Mesenteric Arteriopathy in the Rat Induced by Phosphodiesterase III Inhibitors: An Investigation of Morphological, Ultrastructural, and Hemodynamic Changes

Joseph, Emmanuella; Rees, J A; Dayan, Anthony D.

doi:10.1177/019262339602400406

Cited by 40 publications

(45 citation statements)

References 26 publications

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“…Medial hemorrhage and necrosis of splanchnic arteries, but not myocardial lesions, have been reported in rats (22,23). The mechanism by which SK&F 95654 induces arterial lesions has been ascribed to the con-sequences of excessive regional and systemic hemodynamic activity, such as excessive vasodilation, exaggerated blood ow, and increased vessel wall tension (17,22,23). However, it is not clear whether more complex and speci c discordant interactions between focal cellular reactions, which may not be a consequence of hemodynamic alterations, may contribute to the observed vascular toxicity.…”

Section: Introductionmentioning

confidence: 99%

SK&F 95654-Induced Acute Cardiovascular Toxicity in Sprague-Dawley Rats—Histopathologic, Electron Microscopic, and Immunohistochemical Studies

et al. 2002

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The characteristics and pathogenesi s of the cardiovascula r toxicity induced by the type III selective phosphodiesteras e inhibitor SK&F 95654 were examined in 2 studies. Sprague-Dawley rats received either a single sc injection of 50, 100, or 200 mg/kg SK&F 95654 and were euthanized at 24 hours after administration of the drug (Study 1), or were given a single subcutaneou s (sc) injection of 100 mg/kg SK&F 95654 and euthanized at 1, 2, 4, 6, 8, 12, 24 hours, or 2 weeks after treatment (Study 2). Control rats received either DMSO or saline. Myocardial lesions and vascular lesions of the mesentery, spleen, and pancreas were seen 24 hours after dosing with either 50, 100, or 200 mg/kg SK&F 95654. The frequency and severity of these lesions (evaluated after the 100 mg/kg dose) increased with time over a period of 1 to 24 hours. By 2 weeks, the lesions subsided. Cardiac lesions consisted of myocyte necrosis with hypercontraction bands, in ammatory cell in ltration, interstitial hemorrhage, and interstitial edema. Vascular lesions of the mesentery were most prominent and consisted of vasodilatation and in ammation in the small-sized vessels, arterial medial necrosis and hemorrhage , and venous thrombosis. The vascular lesions included: leukocyt e adhesion to endothelial cells, transendothelia l migration of leukocytes, and in ammatory cell in ltration into vessel walls. Affected vessels included arteries, terminal arterioles, capillaries, postcapillary venules, and veins. Apoptosis of endothelial and smooth muscle cells was detected in the mesenteric vasculature by both TUNEL assay and electron microscopy. Evidence of endothelial cell activation in the mesenteric arteries and veins was also observed by electron microscopy. Immunohistochemica l staining detected enhanced endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF) in the mesenteric arteries and veins. Mast cells were noted to be more prevalent in affected mesenteric tissue from drug-treated animals. The present ndings suggest that apoptosis of endothelial and smooth muscle cells, activation of endothelial cells, recruitment of mast cells, and increased expression of adhesion molecules are important factors to the overall pathogenesi s of SK&F 95654-induce d vasculitis.Keywords. Myocardial necrosis and in ammation; drug-induce d vasculitis; vasodilatation; endothelial cell activation; endothelial and smooth muscle cell apoptosis; intercellular adhesion molecule-1 (ICAM-1); von Willebrand factor; mast cell degranulation . INTRODUCTIONType III phosphodiesterase (PDE) belongs to the cyclic 3 ,5 -adenosine guanosine monophosphate (cGMP)-inhibited PDE family of enzymes that hydrolyze intracellular cAMP (40). Selective inhibitors of PDE III possess bronchodilator activity (40), which offers these agents potential for treating patients with asthma. However, in nonclinical studies, PDE III inhibitors have been reported to cause cardiac and vascular alterations (10, 17, 21-23, 32, 36-38, 44). SK&F 95654, a s...

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Section: Introductionmentioning

confidence: 99%

SK&F 95654-Induced Acute Cardiovascular Toxicity in Sprague-Dawley Rats—Histopathologic, Electron Microscopic, and Immunohistochemical Studies

et al. 2002

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“…Toxicities associated with inhibition of PDE3 have been extensively reported in animals, particularly in rats (Westwood et al, 1990;Sandusky et al, 1991;Joseph et al, 1996b;Hanton et al, 2000a;Zhang et al, 2002) and dogs (Harleman et al, 1986;Isaacs et al, 1989;Means et al, 1989;Sandusky et al, 1993;Joseph et al, 1996a;Hanton et al, 2000b). The most striking effects have been arteriopathy involving the splanchnic vessels of rats and the coronary arteries and cardiac muscle of dogs.…”

Section: Introductionmentioning

confidence: 99%

The Toxicity of SCH 351591, a Novel Phosphodiesterase-4 Inhibitor, in Cynomolgus Monkeys

Losco¹,

Evans²,

Barat³

et al. 2004

Toxicol Pathol

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SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low-and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.

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“…The histologic lesions of small molecule-related DIVI have been well described (Dietsch et al 2006;Hanton et al 2008;Joseph, Rees, and Dayan 1996;Joseph 2000;C. Louden and Morgan 2001;Weaver et al 2008;Yuhas et al 1985), and include perivascular edema, inflammatory cell infiltrates (frequently including macrophages and neutrophils), and mural or perivascular hemorrhage together with degenerative or necrotic changes of the tunica media.…”

Section: Preclinical Divi Associated With Small Moleculesmentioning

confidence: 98%

“…In most types of vascular injury in laboratory animals, mixed inflammatory cell infiltrates are most common and may include macrophages, neutrophils (Albassam et al 1999;C. S. Louden et al 2000;Joseph, Rees, and Dayan 1996), eosinophils (Anderson and Hayes 1989;Bregman et al 1987), and lymphocytes ( Figure 1). Adventitial fibrosis and neovascularization can occur with chronic lesions, especially in large vessels, with differentiation of fibroblasts to myofibroblasts (Siow, Mallawaarachchi, and Weissberg 2003;Zalewski and Shi 1997).…”

Section: Anatomic Considerations and Divi Standard Terminologymentioning

confidence: 99%

“…Many small molecule drugs are known to cause DIVI in preclinical species (Clemo et al 2003;Joseph, Rees, and Dayan 1996; W. Kerns et al 2005;Zhang et al 2008). Despite extensive efforts to define the relevance of DIVI in preclinical studies to humans, and to identify biomarkers for vascular injury across species, the translatability of DIVI from animals to humans remains unclear (Mesfin et al 1996).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Frazier

Engelhardt

Fant³

et al. 2015

Toxicol Pathol

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Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.

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Mesenteric Arteriopathy in the Rat Induced by Phosphodiesterase III Inhibitors: An Investigation of Morphological, Ultrastructural, and Hemodynamic Changes

Cited by 40 publications

References 26 publications

SK&F 95654-Induced Acute Cardiovascular Toxicity in Sprague-Dawley Rats—Histopathologic, Electron Microscopic, and Immunohistochemical Studies

SK&F 95654-Induced Acute Cardiovascular Toxicity in Sprague-Dawley Rats—Histopathologic, Electron Microscopic, and Immunohistochemical Studies

The Toxicity of SCH 351591, a Novel Phosphodiesterase-4 Inhibitor, in Cynomolgus Monkeys

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

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