Advances in cyclosporine therapy: transplantation: thoracic transplantation
Use of cyclosporine in lung transplantation

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Abstract

Prior to the cyclosporine (CsA) era, there were no long-term survivors from lung transplantation as the immunosuppressive drugs made patients very susceptible to opportunistic infections and anastomotic complications. CsA is a calcineurin inhibitor that binds to cyclophilins and inhibits transcription of interleukin 2 in T cells, thereby preventing proliferation of activated T cells. The initial immunosuppressive regimen at our institution includes CsA, azathioprine, and steroids. Blood levels of CsA (whole blood, TDx assay) are maintained between 250 and 350 ng/mL for 0 to 6 months, 200 to 300 ng/mL for 6 to 12 months, and around 200 ng/mL beyond 12 months following lung transplantation. Nephrotoxicity, hypertension, susceptibility to infections, and malignancy are some of the serious side effects of CsA that limit its therapeutic usefulness. Acute rejection is relatively common with this regimen, and about 60% of all lung transplant recipients are treated for an episode of acute rejection within the first 12 months after lung transplantation. Acute rejection is a probable risk factor for chronic rejection, and obliterative bronchiolitis develops in about 50% of the patients who survive 5 years. Treatment of chronic rejection continues to be a challenge in lung transplantation. CsA and tacrolimus seem to have equivalent results in lung transplantation, although a few patients may benefit from the use of tacrolimus.

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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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