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Gastric mucosal injury is frequently observed in nonclinical studies of nonhuman primates. Because microscopic evaluation of stomach is generally a terminal procedure, our objective was to determine whether serum pepsinogen I (PG I) could serve as a noninvasive biomarker for detection of gastric mucosal injury in monkey. Serum PG I was measured using a commercial human immunoassay in cynomolgus monkeys ( n = 166) prior to dosing and/or terminally in 11 studies of up to 1 month duration. Mean ( SD) PG I values (ug/L) for monkeys with ( n = 59) and without ( n = 100) gastric mucosal degeneration were 101 (215) and 28 (12.6), respectively. For monkeys with baseline and terminal PG I data, mean ( SD) fold change (ratio of terminal to baseline PG I) for monkeys with ( n = 57) and without ( n = 76) glandular degeneration were 4.1 (11.3) and 1 (0.28). Receiver operating characteristic area under the curve (AUC) data demonstrated moderate diagnostic accuracy for serum PG I for glandular degeneration, AUC ( SE) 0.789 (0.04), with improved diagnostic accuracy as a fold change of baseline, AUC ( SE) 0.816 (0.04), consistent with the large interindividual but low intraindividual variability of serum PG I values in control monkeys. These data demonstrate that serum PG I is a useful biomarker of drug-induced gastric mucosal injury in the cynomolgus monkey.

Rodent lungs are routinely examined after intratracheal instillation (IT) of fixative. This study compares the histopathologic appearance of the lung after IT fixation with air inflation (AI) followed by immersion fixation. Lungs from mice chronically exposed to cigarette smoke were fixed either by IT or by AI. Increased numbers of macrophages with differing distributions were seen in both groups. Lungs fixed by IT had prominent, large macrophages floating in the alveolar lumina, as well as macrophage clusters and loose aggregates, often near terminal airways. Macrophages in lungs fixed by AI were randomly distributed throughout the lung, lying singly along alveolar walls, with large numbers visible in the interstitium. Clusters of macrophages were seen in the airways after AI but were fewer after IT fixation. The effects of intratracheal fixation on lung macrophages need to be considered carefully when assessing the significance of changes in macrophage appearance and distribution., (© 2015 by The Author(s).)

Chronic administration of drisapersen, a 2'-OMe phosphorothioate antisense oligonucleotide (AON) to mice and monkeys resulted in renal tubular accumulation, with secondary tubular degeneration. Glomerulopathy occurred in both species with species-specific characteristics. Glomerular lesions in mice were characterized by progressive hyaline matrix accumulation, accompanied by the presence of renal amyloid and with subsequent papillary necrosis. Early changes involved glomerular endothelial hypertrophy and degeneration, but the chronic glomerular amyloid and hyaline alterations in mice appeared to be species specific. An immune-mediated mechanism for the glomerular lesions in mice was supported by early inflammatory changes including increased expression of inflammatory cytokines and other immunomodulatory genes within the renal cortex, increased stimulation of CD68 protein, and systemic elevation of monocyte chemotactic protein 1. In contrast, kidneys from monkeys given drisapersen chronically showed less severe glomerular changes characterized by increased mesangial and inflammatory cells, endothelial cell hypertrophy, and subepithelial and membranous electron-dense deposits, with ultrastructural and immunohistochemical characteristics of complement and complement-related fragments. Lesions in monkeys resembled typical features of C3 glomerulopathy, a condition described in man and experimental animals to be linked to dysregulation of the alternative complement pathway. Thus, inflammatory/immune mechanisms appear critical to glomerular injury with species-specific sensitivities for mouse and monkey. The lower observed proinflammatory activity in humans as compared to mice and monkeys may reflect a lower risk of glomerular injury in patients receiving AON therapy., (© 2014 by The Author(s).)

The cynomolgus macaque is the most commonly used nonhuman primate in nonclinical toxicity testing, but the macroscopic and microscopic anatomy of the stomach in the cynomolgus macaque is poorly described. To develop a reliable sampling method for histologic evaluation of the cynomolgus macaque stomach in regulatory toxicity studies, the stomachs of control animals were prospectively evaluated using an extensive sectioning pattern. The stomach of the cynomolgus macaque differs from that described for the human stomach and has a prominent fundus that lacks parietal cells. A description of the macroscopic and microscopic anatomy is presented along with a recommended sectioning pattern for nonclinical toxicity studies and discussion of species differences. A thorough understanding of normal anatomy and species comparisons are critical to interpretation of potential toxicity findings and assessment of risk in humans.

Novel vascular lesions were observed in mice given an alpha vbeta 3, alpha vbeta 5 receptor antagonist (SB-273005) for up to 3 months. Vascular smooth muscle cell (VSMC) necrosis was observed in aorta and renal hilar arteries approximately 6 hours after dosing followed by loss of VSMC, adaptive medial thickening by VSMC hypertrophy and deposition of PAS-positive matrix and collagen. Renal hilar and arcuate arteries developed delayed and transient fibrinoid necrosis and inflammation. Vascular regeneration was not evident following drug-withdrawal after 3 days of dosing. Vascular lesions were associated with necrosis, regeneration and fibrosis of heart, kidney and spleen consistent with initial ischemic injury followed by tissue repair. VSMC toxicity was likely not related to integrin antagonism because lesions were not observed with related compounds and no vascular changes were observed in other preclinical species. In vitro studies failed to demonstrate a direct toxic effect of SB-273005 on VSMC or unique species sensitivity of murine VSMC. In conclusion, SB-273005 caused VSMC necrosis in aorta and renal arteries of mice. Lesions did not progress or recover, but there was medial hypertrophic adaptation even with continued dosing. This is considered direct species-specific VSMC toxicity of unknown mechanism and unrelated to vitronectin receptor antagonism.