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 tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, 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 high-performance liquid chromatography. 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-␣ 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 after induction, whereas bone mineral density changes were greatest at 23 days after induction. After peak response, the time course in IL-1␤, IL-6 mRNA, and paw edema slowly declined toward a disease steady state. Model parameters indicate TNF-␣ and IL-1␤ mRNA most significantly induce paw edema, whereas 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.

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 was produced in male Lewis rats after 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 postdisease induction. Effects on disease progression were measured by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST), and tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-6, and glucocorticoid receptor (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 high-performance liquid chromatography. Cytokine and GR mRNA were assayed by quantitative real-time polymerase chain reaction. Indirect response models, drug interaction models, transduction processes, and the fifth-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 after DEX administration. TNF-␣ mRNA expression and BMD seemed to increase immediately after dosing but were ultimately reduced. Model parameters indicated that IL-6 and IL-1␤ were most sensitive to inhibition by DEX. TNF-␣ seemed to primarily influence edema, whereas IL-6 contributed the most to bone loss. Lower doses of corticosteroids may be sufficient to suppress the cytokines most relevant to bone erosion.

Dexamethasone (DEX) is often given for the treatment of rheumatoid arthritis and clinical dosing regimens of DEX have often been based empirically. This study tests whether the inflammation processes in a rat model of rheumatoid arthritis alters the clearance and volume of distribution of DEX when compared with healthy controls. Groups of healthy and arthritic male Lewis rats received either a low (0.225 mg/kg) or high (2.25 mg/kg) intramuscular dose of DEX. Arthritis was induced by intradermal injection of type II porcine collagen in incomplete Freund's adjuvant emulsion at the base of the tail. DEX was dosed in the arthritic animals 22 days post arthritis induction. Plasma DEX concentrations were determined by HPLC. Plasma concentration versus time data were analysed by non-compartmental analysis and pharmacokinetic model fitting using the population pharmacokinetic software NONMEM V. A linear bi-exponential pharmacokinetic model with extravascular input described the data for both healthy and arthritic animals. Clearance was the only parameter determined statistically different between both groups (healthy=1.05 l/h/kg, arthritic=1.19 l/h/kg). The steady-state volume of distribution for both groups was 4.85 l/kg. The slight difference in clearance was visibly undetectable and unlikely to produce meaningful changes in DEX disposition in arthritic rats.

The oxygen demand, membrane integrity, β-cell function and proliferation, and transcriptomes of islets from API, JPI, and NPI provide a comprehensive physiological comparison for future studies. These assessments will inform the optimal application of each age of porcine islet to expand the availability of islet transplantation.