CsA, Cyclosporine A

Only peptides that are composed of at least two consecutive N-alkylated amino acids are included Cs= cyclosporin CsA = cyclosporin A. b Rs coupling reagent N=N-protected amino acid B= base. e Mixing temp/coupling temp. l (i) = isolated (H) = determined by HPLC. e Estimated by HPLC. 

Fig. II Examples of MS-ffiendly photoreactive compounds used in mixed photoaffinity labeling. CsA cyclosporin A...

Fig. 4 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-Modulating agents. Abbreviations CSA cyclosporin A, VERAP verapamil STAURO staurosporine, ECON econazole, PRAZ prazosine, FTC fumitremor-gin C, PROB probenecide, BBR benzbromarone, SUPYR sulfinpyrazone, INDOM in-domethacin, GENIS genistein, PGA2 prostaglandin A2, CCCP chlorocarbonyl cyanide phenylhydrazine. (Reproduced from [4])...

CRI Cross-reactive idiotype CRPC -reactive protein CSA Cyclosporin A CSF Colony-stimulating fiictor... 

AZA = azathioprine CY = cyclophosphamide CsA = cyclosporine A ConA = concanavalin A LPS = lippopolysaccharide KLH = keyhole limpet hemocyanin PWM = pokeweed mitogen MLR = mixed-lymphocyte reaction PHA = phytohaemagglutinin. 

Figure 9.1-3 Key in utero immune maturation events and toxicant disruption. Seven in utero critical immune maturation events in the rodent are shown with developmental immunotoxicants known to disrupt those processes. In some cases, the processes are blocked by the xenobiotics while in others the integrity of the process may be compromised by early-life exposure. Arrows are not designed to indicate precise in utero timing but rather general periods of prenatal development. CsA = cyclosporin A CY = cyclophosphamide DEX = dexamethasone EPS = lipopolysaccharide. Adapted from Dietert and Piepenbrink (2006a).

Conformational restriction played an important role in the discovery that water induces the bioactive conformation of CsA. Cyclosporin A (Sandimmune , CsA, (23.37), Fig. 23.7), is a major drug for preventing rejection of transplanted human organs and has been the subject of many synthetic, conformational and mechanism of action studies. To produce immunosuppression, CsA first binds to cyclophilin A (CyP A), a peptidyl prolyl cis-trans isomerase (PPIase), to form the CsA-CyP complex, which then binds to and inhibits calcineuiin (CaN), a calmodulin-dependent serine/threonine protein phosphatase, thereby inhibiting interleukin-2 (IL-2) synthesis. ... 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

ACE-I, angiotensin-converting enzyme inhibitors ARB, angiotensin-receptor blockers AZA, azathioprine CMV, cytomegalovirus CPK, creatinine phos-phokinase CSA, cyclosporine HMG-CoA, 3-hydroxy 3-methylglutaryl coenzyme A reductase K+, potassium LFTs, liver function tests Rl, renal insufficiency SCr, serum creatinine SRL, sirolimus TAC, tacrolimus TMP-SMX, trimethoprim-sulfamethoxazole. 

CNS CS diet CsA CyP central nervous system Crotalaria spectabilis seed-supplemented diet cyclosporin A cyclophilin... 

This example illustrates that the reactivity of peptide bonds involving serine residues is not due solely to the presence of serine other, as yet poorly understood factors must also play a role. Threonine residues also show this particular type of reactivity [9]. Here, we examine the case of cyclosporin A (CsA), a cyclic undecapeptide that contains some unusual amino acids (6.57, Fig. 6.23), whose major breakdown reaction is hydrolytic cleavage at a threonine analogue. Position 1 is occupied by 4-[( )-but-2-enyl]-A,4-dimethyl-threonine, whose OH group reacts as a nucleophile at the carbonyl C-atom of the adjacent A-methylvalinc (position 11) [86],... 

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.)...

Figure 6 (A) Chronology (July 1999-May 2000) of CSA trough concentrations in patient 1 self-medicating with SJW dotted lines = desired CSA therapeutic range). (B) Chronology (July 1998-July 1999) of CSA trough concentrations in patient 2 self-medicating with SJW (dotted lines = desired CSA therapeutic range). Abbreviations SJW, St. John s wort CSA, cyclosporine. Source From Ref. 107.

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