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.
Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate three different types of biological activity data with physicochemical properties of some clodronate ester analogues, which act as bone-resorption regulators in cell cultures and rats. The QSAR studies show the importance of the steric properties of these new bisphosphonate derivatives for the inhibition of bone resorption in bone cell cultures and for their bioavailability in rats. This information will be used in predicting the structure of new more potent bisphosphonic compounds.
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.
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