Immunosuppressants cyclosporine

Koal et al. (2004) measured four immunosuppressants (cyclosporine A, tacrolimus, sirolimus, and everolimus) in whole blood samples from transplant recipients. The samples were treated first with a protein precipitation step. The supernatant was extracted with a Poros Rl/20 perfusion column (30 x 2.1 mm, 20 tm, Applied Biosystems, Darmstadt, Germany) online. A Luna phenyl hexyl column (2 x 50 mm, Phenomenex, Schaffenburg, Germany) was used for separation. The total run time was 2.5 min. The lower limit of quantitation was 10 ng/mL for cyclosporine A and 1 ng/mL for the other three analytes. 

Immunosuppressants Cyclosporine (i) Tacrolimus Dexamethasone Rapamycin Valspodar (PSC833) (i)... 

An immunoassay using immobilized antibodies was described by Phillips and Chmielinska (14). By means of this approach the determination of the immunosuppressant cyclosporin A (CsA) in tear fluid was obtained using UV detection. Although the detection limit is sufficient using only immu-noaffinity capillary electrophoresis, overlapping signals can be avoided. A set of tear samples was quantified. Immunoaffinity CE was able to detect... 

Fig. 11 Separation of human cyclophilin 18 (1) and the corresponding complex with the immunosuppressant cyclosporin A (2) by CE. A fixed concentration of cyclophilin (6.1 /xM) and increasing concentrations of cyclosporin (0 /xM, A, 2 /xM, B, 4 /xM, C, 7 /xM CsA, D) dissolved in DMSO (3) were incubated prior to the CE separation. (Reprinted with permission from Ref. 42. Copyright 1999 of Elsevier Science.)...

Two molecular mechanisms for the interactions have been established. First, both hypericin and hy-perforin, two of the pharmacologically active constituents of the herb, cause induction of the enzyme CYP3A4 which is responsible for much of the metabolism of many commonly used drugs. Giving SJW to patients also taking the immunosuppressant, cyclosporine, which is metabolized primarily by CYP3A4, has led to near-rejection of transplanted organs as cyclosporine plasma concentrations fell due to increased metabolism. The same mechanism has led to reduced efficacy of indinavir in patients... 

Also the immunosuppressives cyclosporine, aza-thioprine and methotrexate have been shown to be effective treatment modalities in active Crohn s disease. 

Meyer, K., Fobker, M., Christians, U., Erren, M., Sewing, K. F., Assmann, G., and Benninghoven, A. (1996). Characterization of glucuronidated phase II metabolites of the immunosuppressant cyclosporine in urine of transplant patients using time-of-flight secondary-ion mass spectrometry. Drug Metab. Dispos. 24 1151-1154. 

Clinical Use. Mycophenolate mofetil (CellCept) is primarily used to prevent or treat organ rejection following cardiac and renal transplantation. This drug is typically combined with other immunosuppressants (cyclosporine, glucocorticoids) to provide optimal immunosuppression in patients receiving these transplant types.39,40,70 Mycophenolate mofetil may also be useful in suppressing the immune response associated with autoimmune conditions such as systemic lupus erythematosus.2... 

Mechanism of Action. Unlike other immunosuppressants (cyclosporine, tacrolimus), sirolimus does not interfere directly with cytokine production. Instead, sirolimus inhibits the function of a specific enzyme commonly known as the mammalian target of rapamycin (mTOR).37,42 This enzyme plays a key role in signaling pathways that promote the growth and proliferation of T and B cells.37,45 By inhibiting this enzyme, sirolimus causes cell division to stop at a specific stage (Gl), thereby limiting the ability of these cells to mount an attack on transplanted tissues.65... 

Some plant-derived drugs come from lower organisms, such as fungi (e.g., the antihyperlipidemic agent lovastatin from Aspergillus terreus and the immunosuppressant cyclosporin from Beauveria nivea) whereas others are obtained from higher plants (see Table 5.3 and Table 5.4). 

Lamos and colleagues reported the modification of cyclophilin A (CypA) by binding immunosuppressive cyclosporin A with a benzophenone-Dj j and a biotin moiety (compound 89, Fig. 11a) [91]. As a proof of principle, they used a 1 1 mixture of this TIP and its nondeuterated isoster for the selective PAL and pulldown of CypA among three other proteins. Subsequent tryptic digestion of the elutes and LC-MS/MS analysis allowed the identification of 11 CypA characteristic peptides, two of which were modified with the probe, as evidenced from the double, 11 Da separated, peaks in the mass spectra. The large 11-Da mass difference allowed easy visual recognition of labeled peptides in the mass spectra, which makes this a powerful method for determination of the modification site after PAL however, application in more complex systems still remains to be done. 

A 30-year-old male has had a heart transplant and is being maintained on the immunosuppressant, cyclosporine. He develops a Candida infection and is treated with ketoconazole. Why is this poor therapy ... 

Thaiss et al. (1989) evaluated the effect of the immunosuppressant cyclosporin A on an active model of in situ immune complex glomerulonephritis. Wistar rats were preimmunized with human IgG and 2weeks after the last antigen injection, the left kidney was perfused with cationized human IgG in order to induce unilateral in situ immune complex glomerulonephritis. 

Voclosporin (ISA-247, R1524) 88 (Isotechnika) is being evaluated in a Phase III trial for the treatment of psoriasis,250 as well as a Phase III trial by Lux Biosciences as for the treatment of uveitis (coded as LX211, Luveniq ).251,252 In addition, voclosporin 88 has completed a Phase lib trial for the prevention of kidney graft rejection. Voclosporin 88253,254 is a slightly more potent but less toxic semi-synthetic derivative of the fungal-derived immunosuppressant cyclosporin A 89, which has the same mechanism of calcineurin inhibition. Cyclosporin A 89 was first isolated from Tolypocladium inflatum by workers at Sandoz and its structure was published in 1976.255,256... 

Cyclophilin is a small protein that binds to the immunosuppressant cyclosporin A, a cyclic undecapeptide. 

Wuthrich, K., Von Freyberg, B., Weber, C., Wider, G., Traber, R., Widmer, H., and Braun, W. (1991). Receptor-induced conformation change of immunosuppressant cyclosporin A. Science 254,953 954. 

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