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Aerosol Cyclosporine Spray Improves Lung Function In Transplant Patients, Say Researchers

Date:
April 10, 2003
Source:
University Of Pittsburgh Medical Center
Summary:
An aerosol form of the anti-rejection drug cyclosporine allows for improved lung function in lung transplant patients, according to researchers with the University of Pittsburgh Medical Center.

VIENNA, April 10 – An aerosol form of the anti-rejection drug cyclosporine allows for improved lung function in lung transplant patients, according to researchers with the University of Pittsburgh Medical Center (UPMC) who presented their findings today at the 23rd Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation (ISHLT). Patients whose lungs were capable of depositing greater amounts of the drug had better lung function over the course of the two-year study than those who deposited less after inhalation or than patients who inhaled a spray with a placebo drug, the researchers reported.

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Their results, obtained in a study of 15 patients, are the first to emerge from a larger, multi-year clinical trial looking at the effectiveness of aerosol cyclosporine spray, which is inhaled directly into the lungs, for the prevention of rejection in lung transplant patients. It is the only study of its kind involving an anti-rejection drug designed to be delivered directly to the tissue of a transplanted organ. The concept was developed and the clinical trial initiated more than 10 years ago at the University of Pittsburgh by Aldo T. Iacono, M.D., and Bartley P. Griffith, M.D.

"We plan to examine several endpoints in our study, including whether aerosolized cyclosporine is an effective method to prevent rejection, causes fewer systemic side effects, and has a positive impact on organ function. There is reason to believe that this drug, when given in addition to systemic immunosuppression, may improve overall outcomes for lung transplant recipients who received the drug compared to patients given placebo, and final results are being analyzed," explained Dr. Iacono, principal investigator of the study.

"However, this most recent analysis – our first from the 68-patient study – indicates that aerosol cyclosporine specifically enhances lung function in patients who deposit higher concentrations of the drug," added Dr. Iacono, who is associate professor of medicine and surgery and director, pulmonary transplant medicine at UPMC.

The general hypothesis behind the University of Pittsburgh clinical trial is that an aerosolized form of the standard immunosuppressant agent cyclosporine will achieve higher concentrations in the transplanted lung than through intravenous or oral means, thus preventing rejection more effectively. In addition, inhaling the drug directly into the lungs may make it less likely that systemic infections or complications such as kidney toxicity would occur. Because the drug deposits itself inside the lungs, it works to coat the tissue in a manner akin to a topical corticosteroid that is applied to skin.

In the study presented today, researchers looked at 15 single-lung and double-lung transplant patients who were randomized to receive aerosol cyclosporine as an adjuvant therapy along with standard oral immunosuppression, most often tacrolimus. While immunosuppressive agents generally are given beginning at the time of transplantation, the aerosol cyclosporine was introduced approximately six weeks after transplantation once patients were medically stable and able to use a nebulizer, a device similar to an inhaler that delivers the spray.

As part of the trial, patients underwent the 30-minute treatment – breathing the mist containing aerosolized cyclosporine in a mixture with propylene glycol to help deliver the drug – three times a week for two years. They were then followed for an additional two years.

To examine how much and where the drug was being deposited in the lung tissue, researchers performed a one-time imaging study about six months after transplantation whereby a radioactive isotope was added to the nebulizer to allow visualization of the drug inside the lungs and surrounding tissues.

"Because anatomy and physiology differ from patient to patient, the drug is deposited in tissue in varying degrees," said Timothy E. Corcoran, Ph.D., research assistant professor of medicine and bioengineering at the University of Pittsburgh School and Medicine of the School of Engineering, who reported the findings at the ISHLT meeting.

Although each patient was given about the same cyclosporine dose (300 mg), single-lung transplant recipients absorbed between 2.2 and 9.2 percent of the dose (mean 6.2 percent) in their transplanted lung and double-lung transplant recipients deposited between 3.3 and 7.1 percent (mean 5.4 percent).

How much of the drug found its way into the lungs, particularly in the far reaches of the tissue, correlated with lung function. Researchers determined such changes in lung function by using a patient's best lung function test performed within 100 days after transplantation and making comparisons every 100 days, up to 700 days after transplantation.

Patients who deposited at least 5 mg of the drug showed significant improvement in lung function over time, whereas patients who deposited less than 5 mg and patients who were given an aerosol spray containing a placebo drug demonstrated decline in lung function over the same period. For instance, single-lung recipients who deposited at least 5 mg of the drug showed a 15 percent improvement at 200 days and a 25 percent improvement in lung function by 600 days. Patients who absorbed less of the drug or received placebo had a steady decline in lung function of up to 10 percent below their baseline function by day 600.

The researchers currently are working to develop techniques that will enhance deposition of the aerosol cyclosporine so that all transplant patients can have maximum benefit from the treatment.

"Aerosol cyclosporine appears to have a cumulative positive effect because there was a significant correlation between improvement in lung function tests and dose at all time points studied. Furthermore, the percentage change in lung function increased with each milligram of drug deposited in the periphery of the lung," reported Dr. Corcoran, a biomedical engineer and expert in aerosol drug delivery.

In addition to the lung function study, other results from the aerosol cyclosporine trial to be presented at the ISHLT meeting found that patients who developed post-transplant lymphoproliferative disease (PTLD), a complication from immunosuppression involving tumor growth that is often fatal, fared much better if they were being treated with the spray. The usual treatment for PTLD is to radically reduce or eliminate immunosuppression until the tumors disappear, but rejection of the transplanted organ can result. Aerosol cyclosporine afforded clinicians with the option of halting oral, or systemic immunosuppression, while continuing aerosol delivery directly to the lungs, thereby decreasing the likelihood that rejection would occur or lung function would suffer. Five of seven patients who developed PTLD survived, compared to seven patients from an earlier era who all died, reported Sebastian Gilbert, M.D., a resident in cardiothoracic surgery; Kenneth R. McCurry, M.D., assistant professor of surgery and director of lung and heart-lung transplantation; and others from UPMC.

In addition to Drs. Iacono and Corcoran, other authors of the lung function study are Dr. McCurry; Adriana Zeevi, M.D.; James H. Dauber, M.D.; Diedre A. Smith, R.N., B.S.N.; Gilbert Burckart, Pharm.D.; and Wayne F. Grgurich, all from UPMC; Gerry C. Smaldone, M.D., of State University of New York, Stony Brook; and Bartley P. Griffith, M.D., formerly at UPMC, and now at the University of Maryland.

The aerosol cyclosporine trial was supported by grants from the National Heart, Lung and Blood Institute and the American Lung Association. Novartis Pharmaceuticals Corporation provided the researchers with cyclosporine powder, which was used to produce the aerosolized form of the drug.


Story Source:

The above story is based on materials provided by University Of Pittsburgh Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

University Of Pittsburgh Medical Center. "Aerosol Cyclosporine Spray Improves Lung Function In Transplant Patients, Say Researchers." ScienceDaily. ScienceDaily, 10 April 2003. <www.sciencedaily.com/releases/2003/04/030410071828.htm>.
University Of Pittsburgh Medical Center. (2003, April 10). Aerosol Cyclosporine Spray Improves Lung Function In Transplant Patients, Say Researchers. ScienceDaily. Retrieved November 22, 2014 from www.sciencedaily.com/releases/2003/04/030410071828.htm
University Of Pittsburgh Medical Center. "Aerosol Cyclosporine Spray Improves Lung Function In Transplant Patients, Say Researchers." ScienceDaily. www.sciencedaily.com/releases/2003/04/030410071828.htm (accessed November 22, 2014).

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