Mesenteritis precedes vasculitis in the rat mesentery after subacute administration of a phosphodiesterase type 4 inhibitor

Mecklenburg, Lars; Heuser, Anke; Juengling, Tobias; Köhler, Manfred; Foell, Roman; Ockert, Deborah; Tuch, K.; Bode, Gerd

doi:10.1016/j.toxlet.2005.09.037

Cited by 29 publications

(23 citation statements)

References 21 publications

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“…The toxicity issues of this class of compounds is associated with arteritis in several species (Langle et al, 1994;Larson et al, 1996;Vogel et al, 1999;Mecklenburg et al, 2006), including cynomolgus monkeys (Losco et al, 2004). Recent data also highlighted a role in heart failure and arrhythmias (Lehnart et al, 2005).…”

Section: Figmentioning

confidence: 99%

“…However, this class of compounds has been associated with some toxicity issues (for recent review, see Giembycz, 2005). PDE 4 inhibitors have been shown to cause arteritis and vasculitis (inflammation of the arteries and vessels) in rats (Langle et al, 1994;Larson et al, 1996; http://www.fda.gov/ohrms/ dockets/ac/03/transcripts/3976T1.doc; Mecklenburg et al, 2006) and minipigs (Vogel et al, 1999). This finding was demonstrated more recently in cynomolgus monkeys, which was the first observation using this class of compounds in nonhuman primates (Losco et al, 2004).…”

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confidence: 99%

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Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

McCluskie

Klein²,

Linnevers³

et al. 2006

J Pharmacol Exp Ther

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Phosphodiesterase type 4 (PDE 4 ) inhibitors are currently being evaluated as potential therapies for inflammatory airway diseases. However, this class of compounds has been shown to cause an arteritis/vasculitis of unknown etiology in rats and cynomolgus monkeys. Studies in rodents have demonstrated the anti-inflammatory effects of PDE 4 inhibitors on lipopolysaccharide (LPS)-induced airway inflammation. The aim of this work was to assess the direct effects of PDE 4 inhibitors on inflammatory cells and cytokine levels in the lung in relation to therapeutic effects. The effects of the PDE 4 inhibitors 3-cyclopropylmethoxy-4-difluoromethoxy-N- [3,5-di-chloropyrid-4-yl

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Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

McCluskie

Klein²,

Linnevers³

et al. 2006

J Pharmacol Exp Ther

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“…PDE4 inhibitors generally induce vascular injury during preclinical toxicology tests, an observation found mainly in rats but also in dogs and monkeys [15][16][17][18]. Although the mechanisms of the injury are not well understood and there are no specific biomarkers for its indications, the injury does correlate with marked increases in several serum proteins, including acute phase proteins [16,35,36].…”

Section: Fibrinogen Concentration In Bloodmentioning

confidence: 99%

Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation

et al. 2012

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We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC₅₀ values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3–6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-α production and PHA-induced IL-5 production in human whole blood cells with respective IC₅₀ values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED₅₀ values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an α₂-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with α₂-adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.

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“…Occasionally, edema or hemorrhage including extravasation of red blood cells (RBCs) into the tunica media layer of blood vessels 4 is seen; analysis of these vessels reveals a relatively undisturbed endothelial layer but a widespread deposition of RBCs and few white blood cells into the vessel wall. With some drugs, particular vascular beds in certain species, such as mesenteric vessels in rats (diameter % 200 lm) and coronary arteries in dogs (diameter % 0.5-1 mm), appear to be more predisposed to these lesions [5][6][7] although DIVI can occur in many different vascular beds in these species. Injury to both ECs and SMCs leading to subsequent inflammatory response has been implicated in DIVI pathogenesis, but the individual contributions from each cell type is unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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In pre-clinical safety studies, drug-induced vascular injury (DIVI) is defined as an adverse response to a drug characterized by degenerative and hyperplastic changes of endothelial cells and vascular smooth muscle cells. Inflammation may also be seen, along with extravasation of red blood cells into the smooth muscle layer (i.e., hemorrhage). Drugs that cause DIVI are often discontinued from development after considerable cost has occurred. An in vitro vascular model has been developed using endothelial and smooth muscle cells in co-culture across a porous membrane mimicking the internal elastic lamina. Arterial flow rates of perfusion media within the endothelial chamber of the model induce physiologic endothelial cell alignment. Pilot testing with a drug known to cause DIVI induced extravasation of red blood cells into the smooth muscle layer in all devices with no extravasation seen in control devices. This engineered vascular model offers the potential to evaluate candidate drugs for DIVI early in the discovery process. The physiologic flow within the coculture model also makes it candidate for a wide variety of vascular biology investigations. Published by AIP Publishing. [http://dx

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Mesenteritis precedes vasculitis in the rat mesentery after subacute administration of a phosphodiesterase type 4 inhibitor

Cited by 29 publications

References 21 publications

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation

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

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