Studies on Coronary Arteriopathy in Dogs Following Administration of CI-1020, an Endothelin A Receptor Antagonist

Abstract

A selective nonpeptide endotheli n A (ETA) receptor antagonist, CI-1020, was administered to beagle dogs intravenously (iv) for 4 hours to 4 weeks. One animal/sex received CI-1020 at 1 mg/kg/hr intravenousl y for 4, 8, or 24 hours to investigate onset of arteriopathy. Control animals (1/sex) received the vehicle only. To determine reversibility of arteriopathy, 8 dogs/sex were given CI-1020 at 1 mg/kg/hr for 4 days. Two dogs/sex were sacri ced 1, 3, 8, and 29 days following cessation of infusion. Lesion developmen t with prolonged exposure was investigated in 1 male dog. It was given CI-1020 by iv bolus at 120 mg/kg/day for 4 weeks and Monastral blue dye was administered iv to facilitate localization of vascular lesions. Coronary blood ow was determined in 4 dogs infused with CI-1020 at 0.3, 3, and 30 mg/kg for one hour at each dose. Macroscopically, hemorrhage or blue discoloration of Monastral blue was noted in the extramural coronary arteries along the coronary groove and atrium. Histologically, the earliest coronary changes were noted in animals sacri ced after 24 hours of treatment and characterized by medial hemorrhage and necrosis with a few in ltrating neutrophils. In the reversibility study, incidence and severity of arteriopathy was dependen t on time of sacri ce following cessation of infusion. Acute necrotizing in ammation of arteries was present in all animals (n 4) on day 1 postinfusion, whereas on day 8 postinfusion, lesions characterized by medial small pockets of trapped red cells, cell debris, and adventitial thickening were seen in 1 dog/sex. By day 29 postinfusion, coronary arteries were similar to controls. In the dog given daily IV bolus injections of CI-1020 for 4 weeks, arterial in ammatory lesions varied from acute to chronic, although most lesions were considered chronic active. Monastral blue pigments were noted in the wall of most arteries with chronic or chronic active lesions. Acute lesions were similar to those noted in day 1 postinfusion of the reversibility study. Medial smooth muscle necrosis and/or brosis with mixed in ammatory cell in ltrates characterized chronic or chronic active lesions. Smooth muscle proliferation and migration into the intima were also noted. There were no signi cant changes in coronary blood ow, coronary vascular resistance, or mean arterial blood pressure following CI-1020 infusion for 3 hours. In the 24-hour infusion study, plasma endothelin 1 (ET-1) levels were mildly elevated (1.5-4 fold) during CI-1020 infusion when compared to either pretest or control values. These results indicate that administration of endothelin antagonist (CI-1020) to dogs was associated with development of coronary arteriopathy, which was completely resolved within 29 days following cessation of treatment. With prolonged (4-week) CI-1020 treatment, arterial lesions at varying stages of developmen t (acute, chronic active, chronic) were seen, suggesting that tolerance to treatment (up to 4 weeks) does not occur.

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

“…Arterial changes induced by PDE III inhibitors are limited in distribution to coronary arteries in which both right and 26 CLEMO ET AL TOXICOLOGIC PATHOLOGY (33), theobromine (11), adrenergic inotropes (isoproterenol, norepinephrine, and dopamine) (41), and various types of endothelin receptor antagonists (2,31,47,49), have been reported to induce, in coronary arteries of dogs, an acute lesion that is morphologically similar to that described for PDE III inhibitors. Administration of CI-1020, an endothelin A receptor antagonist, resulted in medial smooth muscle necrosis and hemorrhage of extramural coronary arteries in dogs treated with single to multiple intravenous doses ( Figure 1a) (2). These acute arterial changes are reversed by day 29 after treatment cessation; however, in dogs treated with CI-1020 for 4 weeks, the arterial lesions progressed to chronic proliferative or chronic-active lesions characterized by medial smooth muscle hypertrophy, necrosis and/or fibrosis with mixed inflammatory cell infiltrates ( Figure 1b) (2).…”

“…Medial degeneration and necrosis, adventitial edema, and variable inflammation, can also be associated with chronic proliferative phase of PDE III induced coronary arterial damage (22). Arterial changes induced by PDE III inhibitors are limited in distribution to coronary arteries in which both right and 26 CLEMO ET AL TOXICOLOGIC PATHOLOGY (33), theobromine (11), adrenergic inotropes (isoproterenol, norepinephrine, and dopamine) (41), and various types of endothelin receptor antagonists (2,31,47,49), have been reported to induce, in coronary arteries of dogs, an acute lesion that is morphologically similar to that described for PDE III inhibitors. Administration of CI-1020, an endothelin A receptor antagonist, resulted in medial smooth muscle necrosis and hemorrhage of extramural coronary arteries in dogs treated with single to multiple intravenous doses ( Figure 1a) (2).…”

Coronary and Systemic Arterial Physiology and Immunohistochemical Markers Related to Early Coronary Arterial Lesions in Beagle Dogs Given the Potassium Channel Opener, ZD6169, or the Endothelin Receptor Antagonist, ZD1611

“…Administration of numerous vasoactive substances to beagle dogs has resulted in a relatively small number of cardiac and vascular pathological changes that often show a predictable pattern related to drug class (Albassam et al 2001;Greaves 1998;Herman et al 1989;Isaacs, Joseph, and Betton 1989;Jones et al 2003) and include cardioactive drugs such as endothelin receptor antagonists (ETRAs) or potassium channel openers (KCOs: Albassam et al 2001;Dogterom, Zbinden, and Reznik 1992;Isaacs, Joseph, and Betton 1989;Jones et al 2003;Louden & Morgan, 2001;Louden et al 1998;Metz et al 1991). Cardiac pathology consequent to KCO administration is diverse and often substantial with left ventricular and papillary muscle myocardial necrosis, left ventricular subendocardial hemorrhage, right atrial epicardial hemorrhage, and bilateral, intra-and extramural coronary arterial damage being frequently seen.…”

Scientific and Regulatory Policy Committee Points-to-consider Paper*

“…However, not all small molecules that are associated with DIVI alter clinically measurable hemodynamic parameters (Albassam et al 1999(Albassam et al , 2001Dalmas et al 2011;Jones et al 2003). Hence, there has been an ongoing search for circulating biomarkers that can detect the onset, progression, and reversibility of this type of drug-induced damage.…”