Dataset Information

Effects of oral administration of 5 immunosuppressive agents on activated T-cell cytokine expression in healthy dogs.

ABSTRACT: BACKGROUND:Dogs are often adminstered >1 immunosuppressive medication when treating immune-mediated diseases, and determining whether these different medications affect IL-2 expression would be useful when performing pharmacodynamic monitoring during cyclosporine therapy. HYPOTHESIS/OBJECTIVES:To determine the effects of 5 medications (prednisone, cyclosporine, azathioprine, mycophenolate mofetil, and leflunomide) on activated T-cell expression of the cytokines IL-2 and interferon-gamma (IFN-?). ANIMALS:Eight healthy dogs. METHODS:Randomized, cross-over study comparing values before and after treatment, and comparing values after treatment among drugs. Dogs were administered each drug at standard oral doses for 1?week, with a washout of at least 21?days. Activated T-cell expression of IL-2 and IFN-? mRNA was measured by quantitative reverse transcription polymerase chain reaction. Blood drug concentrations were measured for cyclosporine, mycophenolate, and leflunomide metabolites. RESULTS:Least squares means (with 95% confidence interval) before treatment for IL-2 (2.91 [2.32-3.50] ?Ct) and IFN-? (2.33 [1.66-3.00 ?Ct]) values were significantly lower (both P?

SUBMITTER: Archer TM

PROVIDER: S-EPMC7255661 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Effects of oral administration of 5 immunosuppressive agents on activated T-cell cytokine expression in healthy dogs.

Archer Todd M TM Mulligan Charlee C Narayanan Lakshmi L Riggs Caitlin C Fellman Claire C Thomason John M JM Wills Robert W RW Boothe Dawn M DM Cruz-Espindola Crisanta C Harmon Roy R Mackin Andrew J AJ

Journal of veterinary internal medicine 20200213 3

<h4>Background</h4>Dogs are often adminstered >1 immunosuppressive medication when treating immune-mediated diseases, and determining whether these different medications affect IL-2 expression would be useful when performing pharmacodynamic monitoring during cyclosporine therapy.<h4>Hypothesis/objectives</h4>To determine the effects of 5 medications (prednisone, cyclosporine, azathioprine, mycophenolate mofetil, and leflunomide) on activated T-cell expression of the cytokines IL-2 and interferon ...[more]

PMID: 32052895

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Project description:BackgroundIn dogs, the effects of immunosuppressive medications on hemostasis are not well known.Hypothesis/objectivesThe objective was to determine the effects of immunosuppressive medications on primary and secondary hemostasis. Our hypothesis was that cyclosporine and prednisone would increase markers of hypercoagulability and thromboxane synthesis, while azathioprine, mycophenolate mofetil, and leflunomide would have minimal effects on hemostasis.AnimalsEight healthy dogs.MethodsA randomized, cross-over study used aggregometry, the PFA-100 platelet function analyzer, viscoelastometry, platelet count, and prothrombin and activated partial thromboplastin times to evaluate hemostasis during the administration of prednisone, azathioprine, cyclosporine, mycophenolate mofetil, and leflunomide for 1 week each at standard oral doses. Urine 11-dehydro-thromboxane-B2 (11-dTXB2 ) and 6-keto-prostaglandin-F1? (6-keto-PGF1? ) concentrations, normalized to urine creatinine concentration, were measured.ResultsThe aggregometry amplitude decreased from 51?±?21 to 27?±?14 (P?=?.002) during leflunomide treatment (ADP activation), but there were no differences in amplitude (P?=?.240) for any medications when platelets were activated with collagen. For all medications, there were no significant differences in viscoelastometry indices (ACT, P?=?.666; ClotRate, P?=?.340; and platelet function, P?=?.411) and platelet count (P?=?.552). Compared with pretreatment values, urinary 11-dTXB2 -to-creatinine ratio increased (P?=?.001) after drug administration (from 3.7?±?0.6 to 5.6?±?1.1). Cyclosporine was associated with an increase (P?<?.001) in the 6-keto-PGF1? -to-creatinine ratio (from 10.3?±?4.6 to 22.1?±?5.3).Conclusions and clinical importanceMost immunosuppressive drugs do not enhance platelet function or coagulation in healthy dogs, suggesting that these medications might not predispose hypercoagulable dogs to thromboembolism. The results of our study need to be correlated with the clinical outcomes of hypercoagulable dogs.

Project description:Torasemide is a loop diuretic licensed in dogs for cardiogenic pulmonary oedema. The aim of this pharmacokinetic-pharmacodynamic (PK/PD) study was to define an optimally effective dosage regimen based on preclinical data. In a first study, 5 dogs received once-daily oral torasemide (0, 0.1, 0.2, 0.4, 0.8 mg/kg/day) for 14 days. A second study compared once-daily oral torasemide (0, 0.1, 0.2, 0.3, 0.4 mg/kg/day) to twice-daily furosemide (1, 2, 4, 8 mg/kg/day). For all doses of the second study, 11 dogs received a first day of treatment, followed by a 3 day washout and resumed daily treatment for 10 days (until Day 14). Blood and urine were collected to measure urinary torasemide excretion and plasma torasemide concentrations and daily diuresis and natriuresis. Torasemide PK was linear. After rapid absorption (Tmax 0.5-1 h), 61% of the bioavailable torasemide was eliminated unchanged in urine. Diuresis and natriuresis observed with torasemide were similar to the ones obtained after furosemide (daily dose-ratios: 1/20 to 1/10). The average diuresis increased from baseline (220 ± 53 mL/day for 10 kg dogs) to 730 ±120 mL after the first torasemide administration and up to 1150 ± 252 mL after 10 administrations at the highest dose. At higher doses (?0.3 mg/kg/day), daily diureses after 10 diuretic treatment-days were higher than Day 1 and variable between dogs; in contrast, diureses remained constant over time and less variable for doses up to 0.2 mg/kg/day. Natriuresis peaked after the first day and decreased dramatically after the 2nd treatment-day then stabilized to a value close to baseline, except for 0.4 mg/kg/day. Urinary torasemide excretion predicted pharmacodynamics better than plasma concentrations. The decrease in natriuresis observed was successfully modeled using a resistance mechanism; this is likely due to a reabsorption of sodium which did not seem however to affect the volume of urine excreted. For a daily target diuresis of 460 mL/dog/day in severe pulmonary oedema (net fluid loss 240 mL/dog/day), a computed dose of 0.26 mg/kg/day (3.5 mg/kg/day furosemide-equivalent) was selected for clinical studies. Due to high inter-individual variability in diureses at doses ?0.3 mg/kg, higher doses should be limited to 3-5 days to avoid supra-clinical effects in high responders.

Project description:The administration of an oral probiotic has been demonstrated to impact oral microbial diversity in humans but has not been examined in canines. The objective of this study was to test the hypothesis that oral probiotic administration would impact the oral microbiota of canines compared to control. Working canines in training (n = 13) were assigned to Test or Control groups and acclimated to one of three commercially available study diets utilizing common protein sources (Purina Pro Plan Savor lamb, Purina Pro Plan Sport chicken, Purina Pro Plan Focus salmon) for a minimum of 30 days prior to initiation of the study. Following acclimation, dogs in the Test group began a daily regimen of oral probiotic (Fortiflora® Purina, St. Louis, MO) top-dressed on their midday feeding. Control dogs received their midday feeding with no probiotic. All dogs were sampled once weekly via oral pediatric swabs across the 7-week study. Next generation sequencing (Illumina, MiSeq) was utilized to develop microbial profiles specific to treatment, diet, and time. Bacterial composition was dominated by eight phyla (Proteobacteria 43.8%, Bacteroidetes 22.5%, Firmicutes 18.9%, Actinobacteria 6.1%, Fusobacteria 3.6%, Gracilibacteria 2.1%, SR1 Absconditabacteria 1.5%, and Saccharibacteria 1.3%) representing more than 99% of the relative abundance of the microbial composition. Probiotic administration failed to impact relative abundance at any taxonomic level (P > 0.05). Similarly, no effect on the oral microbiota was measured for diet (P > 0.05). Comparison using a Jaccard Index demonstrate a consistent microbial profile over the 7-week study with no impact evidenced by study week (P = 0.19). The data also revealed a profile of ubiquitous taxa that were present across all dogs and all samples regardless of breed, sex, diet, treatment or other factors. These genera include Actinomyces, Corynebacterium, Capnocytophaga, Flavobacterium, Gemella, Abiotrophia, Streptococcus, and Frederiksenia. These data demonstrate the stability of canine oral microbiota over time.

Dataset Information

Effects of oral administration of 5 immunosuppressive agents on activated T-cell cytokine expression in healthy dogs.

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Effects of oral administration of 5 immunosuppressive agents on activated T-cell cytokine expression in healthy dogs.

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