Coronary Arteriopathy in Monkeys Following Administration of CI-1020, an Endothelin A Receptor Antagonist

Albassam, Mudher; Metz, Alan; Gragtmans, N. J.; King, Lena M.; Macallum, Grace E.; Hallak, Hussein; McGuire, Edward J.

doi:10.1177/019262339902700202

Cited by 29 publications

(23 citation statements)

References 24 publications

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“…This study con rms our hypothesis and others (22) that dogs are uniquely sensitive to development of coronary arterial injury. This hypothesis is also supported by the fact that CI-1020-induced coronary vascular injury in monkeys was not seen earlier than 2 weeks of continuous intravenous infusion (1). In the reversibility study, as expected, the most severe changes were seen on the rst day following the cessation of CI-1020 infusion.…”

Section: Endothelin-1 Levelssupporting

confidence: 61%

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

et al. 2001

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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.

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Section: Endothelin-1 Levelssupporting

confidence: 61%

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

et al. 2001

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“…However, no data on differential distribution of systemic arterial endothelin receptors is currently available. The induction of coronary arteritis by endothelin antagonists in species other than dog remains relatively little explored although the monkey has been shown to be sensitive (1). It is noteworthy, that both dog and human coronary arteries possess high concentrations of endothelin receptors (8).…”

Section: Physiological Assessmentsmentioning

confidence: 99%

Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

et al. 2003

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Two endothelin antagonists, ZD1611 (3-{4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl]phenyl}-2,2-dimethylpropanoic acid) and ZD2574 (2-(4-isobutylphenyl)-N -(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide), selective for the ET A receptor and intended for use in pulmonary hypertension, were tested in Beagle dogs at various doses for periods of up to 4 weeks. These studies included in vivo telemetric hemodynamic assessment, full histopathological and ultrastructural pathological evaluation of coronary arteries. Both drugs produced arteritis in small-and medium-sized coronary arteries after single or multiple doses, some of which were at or below the ED50. The distribution of lesions was predominantly in extramural arteries over the atria and atrioventricular groove of the right side of the heart and consisted of epicardial hemorrhage and arteritis. Systemic arteritis was also present at a lower incidence than the coronary arteritis, was located at different sites and appeared inconsistently. Ultrastructural changes in coronary arteries suggested that damage was the result of mechanical factors. Although these patterns of vascular injury possessed features in common with those induced in dogs by high doses of vasodilating antihypertensive drugs and inotropic agents, they were atypical, as there was no left ventricular myocardial necrosis, papillary muscle damage, or subendocardial hemorrhage suggestive of ischaemia or excessive inotropism. Moreover, physiological monitoring showed no evidence of exaggerated systemic hypotension or reflex tachycardia at doses associated with vascular damage. Consequently, the changes might be the result of a localized pharmacological process such as intense, prolonged vasodilatation in unsupported arteries that are well endowed with endothelin receptors and particularly sensitive to endothelin antagonism.

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“…When endothelin receptor antagonists are given to pri-mates (Albassam et al 1999), lesions occur in the right atrium and coronary arteries. Oral or intravenous doses of an ET A selective receptor antagonist was associated with macroscopic cardiac lesions along the interventricular groove and descending branches of the circumflex and right coronary arteries.…”

Section: Pathology Of Endothelin Receptor Antagonists Induced Arteriamentioning

confidence: 99%

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

Louden

Morgan

2001

Pharmacology & Toxicology

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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-

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Coronary Arteriopathy in Monkeys Following Administration of CI-1020, an Endothelin A Receptor Antagonist

Cited by 29 publications

References 24 publications

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

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

Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

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

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