Characterization of Coronary Arterial Lesions in the Dog Following Administration of SK&amp;F 95654, a Phosphodiesterase III Inhibitor

Joseph, Emmanuella; Jones, Huw B.; Kerns, William

doi:10.1177/019262339602400405

Cited by 23 publications

(27 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SK&F 95654 has been shown to induce vascular lesions in rats and dogs (17, 21-23), but such cardiac lesions have previously been reported in dogs (10,17,21) and not in rats. Wistar rats treated with 50, 100, or 200 mg/kg of SK&F 95654 were reported to develop dose-dependent dilatation, in ammation, medial hemorrhage, and necrosis primarily in muscular mesenteric arteries (22,23).…”

Section: Discussionmentioning

confidence: 98%

“…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 speci c inhibitor of PDE III was found to induce hemorrhage and necrosis of myocardium and coronary arteries in dogs (17,21). Medial hemorrhage and necrosis of splanchnic arteries, but not myocardial lesions, have been reported in rats (22,23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2002

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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

et al. 2002

View full text Add to dashboard Cite

show abstract

“…The vascular changes elicited by vasoactive drugs at excessive dosages in dogs often have distinctive morphology, which is demonstrated by a vasodilator and/or positive inotropic-induced lesion that is seen with high doses of phosphodiesterase (PDE)-III inhibitors (SK&F 94120, SF&K 94836, SK&F 95654, and SK&F 94418) (17,(22)(23)(24)(25). Arterial lesions induced by these PDE-III inhibitors are time-dependent.…”

Section: Vasoactive Induced Arterial Lesions In the Dogmentioning

confidence: 99%

“…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). Like CI-1020, the acute arterial changes are reversible when treatment is discontinued for minoxidil (33) and the PDE III inhibitor SF&K 95654 (24). The arterial changes associated with vasodilator administration in dogs are probably the consequence of hemodynamic changes related to pharmacological activity on the cardiovascular system rather than direct toxicity.…”

Section: Vasoactive Induced Arterial Lesions In the Dogmentioning

confidence: 99%

“…Subacute and chronic lesions from dogs in remission are characterized by intimal hyperplasia and medial hypertrophy with varying degrees of ruptured internal elastic laminae and perivascular mononuclear inflammation (Figure 2b In evaluation of the acute arterial changes associated with idiopathic canine polyarteritis and high dose of vasodilators and/or positive inotropes, the overall profile of histopathology, site predilection, and clinical and laboratory changes can often be differentiating (Table 4). For most vasodilatorinduced arterial lesions associated with hydralazine (35), minoxidil (33), and PDE III inhibitors (22)(23)(24)(25), the location is restricted to the coronary arteries (primarily the right extramural branch, but the left extramural and intramural branches can also be affected). In idiopathic canine polyarteritis, the arterial lesions not only involve extramural coronary arteries, but medium to small arteries of other organs.…”

Section: Idiopathic Polyarteritis Of Beagle Dogsmentioning

confidence: 99%

See 1 more Smart Citation

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

et al. 2003

View full text Add to dashboard Cite

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.

show abstract

In Search of Biomarkers for Drug‐Induced Vascular Injury

Turk¹

2010

Biomarkers

View full text Add to dashboard Cite

Characterization of Coronary Arterial Lesions in the Dog Following Administration of SK&F 95654, a Phosphodiesterase III Inhibitor

Cited by 23 publications

References 15 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

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

In Search of Biomarkers for Drug‐Induced Vascular Injury

Contact Info

Product

Resources

About