Immunosuppressive agents cyclosporine

The ability of lipid vehicles (either in the pharmaceutical formulation or in food) to enhance the absorption of lipophilic drugs has been well known for many years. Recently, successful bioavailability enhancement utilizing lipid-based formulations has been accomplished with the immunosuppressive agent cyclosporine A (Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ), and for the two HIV protease inhibitors ritonavir (Norvir, Abbott Laboratories, IL) and saquinavir (Fortovase, Roche Pharmaceuticals, Nutley, NJ). Consequently, considerable interest in lipid-based formulations has been aroused. 

Cyclosporine is a macrolide antibiotic and has been used as an immunosuppressive agent. Cyclosporine can cause both renal and nonrenal toxicity. Clinically renal toxicity consists of four discrete syndromes which include acute reversible renal functional impairment, delayed renal allograft function, acute vasculopathy, and chronic nephropathy with interstitial fibrosis. Proximal tubular epithelium is uniquely sensitive to the toxic effect. The toxic effect is characterized by isometric cytoplasmic vacuolations (several small equally sized vacuoles in cytoplasm), necrosis with or without subsequent mineralization, inclusion bodies (giant mitochondria), and giant lysosomes. Acute vasculopathy consists of vacuolization of the arteriolar smooth muscles and endothelial cells leading to necrosis. In some cases, thrombotic microangiopathy develops, characterized by thrombosis of the renal micro vasculature. Long-term treatment with cyclosporine results in chronic nephropathy with interstitial fibrosis (Chamey et al., 2004). 

The immunosuppressant agents, cyclosporin A (cys A) and FK506 both have the potential to induce acute renal failure and endothelin has been proposed as the mediator. Cys A and FK506 have both been shown to stimulate ET-1 release from cultured kidney cells [200]. An endothelin antibody prevented the reduction in function induced by cys A in a rat kidney perfusion model [201]. In the same model, BQ 123 also prevented the detrimental renal effects of cys A [202]. 

It has been shown that subjects with renal diseases such as IgA nephropathy, membranous prohferative glomerulonephritis, focal sclerosis, and lupus nephritis have levels of endothelin that are significantly higher than those in healthy subjects [209]. Increased circulating ET-1 concentrations and urinary excretion of ET-1 have been observed in patients treated with the nephrotoxic immunosuppressive agents cyclosporine A and tacrolimus (FK-506) [210]. Other nephrotoxic agents, such as cisplatin, also increase urinary excretion of ET [211]. In patients with chronic renal disease, urinary excretion of ET-1 is significantly elevated when compared to normal values (Table 10). 

Since then, both natural and unnatural cyclic peptides have become important synthetic targets because of their potential applications as antibiotics and other therapeutic agents [50-54]. Selected examples include anticancer agents (ADH-1), antibiotics (colistin), growth hormone inhibitors (octreotide), and immunosuppressant agents (cyclosporine A) (Fig. 6) [55]. 

Several immunosuppressive protocols pursue the same goal to prevent rejection of the transplanted allograft (reduction of the intensity of the immune response to a degree that allows acceptance of the allograft) without increasing the risk of subsequent infection. Since the clinical introduction of the more specific immunosuppressive agent cyclosporin... 

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