Glucocorticoids have been widely used in the treatment of autoimmune and other diseases. Chronic steroid use, however, could cause proximal muscle weakness and atrophy, termed steroid myopathy. The onset of steroid myopathy is usually insidious and there are no specific laboratory findings except for elevated urinary creatine excretion. Muscle biopsy reveals non-specific type II fiber atrophy. There are many reports showing preventive effects of either growth hormone (GH) or insulin-like growth factor (IGF)-I on steroid myopathy. The pathogenesis of steroid myopathy is not fully understood. Recently, glutamine synthetase has been reported to play a key role in steroid myopathy. GH as well as IGF-I decreased the steroid-induced glutamine synthetase activity in skeletal muscle.

We examined the effects of simultaneous administration of recombinant insulinlike growth factor-I (IGF-I) and glucocorticoid on the diameter of muscle fibers in rats. The steroid group received subcutaneous injection of triamcinolone, the IGF-treated group received IGF-I alone, and the steroid plus IGF group received both triamcinolone and IGF-I. After 14 days, each rat was subjected to muscle biopsy of the extensor digitorum longus and soleus. Glucocorticoid treatment caused significant reduction in diameter of muscle fibers, compared to controls. Simultaneous administration of IGF-I significantly attenuated glucocorticoid-induced muscle atrophy. Glucocorticoid increased both urinary concentration of 3-methylhistidine and urinary creatine/creatinine ratio. IGF-I reduced those changes in the urine. We conclude that IGF-I administration prevents, at least partially, the development of steroid myopathy. A well-known side effect of prolonged glucocorticoid treatment is the muscle atrophy and weakness known as steroid myopathy.2 We previously demonstrated the preventive effect of recombinant human growth hormone (GH) on experimental steroid myopathy in rats. 23 Numerous other reports have indicated the anabolic effects of GH on skeletal muscle. 7,13,16,21,34,36 Because muscle cells possess their own receptors for GH, 1 GH possibly exerts a direct anabolic action on skeletal muscle. 13,16,26,34

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Several new phospholipid-ara-C conjugates have been prepared and tested as prodrugs of the parent ara-C. The new derivative include ara-CMP-L-dipalmitin, ara-CDP-L-distearin, ara-CDP-L dimyristin, ara-CDP-L-diolein, and the radioactively labeled derivative ara-CDP-L-di[1-14C]palmitin. In addition, the unusually stable ara-CMP-L-dipalmitin-N-phosphoryldicyclohexylurea adduct was isolated as a crystalline solid (two diastereomers) in the reaction sequence to prepare ara-CMP-L-dipalmitin. The new prodrugs were solubilized by sonication methods and tested for their antiproliferative activity in vitro against mouse myeloma MPC-11 cells and against L1210 lymphoid leukemia. Such studies demonstrated that the antiproliferative activities of the prodrugs (as determined by ED50) were less that ara-C on a molar basis. In the mouse myeloma cell line some evidence was obtained that the antiproliferative activity was related to the chain length of the fatty acid side chains in the prodrugs. In in vivo studies against L1210 lymphoid leukemia in mice, the prodrugs were shown to be much more effective than ara-C, with the overall efficacy apparently being independent of the length of the fatty acid side chain. Some evidence was obtained in the vivo studies that the ara-CDP-L-dimyristin, which bears the shortest fatty acid side chain, was more toxic at the higher dosages than the longer chain length derivatives.