Animal Models of Vasculitis

Bishop, Sanford P.

doi:10.1177/019262338901700106

Cited by 31 publications

(17 citation statements)

References 41 publications

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“…In rats, the lesions involved small mesenteric arteries (Joseph et al, 1996b;Zhang et al, 2002), while in dogs, the site of arteriopathy was exclusively the coronary arteries and/or the heart muscle (Isaacs et al, 1989;Dogterom and Zbinden, 1992). Both rats and dogs are thought to have increased susceptibility to drug-induced vascular lesions due to the common occurrence of spontaneous arteriopathies in these species (Bishop, 1989, Ruben et al, 1989Mitsumori, 1990). Literature on vascular disease in monkeys is sparse.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…To date, there have been no reports of mesenteric vasculitis in patients treated with roflumilast N-oxide or another orally active PDE4 inhibitor cilomilast, widely used in patients with asthma and COPD in phase 3 clinical trials (FDA website). It is therefore plausible that rats and dogs have an increased susceptibility to drug-induced vascular lesions because such arteriopathies commonly occur in these species (used regularly in preclinical toxicology studies [117,118]), with differences across species in terms of both PDE4 expression and the functional effects of PDE4 inhibitors. For example, a recent study demonstrated that levels of PDE4 activity in many tissues are much higher in rats than in humans, which would explain why rats are more susceptible to PDE4 inhibitor-induced toxicities [119].…”

Section: Clinical Datamentioning

confidence: 99%

Phosphodiesterase Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

Page

2014

Int Arch Allergy Immunol

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Xanthines like theophylline have long been recognised as being effective drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). They are of interest as they possess both anti-inflammatory and bronchodilator activity in the same molecule. Since the discovery of phosphodiesterases (PDEs) in the late 1950s, it has been suggested that xanthines work, in part, by acting as non-selective PDE inhibitors. However, it has also been suggested that the ability of xanthines to non-selectively inhibit PDEs contributes to their many unwanted side effects, thus limiting their use since the arrival of inhaled drugs with more favourable safety profiles. As our understanding of PDEs has improved over the last 30 years, and with the recognition that the distribution of different PDEs varies across different cell types, this family of enzymes has been widely investigated as targets for novel drugs. In particular, PDE3 in airway smooth muscle and PDE4 and PDE7 in inflammatory cells have been targeted to provide new bronchodilators and anti-inflammatory agents, respectively. This review discusses the progress made in this field over the last decade in the development of selective PDE inhibitors to treat COPD and asthma.

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“…Spontaneous arterial diseases of the dog have been described by Kelly (26) who pointed out that degenerative and proliferative arterial diseases are either age-related or have well-recognized associations with other diseases. In dogs, inflammatory vascular changes have been caused by a variety of infectious agents (bacteria, fungi, and parasites) or immunemediated processes (3,38,39), but these spontaneous lesions are rarely encountered in nonclinical safety assessment studies, given the pathogen-free status of the dogs. One type of spontaneous arterial change that can pose problems in evaluating potential drug-induced vascular changes is idiopathic polyarteritis of Beagle dogs.…”

Section: Spontaneous Vascular Injury In Dogmentioning

confidence: 99%

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

et al. 2003

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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.

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Animal Models of Vasculitis

Cited by 31 publications

References 41 publications

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

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

Phosphodiesterase Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

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