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1.  Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis I: Mechanistic Disease Progression Model for the Time Course of Collagen-Induced Arthritis in Lewis Rats 
A mechanism-based model was developed to describe the time course of arthritis progression in the rat. Arthritis was induced in male Lewis rats with type II porcine collagen into the base of the tail. Disease progression was monitored by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST) concentrations, and TNF-α, IL-1β, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Bone mineral density was determined by PIXImus II dual energy x-ray densitometry. Plasma CST was assayed by HPLC. Cytokine and GR mRNA were determined by quantitative real-time polymerase chain reaction. Disease progression models were constructed from transduction and indirect response models and applied using S-ADAPT software. A delay in the onset of increased paw TNF-α and IL-6 mRNA concentrations was successfully characterized by simple transduction. This rise was closely followed by an up-regulation of GR mRNA and CST concentrations. Paw swelling and body weight responses peaked approximately 21 days post induction while bone mineral density changes were greatest at 23 days post induction. After peak response the time course in IL-1β, IL-6 mRNA, and paw edema slowly declined towards a disease steady-state. Model parameters indicate TNF-α and IL-1β mRNA most significantly induce paw edema while IL-6 mRNA exerted the most influence on BMD. The model for bone mineral density captures rates of turnover of cancellous and cortical bone and the fraction of each in the different regions analyzed. This small systems model integrates and quantitates multiple factors contributing to arthritis in rats.
doi:10.1124/jpet.108.137372
PMCID: PMC2574807  PMID: 18448865
2.  Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis 
A mechanism-based model for pharmacodynamic effects of dexamethasone (DEX) was incorporated into our model for arthritis disease progression in the rat to aid in identification of the primary factors responsible for edema and bone loss. Collagen-induced arthritis (CIA) was produced in male Lewis rats following injection of type II porcine collagen. DEX was given subcutaneously in single doses of 0.225 or 2.25 mg/kg or 7-day multiple doses of 0.045 or 0.225 mg/kg at 21 days post disease induction. Effects on disease progression were measured by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST), and TNF-α, IL-1β, IL-6, and GR mRNA expression in paw tissue. Lumbar and femur BMD was determined by PIXImus-II dual energy x-ray absorptiometry. Plasma CST was assayed by HPLC. Cytokine and GR mRNA were assayed by quantitative real-time PCR. Indirect response models, drug-interaction models, transduction processes, and the 5th-generation model of corticosteroid dynamics were integrated and applied using S-ADAPT software to describe how dexamethasone binding to GR can regulate diverse processes. Cytokine mRNA, GR mRNA, plasma CST, and paw edema were suppressed following DEX administration. TNF-α mRNA expression and BMD appeared to increase immediately after dosing but were ultimately reduced. Model parameters indicated that IL-6 and IL-1β were most sensitive to inhibition by DEX. TNF-α appeared to primarily influence edema while IL-6 contributed the most to bone loss. Lower doses of corticosteroids may be sufficient to suppress the cytokines most relevant to bone erosion.
doi:10.1124/jpet.108.137414
PMCID: PMC2574741  PMID: 18448864

Results 1-2 (2)