The rat adjuvant arthritis model was used to study the effect of disodium clodronate on inflammation and destruction of tarsal bones and joints. Male Lewis rats were given an intradermal injection of mycobacteria. Fourteen days after immunization, rats with similar scores were assigned to the different experimental groups. They were treated subcutaneously either with saline (controls) or with clodronate at doses of 12.5 and 25 mg/kg/day five times a week for 2 weeks. Clinical signs of arthritis including the severity of paw swelling were assessed weekly. At the time of sacrifice, histological features of the non-decalcified tarsus with ankle, intertarsal and tarsometatarsal joints were assessed for inflammatory soft-tissue, articular and bone changes. The total histological score of the hindpaw indicated that 58% of the control rats developed moderate arthritis and 42%, severe arthritis. The treatment with clodronate (25 mg/kg) decreased clinical signs of arthritis and the activity of the collagen-degrading lysosomal enzyme, beta-N-acetylglucosaminidase, in inflamed hindpaw tissue. Histological evaluation indicated moderate arthritis in 83%, but no severe arthritis. The lower dose of clodronate also decreased the severity of the disease; the decrease was, however, statistically insignificant. The results show that clodronate given therapeutically to adjuvant arthritic rats suppresses the intensity of the inflammation and prevents secondary articular and bone lesions in the tibiotarsal region.

The collagen-induced arthritis model in rats was used to study the effect of disodium clodronate on inflammation and destruction of tarsal, metatarsal, and interphalangeal bones and joints. Female DA rats were immunized with heterologous type II collagen. Fourteen days after immunization, rats with similar scores were assigned to the different experimental groups. They were treated subcutaneously either with saline (controls) or with clodronate at doses of 12.5 and 25 mg/kg/day five times a week for 2 weeks. Clinical signs of arthritis including the severity of paw swelling were assessed weekly. At the time of killing, histological features of the non-decalcified tarsus with tarsal, tarsometatarsal and interphalangeal joints were assessed for inflammatory soft-tissue, articular, and bone changes. All the arthritic control rats developed severe arthritis as shown by the total histological scores of the hindpaw. The treatment with clodronate (25 mg/kg) decreased clinical signs of arthritis, the activity of the collagen-degrading lysosomal enzyme, beta-N-acetylglucosaminidase, in inflamed hindpaw tissue, serum osteocalcin level and serum cross-linked telopeptide of type I collagen level. Histological evaluation indicated moderate arthritis in 29% of the rats and severe arthritis in 71%. The results show that clodronate given therapeutically to arthritic rats, induced with type II collagen, suppresses the intensity of inflammation and bone lesions in the tibiotarsal and tarsometatarsal regions.

Clodronate and indomethacin have fairly similar efficacy in suppressing the intensity of joint swelling and preventing bone lesions in adjuvant arthritic rats.

The transfer of diazepam and N-demethyldiazepam across the placenta in early human pregnancy is studied in a group of 12 patients after a single dose, and in a group of 7 patients after the continued use of diazepam for up to a month. A,fter a single dose the feto-maternal ratio of the diazepam concentrations is 1.2, while after continued use it is 0.4. The main reason for this difference is probably the incomplete distribution of diazepam after a single dose at the time the samples are taken. The transfer of N-demethyldiazepam across the placenta occurs just as easily and the feto-maternal ratio after continued treatment is 0.4, too. The concentration of N-demethyldiazepam in the fetal liver is higher than any other concentration measured and this could constitute indirect evidence of metabolism in the fetal liver. The concentrations of diazepam and N-demethyldiazepam in fetal tissues are at a level comparable to the concentration of diazepam that has a damaging effect on cells in cellular cultures. fetal plasma and in fetal tissues after continued treatment of the mother with diazepam Maternal plasma Patient D ND Fotal plasma Fotal liver Fotal brain Placenta D

Daily oral clodronate treatment was evaluated in Sprague-Dawley rats for its ability to inhibit estrogen-deficiencyinduced changes in femoral neck, femoral diaphysis, and lumbar vertebrae (L4 -L5). Six-month-old ovariectomized (OVX) rats were administered by gavage a vehicle (Veh) or clodronate (100 or 500 mg/kg/day). Shamoperated (SHAM) control rats received the vehicle (n ‫؍‬ 15/group). Treatment was started on the day of operation and continued for 3 months. Trabecular bone volume (BV/TV) and structural variables (trabecular number, Tb.N; thickness, Tb.Th; separation, Tb.Sp; and trabecular bone pattern factor, Tb.Pf) were assessed on secondary spongiosa of the right femoral neck. Furthermore, cantilever bending test of the left femoral neck and compression test of L4, ash weight of L5, and morphometric studies of femoral diaphysis were carried out, and serum and urinary markers of bone turnover were determined. The OVX/Veh group had higher levels of serum osteocalcin and alkaline phosphatase and higher urinary excretion of deoxypyridinoline/creatinine than the SHAM/Veh group at 3 months postsurgery, and clodronate reduced these changes. BV/TV of femoral neck, bone mass of L5, and the maximum loads of the femoral neck and L4 were lower after OVX than SHAM operation. Although clodronate prevented trabecular bone loss in the femoral neck and preserved Tb.Pf at the SHAM control level, it failed to preserve the mechanical strength at the femoral neck. However, in lumbar vertebrae, clodronate prevented the loss of bone mass and mechanical properties. Furthermore, there was a good positive correlation between maximum load of L4 and the ash weight of L5 (n ‫؍‬ 58, r ‫؍‬ 0.69, p < 0.001). In the femoral neck (n ‫؍‬ 55), Tb.Pf correlated negatively with BV/TV and Tb.N (r ‫؍‬ ؊0.59 and r ‫؍‬ ؊0.55; p < 0.001, respectively) and positively with Tb.Sp (r ‫؍‬ 0.61, p < 0.001). In femoral mid-diaphysis, there were no significant changes in cortical bone geometry in any of the groups. We conclude that orally administered clodronate suppresses the enhanced bone turnover in adult OVX rats and preserves trabecular bone volume and connectivity in the femoral neck. In the axial skeleton, clodronate has a beneficial effect on lumbar vertebral bone mass and strength. (J Bone Miner Res 1998;13:287-296)