Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT&lt;sub&gt;1B&lt;/sub&gt; Inhibitor

Chang, Jane; Ciaccio, Paul J.; Schroeder, Patricia; Wright, Lindsay; Westwood, Russell; Berg, Anna‐Lena

doi:10.1293/tox.2013-0033

Cited by 5 publications

(3 citation statements)

References 30 publications

(36 reference statements)

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“…Undesirable side effects have been reported with at least some related drugs. For example, AZD3783, a potent inhibitor of the 5‐HT1B receptor, was neurotoxic in dogs (60). Dox was found to be highly effective in our studies, but it also can evidence negative side effects (61), and whether a more selective α blocker would be safer but just as effective remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability

Du¹,

Cramer²,

Lee³

et al. 2015

FASEB j.

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Reactive oxygen species play an important role in the pathogenesis of diabetic retinopathy. We studied the role of adrenergic and serotonin receptors in the generation of superoxide by retina and 661W retinal cells in high glucose and of the α1-adrenergic receptor (AR) on vascular lesions of the retinopathy in experimentally diabetic C57Bl/6J mice (and controls) after 2 and 8 months. Compared with 5 mM glucose, incubating cells or retinal explants in 30 mM glucose induced superoxide generation. This response was reduced or ablated by pharmacologic inhibition of the α1-AR (a Gq-coupled receptor) or Gs-coupled serotonin (5-HT2, 5-HT4, 5-HT6, and 5-HT7) receptors or by activation of the Gi-coupled α2-AR. In elevated glucose, the α1-AR produced superoxide via phospholipase C, inositol triphosphate-induced Ca(2+) release, and NADPH oxidase, and pharmacologic inhibition of these reactions prevented the superoxide increase. Generation of retinal superoxide, expression of proinflammatory proteins, and degeneration of retinal capillaries in diabetes all were significantly inhibited with daily doxazosin or apocynin (inhibitors of α1-AR and NADPH oxidase, respectively), but increased vascular permeability was not significantly affected. Adrenergic receptors, and perhaps other GPCRs, represent novel targets for inhibiting the development of important features of diabetic retinopathy.

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Section: Discussionmentioning

confidence: 99%

Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability

Du¹,

Cramer²,

Lee³

et al. 2015

FASEB j.

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“…Inhalation of poorly soluble test compounds can also result in the same type of response (Nikula et al 2013). Alveolar macrophage accumulation can also be induced by noninhalation administration of compounds which cause phospholipidosis (Mazue et al 1984;Chang et al 2014). In dog studies, interpretation of a marginal increase in the incidence and/or severity in dosed groups can be challenging because of the small group sizes used in toxicology studies.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous and Dosing Route–related Lung Lesions in Beagle Dogs from Oral Gavage and Inhalation Toxicity Studies

et al. 2016

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This study was conducted to characterize lung microscopic lesions in control beagle dogs from inhalation and oral gavage toxicity studies, to determine differences associated with the route of administration, and to discuss distinguishing features from compound-induced lung lesions. Samples from 138 control dogs from oral gavage studies and 124 control dogs from inhalation (vehicle control) studies were evaluated microscopically. There was no significant sex-related difference in the incidence of all lesions. Perivascular mononuclear cell infiltration, centriacinar mixed cell infiltration, bronchopneumonia, subpleural septal fibrosis, and alveolar macrophage accumulation were the most common lesions. Aspiration pneumonia was more common in dogs from gavage studies, suggesting reflux after gavage dosing or accidental administration of test formulation as possible causes. Centriacinar mixed cell infiltration was more common in dogs from inhalation studies, suggesting mild irritation by the vehicles used. Vascular lesions, which included pulmonary arteriopathy and smooth muscle mineralization, were observed in a few animals. Some of the spontaneous lesions are similar to lesions induced by test compounds. Compared to spontaneous lesions, compound-induced lesions tend to be multifocal or diffuse, follow a pattern of distribution (e.g., centriacinar, perivascular, and interstitial), show a dose response in the incidence and severity, and may show cell-specific toxicity.

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“…The remainder of the presentation centered on phospholipidosis, which Halliwell (1997, 53) stated is “an excessive accumulation of intracellular phospholipids.” On histopathology, phospholipidosis can be suspected in cases of foamy cytoplasmic vacuolation in a wide variety of cells, with single or multiple tissue involvement (Halliwell 1997; Cartwright et al 2009; Chang et al 2014). Phospholipidosis may be subcategorized into “macrophage dominant,” “parenchymal cell dominant,” and “localized” (Ettlin et al 2010, 221).…”

Section: Canine and Rodent Pulmonary Pathology: Are They The Same Or Different? An Ultrastructural Case Studymentioning

confidence: 99%

Proceedings of the 2015 National Toxicology Program Satellite Symposium

Elmore

Farman²,

Hailey

et al. 2016

Toxicol Pathol

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The 2015 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri” was held in Minneapolis, Minnesota at the ACVP/ASVCP/STP combined meeting. The goal of this symposium is to present and discuss diagnostic pathology challenges or nomenclature issues. Because of the combined meeting, both laboratory and domestic animal cases were presented. This article presents summaries of the speakers’ talks, including challenging diagnostic cases or nomenclature issues that were presented, along with select images that were used for audience voting and discussion. Some lesions and topics covered during the symposium included hepatocellular lesions; a proposed harmonized diagnostic approach to rat cardiomyopathy; crop milk in a bird; avian feeding accoutrement; heat exchanger in a tuna; metastasis of a tobacco carcinogen-induced pulmonary carcinoma; neurocytoma in a rat; pituicytoma in a rat; rodent mammary gland whole mounts; dog and rat alveolar macrophage ultrastructure; dog and rat pulmonary phospholipidosis; alveolar macrophage aggregation in a dog; degenerating yeast in a cat liver aspirate; myeloid leukemia in lymph node aspirates from a dog; Trypanosoma cruzi in a dog; solanum toxicity in a cow; bovine astrovirus; malignant microglial tumor; and nomenclature challenges from the Special Senses International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) organ working group (OWG).

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Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT<sub>1B</sub> Inhibitor

Cited by 5 publications

References 30 publications

Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability

Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability

Spontaneous and Dosing Route–related Lung Lesions in Beagle Dogs from Oral Gavage and Inhalation Toxicity Studies

Proceedings of the 2015 National Toxicology Program Satellite Symposium

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