Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

Abstract

When vascular injury is observed in dogs used in preclinical toxicology studies, careful evaluation of the lesions is warranted, especially when differentiating drug-induced vascular changes from spontaneous findings, such as idiopathic canine polyarteritis. The clinical signs as well as the nature and distribution of lesions can often be distinguishing, as is the case with vasoactive drugs, including vasodilators and/or positive inotropes (hydralazine, minoxidil, endothelin receptor antagonists, and phosphodiesterase III inhibitors). For most types of vasodilator-induced vascular injury, the lesion is often restricted to coronary arteries, whereas in idiopathic canine polyarteritis, arterial lesions not only involve coronary arteries, but also medium to small arteries of other organs. In addition, the nature of the changes in vessels yields important clues. Medial and adventitial hemorrhage is generally associated with vasodilator-induced arterial lesion, whereas hemorrhage is generally absent in idiopathic polyarteritis. Although idiopathic canine polyarteritis can generally be differentiated from vasoactive-induced vascular injury in dogs, there are increasing incidences of this type of polyarteritis in dogs receiving any 1 of a number of unrelated classes of compounds, suggestive of an exacerbation of the spontaneous disease. Therefore, in order to differentiate drug-induced injury from idiopathic canine polyarteritis, it is critical that examination of the vascular pathology be conducted with good understanding of clinical, pharmacological, and mechanistic data associated with the drug.

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

“…In the Beagle dog, it may be extremely difficult to distinguish test item-related arterial lesions from (spontaneous) idiopathic canine polyarteritis. In a classical presentation, the characteristic histopathologic features and lesion distribution, clinical signs, and other corroborative study results would aid in the differentiation; however, there are examples in which only the dose-response curve and overall incidence of histomorphologically identical lesions are distinctive, such as treatment with benzodiazepines, endothelin receptor antagonists, vasodilators, or immunomodulators (Clemo et al 2003). Therefore, the sensitive recording of spontaneous arterial lesions in Beagle dogs, leading to robust historical control data, is essential to interpret such lesions (Bodié and Decker 2014).…”

Incidental Histopathological Findings in Hearts of Control Beagle Dogs in Toxicity Studies

“…This spontaneous finding can also confound the interpretation of toxicity studies, particularly if there is a question of whether the test compound is vasoactive. Vascular injury induced by vasoactive drugs is often characterized by hemorrhage and may be localized to the coronary arteries (Joseph 2000), whereas idiopathic canine polyarteritis is less likely to involve hemorrhage and is more likely to affect arteries in other tissues in addition to those in the heart (Clemo et al 2003;Son 2004).…”

Nonclinical Safety Biomarkers of Drug-induced Vascular Injury

“…Hemodynamically active compounds cause systemic or local vasoconstriction or vasodilation, which may or may not be associated with changes in systemic and/or local blood pressure, turbulent blood flow, and/or eNOS signaling. The vascular beds most commonly affected by hemodynamically active compounds are the mesenteric arteries in rodents and the coronary arteries in nonrodent species (Joseph 2000;Clemo et al 2003). These sites are subjected to a turbulent blood flow (Joseph et al 1996a) and are the preferential site of occurrence of spontaneous vasculitis in both species.…”

“…Such changes include those that may be too subtle to be toxicologically relevant, are of chronic duration, or are indirect/secondary sequelae to DIVI (Table 4). The spontaneous background findings/conditions such as polyarteritis nodosa, Beagle Pain Syndrome, fibrinoid necrosis, and plexiform vasculopathy, will be graded using the lexicon and identified as spontaneous changes in comments (Zeek, Smith, and Weeter 1948;Kelly 1989;Westwood, Iswaran, and Greaves 1990;Clemo et al 2003).…”