Pathology and Pathophysiology of Drug‐Induced Arterial Injury in Laboratory Animals and its Implications on the Evaluation of Novel Chemical Entities for Human Clinical Trials

Abstract

Abstract:In toxicology studies, drug-induced arterial injury in laboratory animals continues to be a pressing issue of concern, particularly to those engaged in the discovery and development of novel therapies intended for human use. The concern is justifiably magnified because, currently, there is no unequivocal biochemical marker of arterial injury and/or toxicity in animals or man. Therefore, in laboratory animals used for toxicology studies a precise description of arterial lesions in terms of location, distribution and morphologic character is necessary so that a correlation can be drawn between structural damage and derangement of specific cardiovascular functions. The critical nature of the latter cannot be over-emphasized because this will provide a basis for understanding the mechanism of toxicity, the pathogenesis of the lesion and assessment of human risk. However, in the decision making process, utilization of pattern recognition must be supported by rigorous scientific investigations aimed at establishing a link, where possible, between the deranged cardiovascular function and alterations in cellular, biochemical and molecular events. Conceivably, engagement of the molecular pharmacology target initiates a series of interactive cascades among cellular and non-cellular arterial components that culminate in organ damage. Therefore, any investigative mechanistic studies aimed at understanding the initiation and development of arterial lesions in laboratory animals must make a conscientious attempt to identify and characterize the molecular target of toxicity.Determining the safety of medicines for human use involves careful assessment of clinical, biochemical, physiological and pathological changes in appropriate species suitable for toxicology testing. The rat, dog and monkey are most commonly used. The beagle dog is particularly important for cardiovascular evaluation because in this species, historic haemodynamic and pathological coronary arterial changes associated with administration of novel chemical entities can be related in a manner that will allow clinical investigation of these molecules. However, spontaneous and stressrelated arterial lesions in dogs add confusion and complexity to the interpretation of drug-induced lesions. Therefore, a thorough understanding of the morphologic differentiating features and distribution of these arterial lesions are necessary for a correct and accurate diagnosis. Spon-

Chronic Pharmacological and Safety Evaluation of Hematide™, a PEGylated Peptidic Erythropoiesis‐Stimulating Agent, in Rodents

“…There were several findings in the rat that have been described as age‐related spontaneous lesions, and appear to have been exacerbated by Hematide‐related haemodynamic changes. The age‐related spontaneous changes included chronic progressive nephropathy and/or tubular regeneration as well as periarteritis [14,15]. The periarteritis was considered likely related to altered haemodynamic patterns secondary to an increase in blood viscosity and haemoconcentration and was observed primarily in the high‐dose group at the 3‐month interim sacrifice and in the mid‐ and high‐dose groups at 6 months.…”

Novel Vascular Lesions in Mice Given a Non-Peptide Vitronectin Receptor Antagonist

“…7, 2007 VASCULAR LESIONS IN MICE 965 injury occurring as a direct consequence of intended pharmacology of a drug include minoxidil (potassium channel opener), endothelin receptor antagonists, Fenoldopam (dopamine DA1 agonist) and phosphodiesterase (PD 3) inhibitors (Kerns et al, 2005;Louden et al, 2006). Vascular injury induced by vasoconstrictive agents such as L-norepinephrine, endothelin, or thromboxane, are associated with hypertension and vascular changes including localized or widespread constrictions of small to mid-sized arteries, narrowing of the lumen, VSMC necrosis and hyaline thickening of the media (Louden and Morgan, 2001). Pulmonary hypertension may be induced in rats with monocrotaline causing endothelial necrosis, VSMC proliferation, migration and hypercontraction (Pullamsetti et al, 2005).…”

“…These include biomechanical injury secondary to shear and/or hoop stress, direct pharmacological and/or chemical-mediated injury, and alterations secondary to an immunological response and/or inflammation (Kerns et al, 2005). Several compounds that cause vascular toxicity in preclinical species, such as minoxidel and phosphodiesetrase III inhibitors, are also vasoactive effecting a decrease in systemic blood pressure and reflex tachycardia, (Louden and Morgan, 2001). Although systemic hemodynamic changes may be present, hemodynamic changes localized to specific vascular beds, such as the coronary arteries in dogs and mesenteric arteries in rats, may play a greater role in the pathogenesis of these vascular lesions through alterations in shear and possible hoop stress.…”

A bilayer small diameter in vitro vascular model for evaluation of drug induced vascular injury

“…An extensive iterative design process was required to develop the device features and microfluidic cell culture methodology to achieve stable and phenotypically appropriate cell growth in the device. Device design was modeled in 3D using SolidWorks (SolidWorks Corp., Concord, MA) and analyzed with computational fluid dynamics (CFD) in (1) is continuous with the vascular channel (2). The endothelial cells (EC) were seeded through the seeding inlet channel (3), flown through the vascular channel (2) and exited the device at the outlet (4).…”

“…Druginduced vascular injury (DIVI) in pre-clinical toxicology studies of pharmaceutical agents in particular, involves both the endothelium and tunica media of small vessels to medium sized vessels, but little is known about its mechanism or inciting factors agent. 1,2 In animals, DIVI is diagnosed by postmortem histopathologic examination of vessels from animals exposed to new chemical entities, 3 usually as part of pre-clinical in vivo safety studies. DIVI is characterized by degenerative and hyperplastic changes of endothelial cells (ECs) and vascular smooth muscle cells (SMCs), sometimes accompanied by inflammation.…”