cyclosporin-g and Body-Weight

Administration of cyclosporine A to male and female rats accelerates bone remodeling and causes bone loss, among other side-effects. The newer immunosuppressant drugs, FK506 and CsG, have been synthesized to counteract the toxic effects of CsA, yet maintain clinical efficacy. We investigated the in vivo effects of long-term administration of these drugs on bone mineral metabolism in the rat. Five groups of Sprague-Dawley rats, 15 per group, were allocated to receive by daily gavage for a period of 28 days: (1) Cs-vehicle; (2) CsA 15 mg/kg b.w.; (3) CsG 15 mg/kg b.w.; (4) FK506 vehicle; (5) FK506 5 mg/kg b.w. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium (Ca2+), parathyroid hormone (PTH), 1,25-(OH)2-vitamin D, and bone gla protein (BGP). Tibiae were removed on day 28 after double calcein labeling for histomorphometric analysis. Immunosuppressant groups were compared with the respective vehicle groups. Neither CsA or CsG affected the levels of Ca2+ or PTH, whereas by day 28 FK506 caused a decrease in Ca2+ and a corresponding rise in PTH (P < 0.05). The 1,25-(OH)2-vitamin D and BGP levels in both the CsA and CsG groups were increased on days 14 and 28 (P < 0.05), while FK506 had no effect on these serum levels. Tibial bone histomorphometry revealed that all 3 immunosuppressants increased measures of bone formation and bone resorption, accompanied by a significant reduction in percent trabecular area, most marked with FK506. This report demonstrates that all three immunosuppressants have adverse effects on bone--most deleterious with FK506.

Topics: Animals; Body Weight; Bone Resorption; Calcification, Physiologic; Calcitriol; Cyclosporine; Cyclosporins; Female; Immunosuppressive Agents; Male; Osteocalcin; Osteogenesis; Rats; Rats, Sprague-Dawley; Tacrolimus; Tibia; Time Factors

We have previously shown that CsA administration to rats causes a high turnover bone loss with bone resorption exceeding bone formation. Similar findings have been reported in renal and cardiac transplantation patients administered CsA. Cyclosporine-G (CsG), a natural equipotent immunosuppressive analogue of CsA, has been shown to be less nephrotoxic than CsA. We therefore compared the effects of CsG and CsA on bone mineral metabolism. Sixty male Sprague-Dawley rats were divided into 3 equal groups as follows: group A (n = 20) was the control; group B (n = 20) received CsA 15 mg/kg by daily gavage; and group C received CsG 15 mg/kg by daily gavage for 28 days. Rats were bled weekly for measurement of circulating biochemical parameters of bone mineral metabolism and after sacrifice on day 28, the tibiae were removed for histomorphometric analysis. The tibial bone histomorphometry revealed that the percentage of bone volume was significantly reduced, and the osteoclast count increased in both the CsA and CsG group, but significantly less so in the CsG than the CsA group. Parameters reflecting bone formation in the CsG group were similar to controls but significantly different from the CsA group. Bone Gla protein levels in the CsA group were significantly increased compared with the control and CsG groups from day 14. Serum 1,25 dihydroxyvitamin D was increased significantly in the CsA group on days 14 and 28 compared with both control and CsG groups, and was significantly elevated in the CsG group compared with controls on the same days. We conclude that CsG is significantly less deleterious to bone mineral metabolism than CsA in the rat in vivo.

Topics: Animals; Body Weight; Bone and Bones; Bone Density; Calcitriol; Calcium; Cyclosporine; Cyclosporins; Immunosuppressive Agents; Male; Minerals; Osteocalcin; Parathyroid Hormone; Rats; Rats, Inbred Strains; Tibia

Adult, male Sprague-Dawley rats were given 50 mg/kg cyclosporine (CsA), cyclosporine G (nor-valine2-cyclosporine [CsG], or drug vehicle by orogastric intubation every 24 hr for 14 days. Both drugs profoundly suppressed humoral immune responses. Similar trough whole-blood cyclosporine levels were recorded in each group at days 7 and 14. In CsA-treated animals, significant lymphopenia was evident on day 14, together with monocytosis and neutrophilia. Only the monocytosis was seen in the CsG group. CsA and CsG both caused significant impairment of renal function by day 7, although at this time the effect was less marked with CsG. In both drug-treated groups, there was evidence of further deterioration in glomerular filtration rate (GFR) by day 14. A significant rise in enzymuria was also recorded in each group. Typical cyclosporine-induced proximal straight tubular cell vacuolation was evident in four of the eight rats given CsG and in three of seven CsA-treated animals. Liver function was also significantly impaired in both CsA and CsG groups. These data show that, at the selected dose, CsG shares the nephrotoxic and hepatotoxic properties of CsA. The extent to which these effects of CsG are dose-related and the true clinical potential of this cyclosporine analogue have yet to be evaluated.

Topics: Animals; Antibody Formation; Body Weight; Cyclosporine; Cyclosporins; Hematopoietic System; Kidney; Liver; Male; Rats; Rats, Inbred Strains