Cyclosporine: A new Immunosuppressive agent for organ transplantation

Annals of internal medicine (Impact Factor: 17.81). 12/1984; 101(5):667-82. DOI: 10.7326/0003-4819-101-5-667
Source: PubMed


Cyclosporine, a cyclic endecapeptide of fungal origin, has recently been released for use in clinical transplantation. Trials in kidney, heart, liver and bone marrow recipients were encouraging: 1-year graft survival rates were 70% to 80% for kidney and heart recipients, and 60% to 65% for liver allograft recipients. Cyclosporine is also effective in treating bone marrow recipients with acute graft-versus-host disease. The drug selectively inhibits T-helper cell production of growth factors essential for B cell and cytotoxic T-cell differentiation and proliferation, while allowing expansion of suppressor T-cell populations. Drug absorption varies greatly, necessitating monitoring of drug level and individualization of therapy. Nephrotoxicity is the most frequent side effect of cyclosporine. An increased incidence of B-cell lymphomas seen when cyclosporine was used in conjunction with cytotoxic agents or anti-lymphocyte globulin has very rarely been observed when concomitant immunosuppression has been limited to low-dose corticosteroids. Lower initial doses of cyclosporine, followed by more rapid tapering may reduce the incidence of nephrotoxicity without compromising improved graft outcome.

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    • "[21] This amino acid residue is present in cyclosporine, a cyclic non-ribosomal peptide, which is widely used as immuno- suppressant. [22] The methods for quantitative analysis of cyclosporine metabolites have been reported; [23] however, the relatively inexpensive analytical standards obtained by selective and efficient HDX at α-C in sarcosine residue could be also applied for this purpose. "
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    ABSTRACT: Hydrogens connected to α-carbon (α-C) of amino acid residues are usually resistant to hydrogen-deuterium exchange (HDX) unless reaction conditions promote racemization. Although N-methylglycine (sarcosine) residue has been found in biologically active peptide such as cyclosporine, to the best of our knowledge, the HDX of α-C protons of this residue was not explored yet. Here, we presented a new and efficient methodology of α-C deuteration in sarcosine residues under basic aqueous conditions. The deuterons, introduced at α-C atom, do not undergo back-exchange in acidic aqueous solution. The electrospray ionization-MS and MS/MS experiments on proposed model peptides confirmed the HDX at α-C and revealed the unexpected hydrogen scrambling in sarcosine-containing peptides. Although the observed HDX of α-C protons is only successful in N-acylglycine when the amide possesses a certain degree of alkylation, it offers a new approach to the analysis of sarcosine-containing peptides such as cyclosporine. Copyright © 2014 John Wiley & Sons, Ltd.
    Full-text · Article · Jan 2014 · Journal of Mass Spectrometry
    • "Ciclosporin A (CsA) is used to treat and prevent rejection and graft-versus-host disease (GVHD) after solid organ transplantation (SOT) as well as hematopoietic stem cell transplantation (HSCT).[12] Voriconazole is frequently used in HSCT or SOT recipients for prevention or treatment of invasive fungal infections (IFIs). "
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    ABSTRACT: We report that one 18-year-old female patient with no epilepsia history developed severe epileptiform seizures while she was receiving "ciclosporin A (CsA)-mycophenolate-methylprednisolone" antirejection therapy after combining one week's voriconazole administration following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndromes (MDS). Her blood concentration of CsA was 378 ng/ml (elevated ↑64%, contrasted with the level before the addition of voriconazole) on the second day of admission, and the MRI of head showed leukoencephalopathy in bilateral occipital and left frontal lobe on the 4(th) day of admission. The most likely mechanism is that because of voriconazole's enzyme inhibition and CsA as the substrate of hepatic enzymes, voriconazole elevated the blood concentration of CsA and enhanced its toxicity. This case highlights the importance of clinical pharmacists joining the medical team and optimizing the patients' treatment protocols by performing a systematic literature research, accumulating the knowledge of the potential drug interaction and examining prescriptions.
    No preview · Article · Oct 2013 · Journal of Pharmacology and Pharmacotherapeutics
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    • "Cyclosporine A (CyA) is a lipophilic, cyclic oligopeptide, in wide use as a first line immunosuppressive drug for prevention of allograft rejection in various organ transplantations [1] [2], as well as for the treatment of systemic and local autoimmune disorders [3] [4] [5]. CyA is a critical dose drug with a narrow therapeutic window [6]; however, its bioavailability after oral dosing is very low and highly variable [7]. "
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    ABSTRACT: The present study was aimed at preparation and performance evaluation of pH-sensitive cyclosporine A (CyA) nanoparticles (CyA-NPs) to improve the poor bioavailability of lipophilic CyA. CyA-NPs were prepared with two types of Eudragit® copolymers (Eudragit ® S100 and Eudragit® L100) by a quasi-emulsion solvent diffusion technique. Freeze-dried formulations (Lac-CyA-S100-NP and Lac-CyA-L100-NP) were also prepared. The physical properties, particle size, encapsulation efficiency, and in vitro drug release characteristics were studied. The in vivo bioavailability of CyA-NP and Lac-CyA-S100-NP was investigated in rats at a dose of 15 mg/kg and compared with that of the commercial formulation, Sandimmune Neoral®. The mean particle size of the CyA-NPs was less than 50 nm, and the encapsulation efficiency was over 99%. Characteristics of the freeze-dried nanoparticles were found to remain relatively stable when lactose was used as a cryoprotectant. In vitro release studies revealed that the CyA-NPs exhibited significant pH-sensitivity. The relative bioavailabilities of CyA-L100-NP, CyA-S100-NP, and Lac-CyA-S100-NP were 117.3%, 162.1%, and 130.1%, respectively, when compared with that of Neoral®. Therefore, CyA-NPs were considered to be promising oral delivery systems for enhancement of the absorption of the poorly soluble drug, CyA. Freeze-dried nanoparticles could be developed into a novel and effective CyA formulations.
    Full-text · Article · Oct 2009 · Current Nanoscience
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