dale R. Gardner, Robert H. Garman, Santokh Gill, Peter Glerup, Dale L. Goad, Mary Elizabeth Pecquet Goad, Nanna Grand, Benjamin T. Green, Kathryn E. Gropp, Hans Jørgen G. Gundersen, Diane Gunson, Ramesh C. Gupta, Sharon M. Gwaltney-Brant, Jeffery O. Hall, Wendy Halpern, Gordon C. Hard, Jerry F. Hardisty, Jack R. Harkema, Philip W. Harvey, Wanda M. Haschek, Kathleen Heinz-Taheny, Ronald A. Herbert, Eugene Herman, Mark Hoenerhoff, Ann Hubbs, David Hutto, Evan B. Janovitz, Kanwar Nasir M. Khan, Kevin P. Keenan, Roy L. Kerlin, John M. Kreeger, Kannan Krishnan, C. Frieke Kuper, Stephen T. Lee, Lois D. Lehman-McKeeman, Xiantang Li, Eric D. Lombardini, Calvert Louden, John W. Ludlow, David E. Malarkey, Peter C. Mann, Robert R. Maronpot, Kevin S. McDorman, Mark A. Melanson, Robert Mercer, Rosanna Mirabile, Ronald W. Moch, James P. Morrison, Daniel Morton, Laura Dill Morton, Sureshkumar Muthupalani, Kristen J. Nikula, Ricardo Ochoa, Michelle E. Pacheco-Thompson, Olga M. Pulido, Kip E. Panter, George A. Parker, Dale W. Porter, Douglas Reid Patterson, James A. Pfister, Carl A. Pinkert, Lila Ramaiah, Deepa B. Rao, Donald G. Robertson, Jennifer Rojko, Thomas J. Rosol, Colin G. Rousseaux, Daniel G. Rudmann, Christine Ruehl-Fehlert, Linda Sargent, Christina M. Satterwhite, Kenneth A. Schafer, Philip F. Solter, Robert C. Sills, Liz Simon, Mikala Skydsgaard, Graham S. Smith, Krishnan Sriram, Bryan L. Stegelmeier, John M. Sullivan, Catherine Sutcliffe, James A. Swenberg, Polina Sysa-Shah, Leandro Teixeira, Noriko Tsuchiya, John L. Vahle, John F. Van Vleet, Aurore Varela, Kenneth A. Voss, Robin M. Walker, Matthew A. Wallig, Gail L. Walter, Kevin D. Welch, Paul White, Christopher T. Winkelmann, Zbigniew W. Wojcinski, and Jeffrey C. Wolf
- Published
- 2013
29. Spontaneous metastasis of PC-3 cells in athymic mice after implantation in orthotopic or ectopic microenvironments
- Author
-
Evan B. Janovitz, David J. Waters, and Thomas C.K. Chan
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Urology ,Dermatologic Surgical Procedures ,Transplantation, Heterologous ,Urinary Bladder ,Athymic mouse ,Mice, Nude ,Metastasis ,Mice ,Prostate cancer ,Paraaortic lymph nodes ,Tumor Cells, Cultured ,medicine ,Carcinoma ,Animals ,Humans ,Tumor microenvironment ,Urinary bladder ,business.industry ,Stomach ,Prostate ,Prostatic Neoplasms ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Female ,Lymph ,business ,Neoplasm Transplantation - Abstract
The ability of subcutaneous, prostatic, and nonprostatic intraabdominal organ microenvironments to influence local tumor growth and metastasis of PC-3 human prostate carcinoma cells in athymic mice was determined. Tumorigenesis and metastasis of PC-3 were evaluated 60 days after subcutaneous and intraprostatic (orthotopic) implantation of 5 x 10(5) PC-3 cells in 6-week-old, male athymic mice. Intraprostatic implantation of PC-3 cells resulted in paraaortic lymph node metastases in 10 of 10 (100%) mice with prostatic tumors, whereas metastases were present in only 2 of 9 (22%) mice after subcutaneous implantation. Next, we determined whether the urinary bladder (nonprostatic, urogenital microenvironment) or stomach (nonurogenital, intraabdominal microenvironment) would facilitate the metastasis of PC-3 cells in athymic mice. Tumorigenesis and metastasis were 100% after subserosal implantation of PC-3 cells within the wall of the urinary bladder (n = 6 mice). Subserosal implantation of PC-3 cells into the stomach wall (n = 7 mice) also resulted in tumor formation and metastasis to regional lymph nodes in 100% of mice. In all experiments, regional lymph nodes were the most frequent site of metastasis, regardless of implantation site. We conclude that tumor microenvironment factors responsible for the metastasis of PC-3 cells in athymic mice may not be organ-specific, since nonprostatic visceral microenvironments are sufficient for predictable metastasis. Use of these models may further our understanding of how tumor microenvironment modulates expression of the metastatic phenotype by human prostate carcinoma cells.
- Published
- 1995
30. Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic-adipic aciduria in beagle dogs
- Author
-
Frederic Moulin, Nelly Aranibar, Jeffrey H. Charlap, John C. Kozlosky, Oliver P. Flint, Liya Kang, John R. Megill, Joseph Horvath, Michael J. Bennett, Karl-Heinz Ott, Julieta M. Panzica-Kelly, Katherine M. Dubrow, William E. Achanzar, Kenneth E. Carlson, Haiying Zhang, Evan B. Janovitz, Mark Tirmenstein, Karen A. Augustine, Laura Patrone, Lindsay Tomlinson, Kimberly C. Brannen, and Laura T. Rosini
- Subjects
medicine.medical_specialty ,Sarcosine ,Adipates ,Blotting, Western ,Biology ,Toxicology ,Polymerase Chain Reaction ,Dimethylglycine ,chemistry.chemical_compound ,Radioligand Assay ,Dogs ,Receptor, Cannabinoid, CB1 ,Internal medicine ,Lipid droplet ,Carnitine ,medicine ,Animals ,Metabolomics ,Myopathy ,Muscle, Skeletal ,DNA Primers ,Fatty acid metabolism ,Base Sequence ,Gene Expression Profiling ,Immunohistochemistry ,Malonates ,Endocrinology ,chemistry ,Toxicity ,Female ,medicine.symptom ,Ibipinabant ,medicine.drug - Abstract
Ibipinabant (IBI), a potent cannabinoid-1 receptor (CB1R) antagonist, previously in development for the treatment of obesity, causes skeletal and cardiac myopathy in beagle dogs. This toxicity was characterized by increases in muscle-derived enzyme activity in serum and microscopic striated muscle degeneration and accumulation of lipid droplets in myofibers. Additional changes in serum chemistry included decreases in glucose and increases in non-esterified fatty acids and cholesterol, and metabolic acidosis, consistent with disturbances in lipid and carbohydrate metabolism. No evidence of CB1R expression was detected in dog striated muscle as assessed by polymerase chain reaction, immunohistochemistry, Western blot analysis, and competitive radioligand binding. Investigative studies utilized metabonomic technology and demonstrated changes in several intermediates and metabolites of fatty acid metabolism including plasma acylcarnitines and urinary ethylmalonate, methylsuccinate, adipate, suberate, hexanoylglycine, sarcosine, dimethylglycine, isovalerylglycine, and 2-hydroxyglutarate. These results indicated that the toxic effect of IBI on striated muscle in beagle dogs is consistent with an inhibition of the mitochondrial flavin-containing enzymes including dimethyl glycine, sarcosine, isovaleryl-CoA, 2-hydroxyglutarate, and multiple acyl-CoA (short, medium, long, and very long chain) dehydrogenases. All of these enzymes converge at the level of electron transfer flavoprotein (ETF) and ETF oxidoreductase. Urinary ethylmalonate was shown to be a biomarker of IBI-induced striated muscle toxicity in dogs and could provide the ability to monitor potential IBI-induced toxic myopathy in humans. We propose that IBI-induced toxic myopathy in beagle dogs is not caused by direct antagonism of CB1R and could represent a model of ethylmalonic-adipic aciduria in humans.
- Published
- 2012
31. Cycad (Zamia Puertoriquensis) Toxicosis in a Group of Dairy Heifers in Puerto Rico
- Author
-
Rachel Y. Reams, Carlos Rivera Casanova, Edwin Más, Farrel R. Robinson, Evan B. Janovitz, and John M. Sullivan
- Subjects
0301 basic medicine ,040301 veterinary sciences ,Digestive System Diseases ,Secondary infection ,030106 microbiology ,Cattle Diseases ,Spleen ,Microbiology ,0403 veterinary science ,Schizogony ,03 medical and health sciences ,Central Nervous System Diseases ,parasitic diseases ,medicine ,Animals ,Plant Poisoning ,Lamina propria ,General Veterinary ,biology ,Ecology ,Puerto Rico ,04 agricultural and veterinary sciences ,biology.organism_classification ,Mononuclear cell infiltration ,medicine.anatomical_structure ,Echidna ,Sarcocystis ,Protozoa ,Cattle ,Female - Abstract
tory parenchymal necrosis and lysis associated with groups of bacteria (probably secondary infection), with focal hemorrhages. Structurally distinct types of schizonts with slender merozoites (Fig. 14) or short stubby merozoites (Fig. 15) were seen. Intestinal coccidiosis was seen in echidna nos. 2, 4, and 5 (Figs. 16-20). Lesions were more severe in the small intestines of echidna nos. 2 and 5 and consisted of desquamation of epithelial cells of glands of Lieberkiihn and surface epithelium, hypertrophy of villous epithelium, and mononuclear cell infiltration in lamina propria. Gamonts and oocysts The intravascular schizonts in the lungs of the echidnas were structurally similar to schizonts of Sarcocystis, particularly of the Sarcocystis species in cattle, sheep, and goats. Some of the schizonts in the liver, lungs, and spleen were difficult to distinguish from tachyzoites of T. gondii. However, T. gondii tachyzoites always divide into 2 by endodyogeny, whereas the extraintestinal protozoa of the echidnas divided into many organisms by schizogony. Acknowledgements. We thank the staff of the Veterinary Research Institute in Melbourne who made 3 of the cases available for examination. were seen in all 3 echidnas. Oocysts were approximately 25 x 20 μm and were unsporulated (Figs. 18-20). Few schizonts were seen only in 1. echidna no. 2. A 45x 25-μm schizont with numerous tiny merozoites in the lamina propria of the small intestine is shown in Fig. 17. Protozoa in the lung and liver of echidna no. 1 did not 2. react to T. gondii, N, caninum, or S. cruzi antisera. Protozoa in extraintestinal tissues of echidnas were un3= identified. Protozoa in the intestines of echidnas in the present study appeared to be structurally similar to the intestinal 4.
- Published
- 1993
32. Sarcocystosis with Involvement of the Central Nervous System in Lambs
- Author
-
Scott D. Fitzgerald, Evan B. Janovitz, Duane A. Murphy, Jitender P. Dubey, and Kevin R. Kazacos
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Sarcocystosis ,040301 veterinary sciences ,animal diseases ,030106 microbiology ,Sheep Diseases ,Pseudorabies ,Disease Outbreaks ,0403 veterinary science ,03 medical and health sciences ,Dogs ,Neospora ,Central Nervous System Diseases ,parasitic diseases ,medicine ,Animals ,Disease Reservoirs ,Sheep ,Lung ,General Veterinary ,biology ,business.industry ,Toxoplasma gondii ,04 agricultural and veterinary sciences ,biology.organism_classification ,Mononuclear cell infiltration ,medicine.anatomical_structure ,Sarcocystis ,Female ,Flock ,business - Abstract
An outbreak of neurologic disease in a flock of 5-month- taining large rounded metrocytes and early bradyzoites, and old Rambouillet lambs on a sheep farm in west-central In- were associated with some degree of myositis with degendiana was investigated. Over a 4-week period during the eration of muscle fibers and lymphocytic perimysial infiltrasummer of 1990, 32 of 48 lambs in 1 pen were affected, and tion. 22 of these lambs died. Approximately 300 sheep were on Multifocal, nonsuppurative meningoencephalomyelitis was the farm. The affected lambs were confined to a single pen evident in the cerebrum, cerebellum, brain stem, and cerin a large open-sided pole barn and were the youngest group vital, thoracic, and lumbar spinal cord of all 3 lambs (Fig. of spring lambs on the farm. 1). Inflammation was characterized by glial nodules, multiClinical signs described by the owner and referring vet- focal necrosis with gliosis and mononuclear cell infiltration, erinarian included anorexia, weight loss, incoordination, stiff and lymphocytic infiltration around blood vessels and in the limbs, trembling, and generalized weakness. The condition meninges (Fig. 2). An immature schizont was found in the progressed rapidly in fatal cases, and death generally occurred pons of 1 of these lambs (Fig. 3). The density of neuroglia within 7 days of the onset of clinical signs. around this schizont was increased, but the schizont was not Three clinically affected lambs (2 live and 1 dead) were surrounded by microglia. Immunohistochemical examinasubmitted to the Animal Disease Diagnostic Laboratory, tion of paraffin-embedded sections of samples of brain from Purdue University, West Lafayette, Indiana, for diagnostic all 3 lambs using antisera to Toxoplasma gondii, Neospora evaluation. Both live lambs were thin, weak, and ataxic. All caninum, and Sarcocystis spp. was negative. 11 The FA test 3 lambs had bronchopneumonia of varying severity. One for pseudorabies was negative, and no viral agent was isolamb had moderate subcutaneous edema of the neck and lated. inguinal region and mild serous effusions in the pleural, peri- The small intestine of 1 lamb was infected by coccidia and cardial, and peritoneal cavities. Tissue samples from all 3 cryptosporidia. After the diagnosis of intestinal coccidiosis lambs were routinely processed for histopathologic exami- was conveyed, the referring veterinarian directed the owner nation. Samples of pneumonic lung were inoculated on blood to add amprolium to the lambs’ feed. Following treatment, and MacConkey’s agar in an attempt to culture for aerobic affected lambs improved clinically, no more died, and no bacteria. Selected areas of the pneumonic lungs were ex- additional lambs developed clinical signs. amined for bovine respiratory syncytial virus (BRSV), in- Approximately 6 weeks later, a team of diagnostic perfectious bovine rhinotracheitis virus (IBR), and sonnel visited the farm for an on-site evaluation, to collect Parainfluenza-3 virus (P13) by direct immunofluorescence convalescent sera from affected and nonaffected lambs, to (FA) and were inoculated onto bovine turbinate cells for virus collect fecal samples from dogs, and to choose a convalescent isolation. A portion of the brain from 1 of the live lambs lamb for further diagnostic evaluation. was examined for pseudorabies virus by FA and was also Hay was found stacked in 1 comer of the pole barn, and inoculated onto cell cultures. grain was stored in uncovered wooden bins at the opposite
- Published
- 1993
33. Septicemic Enterococcus Infection in an Adult Llama
- Author
-
Terry L. Bowersock, Robert Higgins, Evan B. Janovitz, and John Burkhardt
- Subjects
Male ,0301 basic medicine ,040301 veterinary sciences ,030106 microbiology ,Physiology ,Bacteremia ,Hemorrhage ,Biology ,Abortion ,medicine.disease_cause ,0403 veterinary science ,Necrosis ,03 medical and health sciences ,Meninges ,Immune system ,Listeria monocytogenes ,medicine ,Animals ,Ingestion ,Meningitis ,Gram-Positive Bacterial Infections ,Pregnancy ,General Veterinary ,Muscles ,Brain ,Meningoencephalitis ,04 agricultural and veterinary sciences ,medicine.disease ,biology.organism_classification ,Enterococcus ,Immunology ,Gestation ,Kidney Diseases ,Camelids, New World - Abstract
>> the meningoencephalitic form of the disease. 2,11 Listeria1 abortion is relatively common in sheep, cattle, and goats, is rare in other species, 1 and has not been reported previously in llamas. In sheep and cattle, there is often clinical illness with fever of up to 40.5 C in the dam, but meningoencephalitis does not usually occur concomitantly with abortion. Abortion usually occurs during the latter stages of gestation, as in this case. Ingestion is considered the most common route of infection leading to abortion. 3 Listeria monocytogenes is ubiquitous in nature and in human and animal feces, so llamas will almost certainly be exposed to the organism. Infection has been repeatedly associated with spoiled silage with a pH >5.0-5.5 1,3 and with various circumstances that might lower the animal’s resistance, including pregnancy. 3 Eperythrozoonosis has also been associated with conditions causing immune suppression 5,9
- Published
- 1993
34. Transmission Electron Microscopy Used to Diagnose Acute Toxoplasmosis in a Quarantined, Captive Born Cynomolgus Macaque
- Author
-
Jamus MacGuire, Evan B. Janovitz, R.K. Jackson, J. P. Dubey, and John Megill
- Subjects
Transmission electron microscopy ,medicine ,Biology ,medicine.disease ,Instrumentation ,Cynomolgus macaque ,Virology ,Toxoplasmosis - Published
- 2014
35. Proposal of a 2-Tier Histologic Grading System for Canine Cutaneous Mast Cell Tumors to More Accurately Predict Biological Behavior
- Author
-
Julie A. Yager, Scott D. Fitzgerald, Ken C. Smith, Matti Kiupel, Paul C. Stromberg, D Gamble, Thomas P. Mullaney, F. Y. Schulman, Steven E. Weisbrode, Pamela E. Ginn, T. J. Scase, Barbara A. Steficek, Thomas P. Lipscomb, Evan B. Janovitz, Paul W. Snyder, W. Misdorp, K L Bailey, N L Stedman, S. D. Lenz, José A. Ramos-Vara, I Neyens, Mattie J. Hendrick, Susan J. Best, Josepha DeLay, E Southorn, Elizabeth W. Howerth, S. D. Moroff, Jane Heller, Rebecca C. Smedley, Ingeborg M. Langohr, Michael H. Goldschmidt, R. Miller, Victor E. Valli, Donal O’Toole, Margaret A. Miller, Dodd G. Sledge, Joshua D. Webster, and C J Detrisac
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,General Veterinary ,business.industry ,Concordance ,Mastocytoma ,medicine.disease ,Mast cell tumors ,Article ,Metastasis ,Dogs ,Histologic grade ,Medicine ,Animals ,Neoplasm staging ,Female ,Dog Diseases ,business ,Grading (education) ,Median survival ,Blinded study ,Neoplasm Staging - Abstract
Currently, prognostic and therapeutic determinations for canine cutaneous mast cell tumors (MCTs) are primarily based on histologic grade. However, the use of different grading systems by veterinary pathologists and institutional modifications make the prognostic value of histologic grading highly questionable. To evaluate the consistency of microscopic grading among veterinary pathologists and the prognostic significance of the Patnaik grading system, 95 cutaneous MCTs from 95 dogs were graded in a blinded study by 28 veterinary pathologists from 16 institutions. Concordance among veterinary pathologists was 75% for the diagnosis of grade 3 MCTs and less than 64% for the diagnosis of grade 1 and 2 MCTs. To improve concordance among pathologists and to provide better prognostic significance, a 2-tier histologic grading system was devised. The diagnosis of high-grade MCTs is based on the presence of any one of the following criteria: at least 7 mitotic figures in 10 high-power fields (hpf); at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; at least 3 bizarre nuclei in 10 hpf; karyomegaly (ie, nuclear diameters of at least 10% of neoplastic cells vary by at least two-fold). Fields with the highest mitotic activity or with the highest degree of anisokaryosis were selected to assess the different parameters. According to the novel grading system, high-grade MCTs were significantly associated with shorter time to metastasis or new tumor development, and with shorter survival time. The median survival time was less than 4 months for high-grade MCTs but more than 2 years for low-grade MCTs.
- Published
- 2010
36. Biomarkers of drug-induced skeletal muscle injury in the rat: troponin I and myoglobin
- Author
-
Jeffrey D. Vassallo, Evan B. Janovitz, Linda J. Lowe-Krentz, Lois D. Lehman-McKeeman, Debra Wescott, and Chris Chadwick
- Subjects
Male ,medicine.medical_specialty ,Molecular Sequence Data ,Toxicology ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,Troponin I ,medicine ,Animals ,Amino Acid Sequence ,Myopathy ,Muscle, Skeletal ,Creatinine ,biology ,Myoglobin ,Cardiac muscle ,Skeletal muscle ,Muscle atrophy ,Rats ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Toxicity ,biology.protein ,Creatine kinase ,Female ,medicine.symptom ,Biomarkers - Abstract
The purpose of this investigation was to determine the utility of fast-twitch skeletal muscle troponin I (fsTnI) and urinary myoglobin (uMB) as biomarkers of skeletal muscle injury in 8-week-old Sprague-Dawley rats. fsTnI and uMB were quantified by enzyme-linked immunosorbent assay and compared with standard clinical assays including creatine kinase, aldolase, aspartate aminotransferase, and histopathological assessments. Detectable levels of uMB were normalized to urinary creatinine to control for differences in renal function. Seven compounds, including those with toxic effects on skeletal muscle, cardiac muscle, or liver, were evaluated. fsTnI was typically nondetectable (< 5.9 ng/ml serum) in vehicle-treated female and male rats but increased in a dose-dependent manner to at least 300 ng/ml in cerivastatin-induced severe fast-twitch specific myotoxicity. Minimal myopathy induced by investigational compounds BMS-600149 and BMS-687453 increased serum fsTnI to about 30-50 ng/ml, suggesting a reasonable dynamic range for detecting mild to severe skeletal muscle toxicity. In direct contrast, fsTnI was only marginally increased relative to population control values in rats treated with triamcinolone acetonide, which produces muscle atrophy or the cardiotoxins isoproterenol and CoCl2. uMB was typically nondetectable (< 1.6 ng/ml urine) in vehicle-treated female and male rats but increased to approximately 140, 300, and 30 ng/mg creatinine in rats treated with cerivastatin, BMS-687453, and triamcinolone acetonide, respectively. Cardiotoxicity also increased uMB in rats treated with isoproterenol and CoCl2 with urine concentrations ranging from 20 to 30 ng/mg creatinine. Severe hepatotoxicity (coumarin) did not significantly affect serum fsTnI or uMB levels. Collectively, these data suggest that fsTnI is specific for skeletal muscle toxicity, whereas uMB is nonspecific, increasing with skeletal muscle and cardiac toxicity. Accordingly, the complement of fsTnI and uMB, in conjunction with standard clinical assays may comprise a useful diagnostic panel for assessing drug-induced myopathy in rats.
- Published
- 2009
37. Copper Toxicosis in Veal Calves
- Author
-
John M. Sullivan, Farrel R. Robinson, and Evan B. Janovitz
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Necrosis ,040301 veterinary sciences ,Nephrosis ,Cattle Diseases ,Physiology ,chemistry.chemical_element ,Kidney ,0403 veterinary science ,Peritoneal Hemorrhage ,03 medical and health sciences ,Fibrosis ,medicine ,Animals ,Hematinic ,General Veterinary ,business.industry ,Poisoning ,04 agricultural and veterinary sciences ,medicine.disease ,Copper ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,chemistry ,Cattle ,Hemoglobinuria ,medicine.symptom ,business - Abstract
Copper toxicosis was diagnosed in 7 veal calves, 10–16 weeks old, from 5 separate farms. All calves died without specific clinical signs, although 4 of the calves were icteric. The calves' dietary rations had been supplemented with various copper-containing hematinics. Peritoneal hemorrhage was reported at postmortem in 2 calves. Microscopic evidence of hepatopathy consisted of hepatocellular degeneration and necrosis, hemorrhage, and fibrosis. Concentrations of copper in livers from intoxicated calves ranged from 277 to 684 ppm and in kidneys from 1.1 to 82.0 ppm. The extent and severity of lesions in livers appeared to correlate with concentrations of copper. Nephrosis was minimal, without evidence of hemoglobinuria.
- Published
- 1991
38. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes
- Author
-
William G. Humphreys, Songping Han, Robert Zahler, Nathan Morgan, Wei Meng, Philip M. Sher, Mary T. Obermeier, Aiying Wang, Alexandra A. Nirschl, Lorell Discenza, Evan B. Janovitz, Joseph R. Taylor, Ashish Khanna, Manorama Patel, John R. Wetterau, Ravindar N. Girotra, Annie Pullockaran, Oliver P. Flint, Scott A. Biller, Prashant P. Deshpande, Eamonn P. Morrison, James G. Robertson, Jean M. Whaley, Gang Wu, P.J. McCann, William N. Washburn, Bruce A. Ellsworth, and Deborah Hagan
- Subjects
Blood Glucose ,medicine.medical_specialty ,Administration, Oral ,Type 2 diabetes ,Kidney ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Glucosides ,Sodium-Glucose Transporter 2 ,Diabetes mellitus ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Dapagliflozin ,Benzhydryl Compounds ,Sodium-Glucose Transporter 2 Inhibitors ,Chemistry ,Kidney metabolism ,Stereoisomerism ,medicine.disease ,Streptozotocin ,Renal glucose reabsorption ,Rats ,medicine.anatomical_structure ,Endocrinology ,Diabetes Mellitus, Type 2 ,Molecular Medicine ,SGLT2 Inhibitor ,medicine.drug - Abstract
The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
- Published
- 2008
39. LIST OF CONTRIBUTORS
- Author
-
Carl L. Alden, Brian R. Berridge, Brad Bolon, Denise I. Bounous, Mark T. Butt, Russell C. Cattley, Robert E. Chapin, Sandrine F. Chebekoue, Dianne M. Creasy, John M. Cullen, Dimitry M. Danilenko, Barbara Davis, Kelly L. Diegel, David C. Dorman, Richard R. Dubielzig, Susan A. Elmore, Suzanne E. Fenton, Duncan C. Ferguson, George L. Foley, Robert H. Garman, Kathryn E. Gropp, Diane Gunson, Gordon C. Hard, Jack R. Harkema, Wanda M. Haschek, Eugene Herman, Mark J. Hoenerhoff, Evan B. Janovitz, Kanwar N.M. Khan, Kannan Krishnan, C. Frieke Kuper, Lois D. Lehman-McKeeman, Xiantang Li, David E. Malarkey, Robert R. Maronpot, Kristen J. Nikula, Ricardo Ochoa, George A. Parker, Lila Ramaiah, Colin G. Rousseaux, Daniel G. Rudmann, Christine Ruehl-Fehlert, Stefan U. Ruepp, Kenneth A. Schafer, John M. Sullivan, Leandro Teixeira, John F. Van Vleet, Aurore Varela, Matthew A. Wallig, and Zbigniew W. Wojcinski
- Published
- 2008
40. The Guinea pig as a preclinical model for demonstrating the efficacy and safety of statins
- Author
-
Thomas Harrity, Susan Scheer, Evan B. Janovitz, Robert Setters, Jeffrey A. Robl, Hossain Monshizadegan, Michael A. Blanar, Andrew Peters, Carol S. Ryan, Ming Chang, Atsu Apedo, Chongqing Sun, Mark C. Kowala, Lori Kunselman, Christine Huang, Xing Chen, Carolyn A. Cuff, Shaobin Zhuang, Celia D’Arienzo, Debra Search, Philip D. Stein, Xiaohong Yin, Cort S. Madsen, Van Nguyen-Tran, and Rongan Zhang
- Subjects
Male ,Statin ,medicine.drug_class ,Atorvastatin ,Guinea Pigs ,Drug Evaluation, Preclinical ,Pharmacology ,Rats, Sprague-Dawley ,In vivo ,medicine ,Potency ,Animals ,Rosuvastatin ,Muscle, Skeletal ,Cells, Cultured ,business.industry ,nutritional and metabolic diseases ,Cerivastatin ,Rats ,Toxicity ,Models, Animal ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Pravastatin ,medicine.drug - Abstract
Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 [{(3 R ,5 S )-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5 H -benzo[6,7]cyclohepta[1,2- b ]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED50 for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.
- Published
- 2007
41. The dual peroxisome proliferator-activated receptor alpha/gamma activator muraglitazar prevents the natural progression of diabetes in db/db mice
- Author
-
Jean M. Whaley, Andrew Peters, Rachel Zebo, Lori Kunselman, Pratik Devasthale, Evan B. Janovitz, Thomas Harrity, Randolph P. Ponticiello, Narayanan Hariharan, Ada Staal, Dennis Farrelly, Michele H. French, JoAnn Swartz, Donald Egan, Effie Tozzo, Peter T. W. Cheng, Gustav E Welzel, Simeon Taylor, Rene Belder, Chen Sean, and Liqun Gu
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Glycine ,Mice, Inbred Strains ,Type 2 diabetes ,Fatty Acids, Nonesterified ,Diabetes Mellitus, Experimental ,Impaired glucose tolerance ,Muraglitazar ,Islets of Langerhans ,Mice ,Insulin resistance ,Internal medicine ,Diabetes mellitus ,medicine ,Hyperinsulinemia ,Animals ,Hypoglycemic Agents ,Insulin ,PPAR alpha ,Oxazoles ,Pancreas ,Triglycerides ,Pharmacology ,Glycated Hemoglobin ,C-Peptide ,business.industry ,Body Weight ,Glucose Tolerance Test ,medicine.disease ,Insulin oscillation ,Mice, Inbred C57BL ,PPAR gamma ,Endocrinology ,Disease Progression ,Molecular Medicine ,Female ,business - Abstract
There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.
- Published
- 2007
42. Fatal herpesvirus encephalitis in a reticulated giraffe (Giraffa camelopardalis reticulata)
- Author
-
T. C. Butler, D. A. Murphy, Laura K. Richman, M. J. Hoenerhoff, Matti Kiupel, and Evan B. Janovitz
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,040301 veterinary sciences ,Equine herpesvirus 1 ,Antibodies, Viral ,0403 veterinary science ,Gross examination ,03 medical and health sciences ,Fatal Outcome ,medicine ,media_common.cataloged_instance ,Animals ,media_common ,General Veterinary ,biology ,Cerebrum ,Meningoencephalitis ,Brain ,Reticulated giraffe ,04 agricultural and veterinary sciences ,Anatomy ,Herpesviridae Infections ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Gliosis ,Antelopes ,Encephalitis ,medicine.symptom ,Giraffa camelopardalis ,Herpesvirus 1, Equid - Abstract
Fatal meningoencephalitis caused by equine herpesvirus-1 (EHV-1) was diagnosed in a reticulated giraffe ( Giraffa camelopardalis reticulate). The giraffe died following a history of stumbling, incoordination, and abdominal pain. Gross examination of the brain revealed asymmetric edema and red-brown discoloration, predominantly within the telencephalon. Microscopically, there was perivascular lymphohistiocytic cuffing, multifocal gliosis, and neuronal necrosis in the cerebrum. Necrotic neurons contained acidophilic intranuclear inclusions. EHV-1 was isolated from the brain of the giraffe, and polymerase chain reaction was positive on sections of the brain. Immunohistochemistry using an EHV-1-specific antibody identified positive staining in neurons, astrocytes, and endothelial cells. The giraffe had been housed with a group of zebras that were serologically positive for EHV-1 and suspected as the source of infection. This raises concerns for cross-species transmission of EHV-1 when housing equids together with other species in zoologic collections.
- Published
- 2006
43. Retinoblastoma in the eye of a llama (Llama glama)
- Author
-
Jan F. Hawkins, Fabiano Montiani-Ferreira, Michael N. Fugaro, Evan B. Janovitz, and Matti Kiupel
- Subjects
Pathology ,medicine.medical_specialty ,genetic structures ,Retinal Neoplasms ,Enucleation ,Diagnosis, Differential ,Pregnancy ,medicine ,Animals ,Retinal Tumor ,Retina ,General Veterinary ,biology ,Glial fibrillary acidic protein ,Retinoblastoma ,medicine.disease ,Immunohistochemistry ,eye diseases ,Buphthalmos ,medicine.anatomical_structure ,Rhodopsin ,biology.protein ,Female ,sense organs ,Camelids, New World ,Pregnancy Complications, Neoplastic - Abstract
Animal studied A 6-year-old, pregnant female llama experienced a 6-month history of epiphora, buphthalmos, and acute loss of vision in the left eye. The condition was unresponsive to topical antimicrobial and anti-inflammatory therapy and progressed to corneal rupture. Procedures Transpalpebral enucleation was performed and an intraorbital silicone prosthesis was implanted. The eye was fixed in formalin and processed according to routine paraffin technique. Sections of a mass were immunohistochemically prepared routinely and stained for glial fibrillary acidic protein (GFAP), S-antigen, and rhodopsin. Results Gross, histopathologic, and immunohistochemical analysis revealed a retinal tumor consistent with a retinoblastoma. The neoplastic tissue formed Flexner– Wintersteiner and Homer–Wright rosettes, originated from the retina, and demonstrated photoreceptor differentiation with S-antigen and rhodopsin expression. Neoplastic cells were negative for GFAP. Four years after enucleation, the llama showed no signs of recurrent neoplasia. Conclusions This report describes the diagnosis and successful treatment of the first known retinoblastoma in a llama.
- Published
- 2005
44. Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3)
- Author
-
Ning Lee, Adam Rich, Paul Levesque, Kevin R. Gray, Michael A. Blanar, Shujian Wu, Lucy Sun, Jun-Hsiang Lin, Jian Chen, Evan B. Janovitz, John N. Feder, and Minxue Huang
- Subjects
Central Nervous System ,Male ,Thapsigargin ,Molecular Sequence Data ,Gene Expression ,TRPM Cation Channels ,Gadolinium ,In situ hybridization ,Biology ,Biochemistry ,Lanthanoid Series Elements ,Ion Channels ,chemistry.chemical_compound ,Transient receptor potential channel ,Testis ,TRPM3 ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Kidney Tubules, Collecting ,Molecular Biology ,Cells, Cultured ,HEK 293 cells ,Cell Membrane ,Cell Biology ,Calcium Channel Blockers ,Molecular biology ,Protein Structure, Tertiary ,chemistry ,Calcium ,Heterologous expression ,Chromosomes, Human, Pair 9 ,Intracellular - Abstract
Transient receptor potential (TRP) cation-selective channels are an emerging class of proteins that are involved in a variety of important biological functions including pain transduction, thermosensation, mechanoregulation, and vasorelaxation. Utilizing a bioinformatics approach, we have identified the full-length human TRPM3 (hTRPM3) as a member of the TRP family. The hTRPM3 gene is comprised of 24 exons and maps to human chromosome 9q-21.12. hTRPM3 is composed of 1555 amino acids and possesses the characteristic six-transmembrane domain of the TRP family. hTRPM3 is expressed primarily in kidney and, at lesser levels, in brain, testis, and spinal cord as demonstrated by quantitative RT-PCR and Northern blotting. In situ hybridization in human kidney demonstrated that hTRPM3 mRNA expression is predominantly found in the collecting tubular epithelium. Heterologous expression of hTRPM3 in human embryonic kidney cells (HEK 293) showed that hTRPM3 is localized to the cell membrane. hTRPM3-expressing cells exhibited Ca2+ concentration-dependent Ca2+ entry. Depletion of intracellular Ca2+ stores by lowering extracellular Ca2+ concentration and treatment with the Ca2+-ATPase inhibitor thapsigargin or the muscarinic receptor agonist carbachol further augmented hTRPM3-mediated Ca2+ entry. The nonselective Ca2+ channel blocker, lanthanide gadolinium (Gd3+), partially inhibited hTRPM3-mediated Ca2+ entry. These results are consistent with the hypothesis that hTRPM3 mediates a Ca2+ entry pathway that apparently is distinct from the endogenous Ca2+ entry pathways present in HEK 293 cells.
- Published
- 2003
45. Oronasal Squamous Cell Carcinoma in an African Hedgehog (Erinaceidae albiventris)
- Author
-
Rachel Y. Reams Rivera and Evan B. Janovitz
- Subjects
Nasal cavity ,Pathology ,medicine.medical_specialty ,Maxillary Sinus Neoplasms ,Nose Neoplasms ,otorhinolaryngologic diseases ,medicine ,Carcinoma ,Animals ,Basal cell ,Hedgehog ,Ecology, Evolution, Behavior and Systematics ,Nose ,Maxillary Neoplasms ,Palatal Neoplasms ,Ecology ,biology ,Erinaceidae ,Anatomy ,biology.organism_classification ,medicine.disease ,stomatognathic diseases ,medicine.anatomical_structure ,Hedgehogs ,Maxilla ,Carcinoma, Squamous Cell ,Female ,Hard palate - Abstract
Oronasal squamous cell carcinoma was diagnosed in an adult African hedgehog (Erinaceidae albiventris). Clinically, the carcinoma presented as a firm right maxillary swelling with deviation of the nose to the left. The carcinoma was attached to the hard palate and protruded into the oral cavity. At necropsy, the carcinoma appeared centered in the right maxillary sinus, and had replaced the maxilla and extended into the nasal cavity. Metastatic foci were not found.
- Published
- 1992
46. Nephrotoxicosis in a cat following ingestion of Asiatic hybrid lily (Lilium sp)
- Author
-
Evan B. Janovitz and Mark A. Brady
- Subjects
0301 basic medicine ,Male ,Kidney Cortex ,040301 veterinary sciences ,viruses ,030106 microbiology ,Kidney ,Virus ,0403 veterinary science ,03 medical and health sciences ,Electrolytes ,Fatal Outcome ,Botany ,medicine ,Liliaceae ,Animals ,Subclinical infection ,Pregnancy ,General Veterinary ,biology ,business.industry ,Poisoning ,Pestivirus ,Border Disease ,Antibody titer ,04 agricultural and veterinary sciences ,medicine.disease ,biology.organism_classification ,Virology ,Diarrhea ,biology.protein ,Cats ,Antibody ,medicine.symptom ,business ,Orchiectomy ,Blood Chemical Analysis - Abstract
A virus known to cause multiple problems in cattle, bovine viral diarrhea virus, was isolated from 3 different cases in New World camelids. Virus isolation, immunoperoxidase staining, and fluourescent antibody staining were used to detect the virus. The herds involved were screened for antibody titers to bovine viral diarrhea and virus isolation from the buffy coat. Bovine viral diarrhea virus should be considered as a cause of death in young and old New World camelids. Bovine viral diarrhea virus (BVDV) is a small, enveloped, positive-stranded RNA virus classified in the family Flavi- viridae as a pestivirus along with hog cholera virus of swine and border disease of sheep.5 Many strains of BVDV exist and, based on sequence homology, BVDV can be further classified as either genotype I or II. Two biotypes of BVDV exist based on the cytopathogenicity in cell culture: cyto- pathic and noncytopathic BVDV. Infection of cattle with ei- ther viral biotype or simultaneous infection of cattle with both biotypes may induce a variety of clinical presentations affecting multiple organ systems.1 Clinical disease ranges from the more common subclinical infections to the fatal form known as mucosal disease. In immunocompetent ani- mals, clinical signs may include diarrhea, oral ulcerations, and depression. In pregnant immunocompetent animals, in- fertility, abortions, and congenital defects may be observed. From the Departments of Clinical Sciences (Belknap, Larsen) and Microbiology (Collins), College of Veterinary Medicine and Bio- medical Sciences, Colorado State University, Fort Collins, CO 80523, and the Woodland Veterinary Clinic (Conrad), Woodland Park, CO 80886. Received for publication August 6, 1998. While normally a pathogen of cattle, BVDV has been iso- lated from goats, captive and free-living ruminants, a camel, and pigs.2,7,10 Antibody titers to BVDV have been detected in New World camelids (NWC) housed with persistently in- fected cattle and following a BVDV abortion episode in pyg- my goats.8,9 While there is mention of isolations of BVDV from llamas associated with abortion, excessive nasal dis- charge, or diarrhea,3,8,10 there are no reports of clinical cases in NWC or herd BVDV status. A 13-year-old, 524-pound pregnant llama was admitted for an elective cesarean section due to physical constraints relative to excessive fat deposits within the pelvic canal. The llama had delivered 9 previous crias and was 338 days in gestation with the current pregnancy. The immediately preceding pregnancy had resulted in delivery of a dead fetus. Dexamethasone (10 mg IM) was administered 24 hours prior to the planned surgery to enhance pulmonary maturation of the fetus. Due to the dam’s excessive body condition, ultrasound of the fetus was not pos- sible. At surgery, the male cria was stillborn, the hair epilated easily, and the corneas were cloudy. Gross necropsy of the cria revealed no other abnormalities. Fluorescent antibody (FA) test- ing for BVDV (Table 1), equine herpesvirus-1 (EHV-1), chla- mydia, and bovine herpesvirus-1 (BHV-1) was negative, and
- Published
- 2000
47. Pseudorabies in captive coyotes
- Author
-
Robert G. Gillespie, Mary Woodruff, James T. Raymond, and Evan B. Janovitz
- Subjects
Male ,medicine.medical_specialty ,Indiana ,viruses ,Virus isolation ,Carnivora ,Pseudorabies ,Intranuclear Inclusion Body ,Virus ,medicine ,Animals ,Ecology, Evolution, Behavior and Systematics ,Ecology ,biology ,Meningoencephalitis ,Brain ,medicine.disease ,biology.organism_classification ,Virology ,Herpesvirus 1, Suid ,Canis ,biology.protein ,Histopathology ,Animals, Zoo ,Antibody - Abstract
Pseudorabies (Aujeszky's disease) was diagnosed in three adult captive coyotes (Canis latrans) from southern Indiana (USA). The coyotes died in their outdoor enclosure within a 48 hr period. Histopathology revealed multifocal, nonsuppurative meningioencephalitis and eosinophilic intranuclear inclusion bodies within neurons. Samples of brain were positive for pseudorabies virus by fluorescent antibody testing and virus isolation. Source of infection was the probable consumption of pseudorabies virus-infected pig carcasses.
- Published
- 1997
48. Malignant mast cell tumor in an African hedgehog (Atelerix albiventris)
- Author
-
Evan B. Janovitz, M. Randy White, and James T. Raymond
- Subjects
SUBCUTANEOUS MASS ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Ecology ,biology ,Mast-Cell Sarcoma ,Mastocytoma ,Atelerix albiventris ,medicine.disease ,biology.organism_classification ,Mast cell ,Metastasis ,Microscopy, Electron ,medicine.anatomical_structure ,Hedgehogs ,Lymphatic Metastasis ,medicine ,Neoplasm ,Animals ,African hedgehog ,Female ,Hedgehog ,Ecology, Evolution, Behavior and Systematics ,Neoplasm Staging - Abstract
In November 1995, a malignant mast cell tumor (mastocytoma) was diagnosed in an adult African hedgehog (Atelerix albiventris) from a zoological park (West Lafayette, Indiana, USA). The primary mast cell tumor presented as a firm subcutaneous mass along the ventrum of the neck. Metastasis to the right submandibular lymph node occurred.
- Published
- 1997
49. Feline fibrosarcomas at vaccination sites and non-vaccination sites
- Author
-
N.W. Glickman, Larry T. Glickman, F.D. Doddy, and Evan B. Janovitz
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Necrosis ,Time Factors ,Fibrosarcoma ,Pathology and Forensic Medicine ,Sex Factors ,medicine ,Carnivora ,Animals ,neoplasms ,CATS ,integumentary system ,General Veterinary ,business.industry ,Vaccination ,Age Factors ,medicine.disease ,Inflammatory cell infiltration ,stomatognathic diseases ,Cats ,Pleomorphism (microbiology) ,Female ,Sarcoma ,medicine.symptom ,business - Abstract
A retrospective study of 195 feline sarcomas diagnosed histologically between July 1988 and June 1994 showed that 170 (87.2%) were fibrosarcomas. Cats with vaccination site (VS) fibrosarcomas were younger (8.6 +/- 3.9 years; median = 8 years) than cats with non-vaccination site (NVS) fibrosarcomas (10.2 +/- 4.7 years; median = 11 years) (P = 0.03), but there was no such association with breed, sex, or "neuter status". Microscopical features more characteristic of VS fibrosarcomas than of NVS fibrosarcomas were (1) subcutaneous location (P < 0.001), (2) necrosis (P < 0.001), (3) inflammatory cell infiltration (P < 0.001), (4) increased mitotic activity (P < 0.02), (5) pleomorphism (P < 0.001), and (6) variability in the density of the extracellular matrix (P < 0.001). When these data were fitted to a logistic regression model, younger age (P = 0.003), subcutaneous location of the fibrosarcoma (P = 0.0002), and the presence of inflammation (P = 0.017) were more characteristic of VS fibrosarcomas than of NVS fibrosarcomas. The study showed that in the absence of any vaccination history, the age of a cat, coupled with certain histological characteristics (e.g., tumour location in skin, and inflammation), may help in distinguishing VS fibrosarcomas from NVS fibrosarcomas. The characteristic histological features of VS fibrosarcomas, such as necrosis, increased mitotic activity and pleomorphism, are those of aggressive tumours.
- Published
- 1996
50. Baylisascaris procyonis larva migrans in a puppy: a case report and update for the veterinarian
- Author
-
Evan B. Janovitz, Kevin R. Kazacos, DG Rudmann, S. T. Storandt, and DL Harris
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Autopsy ,Baylisascaris ,Dogs ,Puppy ,Central Nervous System Diseases ,biology.animal ,Eosinophilic ,Ascaridoidea ,Eosinophilia ,Medicine ,Animals ,Dog Diseases ,Small Animals ,Pleocytosis ,Cerebrospinal Fluid ,biology ,business.industry ,Antemortem Diagnosis ,Baylisascaris procyonis ,Brain ,biology.organism_classification ,Ascaridida Infections ,Eosinophils ,Larva Migrans ,Raccoons ,medicine.symptom ,business - Abstract
Baylisascaris larva migrans (LM) has been recognized as a cause of central nervous system (CNS) disease in puppies. A presumptive antemortem diagnosis is based on a history of raccoon exposure, clinical signs, cerebrospinal fluid eosinophilic pleocytosis, and peripheral blood eosinophilia. Early diagnosis is critical for treatment or prevention of disease in other dogs, animals, or humans exposed to the suspected contaminated area. In the present case, an antemortem diagnosis was not made, emphasizing the importance of postmortem examination in cases of CNS disease in puppies.
- Published
- 1996
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