Chronic Effects of the Novel Glucocorticosteroid RPR 106541 Administered to Beagle Dogs by Inhalation

Miller, G. K.; Valerio, Marion G.; Pino, Michael V.; Larson, Jeffrey; Viau, André; Hamelin, N; Labbé, Raymond; Banks, Christopher M.

doi:10.1177/019262330002800202

Cited by 13 publications

(13 citation statements)

References 38 publications

(51 reference statements)

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“…Urine cortisol was assayed by radioimmunoassay c validated for use in canine urine 21,22 and urine creatinine was measured in a routine manner in the same laboratory. UCC ratio was calculated from the 2 results (reference range, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Additionally, ACTH stimulation was performed at the dogs' homes before 10:00 AM.…”

Section: Endocrine Assessmentmentioning

confidence: 99%

“…[17][18][19] There is little published information regarding the effects of clinically relevant inhalant GC administration to dogs, 13 and we are aware of only a single prospective study examining the effects of any inhalant GC in this species. 20 The purpose of the study reported here was to compare systemic clinical, endocrine, and immunologic effects of inhaled GC (220 mg fluticasone q12h delivered through a spacer device) with PO-administered GC (1 mg/kg prednisone q24h) and placebo. We hypothesized that in healthy dogs the inhalant GC would result in fewer observable clinical effects and less HPAA and immunologic suppression than the PO-administered GC.…”

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confidence: 99%

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Endocrine and Immunologic Effects of Inhaled Fluticasone Propionate in Healthy Dogs

Cohn

DeClue

Reinero

2008

Veterinary Internal Medicne

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Background: Inhaled glucocorticoids reduce airway inflammation while minimizing systemic effects in several species. Hypothesis: Inhaled fluticasone suppresses the hypothalamic-pituitary-adrenal axis (HPAA), modifies immune function, and induces clinical signs to a lesser extent than PO-administered prednisone in dogs.Animals: Seven healthy adult pet dogs. Methods: Dogs were randomized to 1 of 3 treatment groups in a crossover design: fluticasone propionate (220 mg actuation of a metered dose inhaler delivered via a spacer and mask, q12h), placebo (spacer and mask alone, q12h), or prednisone (1 mg/ kg PO q24h). Each treatment was administered for 3 weeks followed by a 4-week washout. Appetite, attitude, and water consumption were recorded during the last week of each treatment period. Urine cortisol : creatinine ratios, ACTH stimulation tests, white blood cell counts, lymphocyte phenotype, and serum IgM and IgA concentrations were recorded at each baseline and after the last day of each treatment. Clinical observations were expressed descriptively. Friedman's test was applied to all data comparisons. Pairwise comparisons were made with a mixed model analysis when data were normally distributed, whereas signed rank tests were used otherwise (significance P-value o.01).Results: Appetite and water consumption increased during prednisone treatment. Peak serum cortisol concentrations post-ACTH were significantly decreased in prednisone-and fluticasone-treated dogs compared with placebo (prednisone 4 fluticasone). Serum IgM concentrations were significantly decreased in dogs treated with prednisone.Conclusions and Clinical Importance: As used, fluticasone suppresses the HPAA to a lesser extent than prednisone and may avert systemic signs associated with PO-administered glucocorticoids in dogs.

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Section: Endocrine Assessmentmentioning

confidence: 99%

mentioning

confidence: 99%

Endocrine and Immunologic Effects of Inhaled Fluticasone Propionate in Healthy Dogs

Cohn

DeClue

Reinero

2008

Veterinary Internal Medicne

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“…The best predictor was a combination of studies in multiple species including the rodent, and for certain classes of drug, such as cytotoxic anticancer agents, the mouse alone was reported to best predict for human side effects (Newell et al, 2004). An excellent example of a drug-induced hepatic change in the beagle dog is the vacuolation induced by excessive glucocorticoid administration also referred to as steroid hepatopathy (Dillon et al, 1983;Rutgers et al, 1995;Miller et al, 2000). Figure 9 shows the effect of chronic administration of prednisone to the beagle dog on the liver weight following both a subacute (14 days) and a chronic dosing regime (52 weeks).…”

Section: Drug-induced Nonneoplastic Hepatic Changesmentioning

confidence: 99%

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Foster

2005

Toxicol Pathol

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This review focuses on the background hepatic pathology present in three of the most commonly used species in the safety assessment of drugs, namely the beagle dog, the marmoset and the cynomolgus macaque. Both the nonneoplastic and neoplastic pathology are reviewed with a discussion on the potential impact that significant background pathology might have on the interpretation of any drug-induced pathology during subsequent testing. Although specific instances, such as parasitological infection in wild-caught primates can pose problems of interpretation, in general the background pathology in both the dog and the nonhuman primates, is not significantly different from that seen in the liver of laboratory rodents and with experience should not pose significant problems for the experienced pathologist. The relative merits of the primate versus the dog as a choice of second species are also considered in some detail. Although there is an inbuilt prejudice that the primate will more closely mimic subsequent effects that might occur in man in the clinic, insofar as the liver is concerned, there are many instances where the dog has been more representative of human exposure and metabolism and there is little evidence to show that the nonhuman primate is consistently better than dog in predicting human liver toxicity. As with most areas of science, comparative toxicology would dictate that the more information gained, from as wide a range of species as is practical, will give the best assessment for any subsequent problems in the clinic. This pragmatic approach should prove to be more successful than one based entirely upon an assumption, and in many cases the assumption is incorrect, that the primate always predicts human toxicity better than the nonprimate, including the dog.

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“…48 Our understanding of the mechanisms involved in glucocorticoid-induced osteoporosis is far from complete. Similar effects also occur in laboratory animals treated with corticosteroids.…”

Section: Osteoporosismentioning

confidence: 99%

Musculoskeletal System

Greaves

2012

Histopathology of Preclinical Toxicity Studies

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Chronic Effects of the Novel Glucocorticosteroid RPR 106541 Administered to Beagle Dogs by Inhalation

Abstract: The preclinical safety of RPR 106541, a novel 17-thiosteroid, was

Cited by 13 publications

References 38 publications

Endocrine and Immunologic Effects of Inhaled Fluticasone Propionate in Healthy Dogs

Endocrine and Immunologic Effects of Inhaled Fluticasone Propionate in Healthy Dogs

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Musculoskeletal System

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