Advances in cyclosporine therapy: transplantation: thoracic transplantationUse of cyclosporine in lung transplantation
Section snippets
Mechanism of action
Cyclosporine was the first calcineurin inhibitor, and it was isolated from the fungus Tolypocladium inflatum gams. It is a lipophilic cyclic peptide of 11 amino acids that binds with a high affinity to a family of cytoplasmic proteins present in most cells (cyclophilins).6, 7 This drug-receptor complex specifically and competitively binds to calcineurin, a serine-threonine phosphatase found in T lymphocytes. This binding inhibits transcription of early cytokine genes for interleukin 2,
Pharmacokinetics
Following oral administration, CsA is only partially absorbed in the small intestine with moderate inter- and intra-individual variability. The average bioavailability is approximately 30%, and peak serum levels are reached 1.5 to 2.0 hours after administration. The average terminal half-life is approximately 8.4 hours (range, 5 to 18 hours). The drug is almost completely metabolized by hepatic enzymes in the cytochrome P450 family and excreted in the bile. Elimination is primarily biliary with
Oral CsA
CsA is available as soft gelatin capsules of various strengths (25 mg, 50 mg, 100 mg) and as an oral solution of 100 mg/mL in 50-mL bottles.
Intravenous csa
CsA for intravenous injection is available at a concentration of 50 mg/mL in 5-mL ampules.
Aerosolized csa
Although this form of CsA is not commercially available at present, the University of Pittsburgh pioneered the use of aerosolized CsA as a safe and effective therapy for refractory acute and chronic rejection in a small number of patients.10, 11 CsA (300 mg in 4.8 mL
Drug interactions
Drugs that interact with the cytochrome P450 enzyme system can alter the serum levels of CsA. The drugs that inhibit the cytochrome P450 enzymes increase the CsA blood levels, while the drugs that augment the action of the cytochrome P450 system decrease CsA levels. Although there are many drugs that can alter CsA serum levels, the drugs that are commonly prescribed for lung transplant recipients are listed in Table 1.
There are other drugs that can potentiate the nephrotoxicity of CsA without
Use in lung transplantation
The immunosupression regimen for adult lung transplant recipients at the Barnes-Jewish Hospital includes an induction and a maintenance regimen (Table 2).
Nephrotoxicity
This is the most common and clinically significant adverse reaction of CsA. The toxicity can be either acute or chronic. Acute CsA nephrotoxicity is usually reversible with stopping the medication or reducing the dose. In contrast, chronic CsA nephrotoxicity is typically irreversible and occasionally leads to end-stage renal disease (ESRD) requiring dialysis or renal transplantation. According to the International Registry for Heart and Lung Transplantation about 25% of the 1-year survivors and
Cyclosporine versus tacrolimus
Two prospective, randomized trials have compared cyclosporine and tacrolimus in lung transplantation. Keenan et al23 reported no significant difference in the incidence of acute rejection and survival rates at 2 years between the CsA- and tacrolimus-treated patients, but significantly fewer patients who received tacrolimus developed OB.23 The main drawback of this trial was that their endpoint was a histologic confirmation of OB, which is less sensitive than the physiologic definition of BOS.
Summary
CsA has revolutionized the field of solid organ transplantation since its discovery and remains a cornerstone of most immunosuppressive regimens. Survival following lung transplantation has dramatically improved since the introduction of CsA. However, acute rejection continues to be a significant problem after lung transplantation, and although it is generally a treatable condition, its significance lies in its contribution to the pathogenesis of BOS. Treatment of BOS, on the other hand,
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