Arthritis In Lewis Rats Research Articles

Ｎ‐（２‐Ｍｅｒｃａｐｔｏ‐２‐ｍｅｔｈｙｌｐｒｏｐａｎｏｙｌ）‐Ｌ‐ｃｙｓｔｅｉｎｅ（ＳＡ９６）の薬理学的研究 （第４報） ＳＡ９６とその主代謝物（ＳＡ６７９）のヒトγ‐Ｇｌｏｂｕｌｉｎ熱変性およびラットＡｄｊｕｖａｎｔ関節炎に対する作用

SA96 and its main metabolite, SA679, were investigated for their effects on denaturation of human gamma-globulin and bovine serum albumin (BSA) and on adjuvant arthritis in Lewis rats. The heat denaturation of human gamma-globulin and BSA enhanced by Cu2+ was inhibited by SA96, SA679 and D-penicillamine, and the inhibitory effect of SA96 was the most potent. In adjuvant arthritis rats, SA96 given orally at a dose of 10 mg/kg from the same day as the adjuvant injection inhibited significantly the swelling of adjuvant treated foot and untreated foot, increase of the relative organ weights of the adrenals, liver and kidney, and increase of serum Cu concentration; but at a dose of 100 mg/kg, it did not show any effects on these parameters. On the other hand, SA96 given from three days before the adjuvant injection showed the inhibitory effects at a dose of 100 mg/kg as well as 10 mg/kg. These results suggest that the effect of SA96 on adjuvant arthritis in rats depends on its administration schedule. SA679 also inhibited the adjuvant arthritis at a dose of 100 mg/kg, but its effect was less potent than that of SA96.

Lymphoid abnormalities in rats with adjuvant-induced arthritis. I. Mitogen responsiveness and lymphokine synthesis.

Lewis rats injected in the hind paw with Mycobacterium butyricum develop a severe polyarthritis which shares certain features in common with rheumatoid arthritis in man. Spleen and peripheral blood mononuclear cells from rats with this form of arthritic disease proliferate poorly in vitro in response to concanavalin A (con A), phytohaemagglutinin (PHA), and pokeweed mitogen (PWM). The splenic hyporesponsiveness appears within four days of M. butyricum injection (three to five days prior to the development of detectable arthritis), reaches a peak 16-22 days following injection, and persists for at least 40 days. Buffalo strain rats injected with M. butyricum do not develop arthritis, and their spleen cells respond normally to con A, PHA, and PWM. In response to lipopolysaccharide (LPS) the synthesis of interleukin 1 (IL-1) by spleen or peritoneal macrophages from arthritic Lewis rats equalled or exceeded that of macrophages from normal rats. In contrast splenic T cells from arthritic rats produced reduced amounts of interleukin 2 (IL-2; T cell growth factor) in response to stimulation with PHA or con A. Moreover, con-A-activated spleen cells from arthritic rats failed to bind IL-2 and to respond to this growth factor with increased 3H-TdR uptake as did normal spleen cells. In-vitro treatment of 'arthritic' cells with 10(-5) M indomethacin did not restore to normal their reduced mitogen responsiveness, and spleen cells from normal and arthritic rats were equally sensitive to the inhibitory effects of prostaglandin E2 on con-A-induced proliferative responses. These results indicate that peripheral lymphoid function is compromised in rats with adjuvant-induced arthritis and that this functional deficit is mediated by aberrant synthesis of and response to IL-2 by T cells of arthritic animals.

Infection with Mycoplasma pulmonis modulates adjuvant- and collagen-induced arthritis in Lewis rats.

Infection with Mycoplasma pulmonis modulates adjuvant- and collagen-induced arthritis in Lewis rats.

Pharmacokinetics and metabolism of tolmetin in normal and adjuvant arthritic Lewis rats.

The pharmacokinetics and metabolism of tolmetin, a non-steroidal anti-inflammatory drug, were studied in healthy control and adjuvant arthritic (AA) female Lewis rats. Tolmetin was rapidly and completely absorbed by both groups of rats. Peak plasma concentrations of tolmetin and the area under the tolmetin plasma concentration — time curve (AUC) were significantly (p<.05) decreased in A A rats after a single oral dose of tolmetin sodium (50 mg/kg). Fourteen days of treatment at 50 mg/kg/day caused no significant change in these parameters. The plasma protein binding of tolmetin was decreased three to five fold in AA rats as compared with healthy controls. This was reflected in an increase in volume of distribution (Vd) for tolmetin and a marked increase in renal clearance (ClR) of tolmetin for AA rats. Plasma hepatic clearance (ClPH/f) was increased for AA rats, indicating no decrease in hepatic functon for AA rats. The dicarboxylic acid metabolite (MCPA) also had decreased peak concentrations and AUC in AA rats with an increase in oral plasma clearance (Clp/f) and ClR. However, excretion of MCPA conjugates in feces was reduced ten fold with a concomitant increase in urinary tolmetin due to the marked increase in tolmetin ClR for AA rats.