Cyclosporin Neoral

Structural Formula

Ball-and-Stick Model chj o i II ; i II s CH, >=0

= Carbon

Ball-and-Stick Model

= Hydrogen

= Oxygen

= Hydrogen

= Oxygen

= Nitrogen

Year of discovery of immunosuppressant activity: 1976 (Sandoz, later Novartis); Year it entered the market. 1983; Drug category: Immunosuppressant; Main uses: Prevention of organ transplant rejection, treatment of rheumatoid arthritis and psoriasis; Other brand names: Sandimmune, Gengraf, Restasis; Related drugs: Tacrolimus (Prograf).

Cyclosporin A has played an important role in the modern era of organ transplantation. It allowed for the first time selective suppression of T-cells without the bone marrow toxicity that is associated with azathioprine therapy (see page 122). Cyclosporin A extends kidney graft survival rates and greatly improves heart, liver, lung and even combined heart+lung transplantation. It also has been applied to the treatment of several autoimmune diseases, including severe rheumatoid arthritis and psoriasis.1

Cyclosporin A is a fungal metabolite that was first isolated in the early 1960s at Sandoz (later Novartis) in an effort to identify compounds with antibiotic activity. However, due to a narrow spectrum of antimicrobial activity, it was never developed as an antibiotic. The reemergence of cyclosporin A came as a result of a screening program to find other biological activities in the crude fungal extract containing it. The extract was found to inhibit lymphocyte proliferation without affecting other somatic cells. The active immunosuppressive ingredient was found to be cyclosporin A. The exact chemical structure of cyclosporin A was first reported in 1976. Animal tests of the drug were conducted by Roy Calne, who participated in the development of azathioprine. His experiments supported the earlier findings that the compound suppresses the immune response more potently than other drugs. The first human trials started in 1976 and the drug was approved for use in the US in 1983. Long-term use of cyclosporin A can lead to nephrotoxicity, susceptibility to infection, hypertension, and hyperlipemia.2

Cyclosporin A acts by forming a complex with a binding protein, cyclophilin, and this complex inhibits the enzyme calcineurin. The three-component complex of cyclosporin A, cyclophilin and calcineurin is depicted in the figure below.3 Calcineurin dephosphorylates the nuclear factor for activated T-lymphocytes (NFAT), and causes its translocation into the nucleus, where it activates the transcription of several cytokines, including interleukin-2 (IL-2), which stimulate the growth, differentiation, and survival of antigen activated T-cells. Inhibition of this process results in diminished T-cell response to antigen stimulation. Cyclosporin also increases the expression of the cytokine TGF-p, which is a potent inhibitor of T-cell proliferation and of cytotoxic T-lymphocyte formation.

Calcineurin

Cyclophilin

Calcineurin

Cyclophilin

Ternary complex of cyclosporin A, cyclophilin and calcineurin.

1. Transplant. Proc. 2004, 36, 13S-15S; 2. Transplant. Proc. 1999, 31. 14S-15S; 3. Proc. Natl. Acad. Sci. U. S. A 2002, 99, 13522-13526 (1MF8); Refs. p. 173

Ternary complex of cyclosporin A, cyclophilin and calcineurin.

1. Transplant. Proc. 2004, 36, 13S-15S; 2. Transplant. Proc. 1999, 31. 14S-15S; 3. Proc. Natl. Acad. Sci. U. S. A 2002, 99, 13522-13526 (1MF8); Refs. p. 173

PART IV. IMMUNOSUPPRESSIVE AGENTS

0 0

Post a comment