Dose-related reversal of acute lung rejection by aerosolized cyclosporine.

Iacono, Aldo; Smaldone, Gerald C.; Keenan, Robert J.; Diot, Patrice; Dauber, James H.; Zeevi, Adriana; Burckart, Gilbert J.; Griffith, B.

doi:10.1164/ajrccm.155.5.9154878

Cited by 70 publications

(35 citation statements)

References 12 publications

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“…The radioisotope techniques used for deposited aerosol dose quantification have previously been described [5,7]. To summarise, a known quantity of radioactive tag (Technetium 99m bound to diethylenetriaminepentaacetic acid) was mixed into the study medication (drug or placebo) prior to nebulisation.…”

Section: Methodsmentioning

confidence: 99%

“…The dose deposited can be divided into a central and a peripheral component, based on an area-convention which is applied to planar, gamma-camera images [5]. Left and right lung doses were averaged in double lung recipients so that transplant dose could be represented by a single quantity.…”

Section: Methodsmentioning

confidence: 99%

“…Aerosol (nebulised) cyclosporin (ACsA) has been studied for use as an adjuvant therapy for refractory acute rejection of the lung allograft. In two small open-label cohort studies, improvements in rejection grade and pulmonary function were noted after initiation of ACsA [4,5]. ACsA was also used to stabilise pulmonary function in subjects suffering from chronic rejection [6].…”

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confidence: 99%

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Preservation of post-transplant lung function with aerosol cyclosporin

Corcoran¹,

Smaldone²,

Dauber³

et al. 2004

Eur Respir J

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Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect.In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant).Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing o5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial.A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection. Rejection of the transplanted lung occurs at a rate exceeding that of most other solid organ allografts. Rejection of the allograft typically results in decreased pulmonary function and requires potent immunosuppressive treatments that predisposes the patient to opportunistic infections. Persistent acute rejection is the primary risk factor for bronchiolitis obliterans (OB), the pathological marker of chronic rejection [1]. Chronic rejection is the leading cause of late mortality in the lung-transplant population with a median survival after a diagnosis of y3 yrs [2,3].The lung offers a unique opportunity for topical immunosuppression and the potential sparing of the significant sideeffects associated with systemic immunosuppressive agents. Aerosol (nebulised) cyclosporin (ACsA) has been studied for use as an adjuvant therapy for refractory acute rejection of the lung allograft. In two small open-label cohort studies, improvements in rejection grade and pulmonary function were noted after initiation of ACsA [4,5]. ACsA was also used to stabilise pulmonary function in subjects suffering from chronic rejection [6].A randomised, double-blind, placebo controlled trial of the prophylactic use ACsA was initiated to determine whether the drug is effective in preventing acute and chronic rejection. A deposition sub-study was later initiated to gage how well the subjects were depositing the study medication in their lungs. Deposition tests were performed on both drug and placebo subjects and both deposited and mock doses were calculated.The authors hypothesised the following: 1) deposited dose would correlate to an improvement in lung function in the drug subjects but that mock dose wo...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Preservation of post-transplant lung function with aerosol cyclosporin

Corcoran¹,

Smaldone²,

Dauber³

et al. 2004

Eur Respir J

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“…156 The same group studied the addition of either inhaled CsA or placebo to a typical maintenance regimen after lung transplantation. 157,158 160,164,172 CsA may also cause neurotoxicity, which can range from mild tremor or paresthesias to frank delirium and seizures.…”

Section: Information For Patientsmentioning

confidence: 99%

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

Baughman

Meyer

Nathanson

et al. 2012

Chest

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Objectives: Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and infl ammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. Methods: Committee members developed and refi ned a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. Conclusions: It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease. CHEST 2012; 142(5):e1S-e111SAbbreviations: ACCP 5 American College of Chest Physicians; ALT 5 alanine aminotransferase; ATG 5 antithymocyte globulin; CHF 5 congestive heart failure; CMV 5 cytomegalovirus; CNI 5 calcineurin inhibitor; COI 5 confl ict of interest; CsA 5 cyclosporin A; FDA 5 US Food and Drug Administration; HBV 5 hepatitis B virus; HMG-CoA 5 b -hydroxy-bmethylglutaryl-coenzyme A; HSP 5 Health and Science Policy Committee; IL2RA 5 IL-2 receptor a ; ILD 5 interstitial lung disease; IPF 5 idiopathic pulmonary fi brosis; ITP 5 idiopathic thrombocytopenia purpura; LAM 5 lymphangioleiomyomatosis; MESNA 5 sodium 2-sulfonylethanesufonate; MPA 5 mycophenolic acid; mTOR 5 mammalian target of rapamycin; PTLD 5 posttransplant lymphoproliferative disease; RCT 5 randomized controlled trial; SIRS 5 systemic infl ammatory response syndrome; TNF 5 tumor necrosis factor; TPMT 5 thiopurine methyltransferase

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“…In contrast, no differences in longitudinal functional values were observed among randomized single lung patients. Significant variability of the cyclosporine deposited in the transplanted lung has been previously demonstrated, with drug deposition per allograft ranging from 6.5 to 26.9 mg. (22,23) There also appears to be a threshold drug dose of cyclosporine that is necessary to provide an improvement in lung function. In a subset of 15 ACsA recipients from the randomized trial who underwent aerosol deposition testing, higher peripheral allograft cyclosporine concentrations were found to offer a therapeutic advantage in longitudinal FEV 1 improvement in a dose-dependent fashion with higher peripheral lung doses resulting in the greatest augmentation of FEV 1 over a 6-month interval.…”

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confidence: 99%

Inhaled Cyclosporine and Pulmonary Function in Lung Transplant Recipients

Groves

Galazka

Johnson

et al. 2010

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: Chronic rejection, manifesting as bronchiolitis obliterans, is the leading cause of death in lung transplant recipients. In our previously reported double-blinded, placebo-controlled trial comparing inhaled cyclosporine (ACsA) to aerosol placebo, the rate of bronchiolitis-free survival improved. However, an independent analysis of pulmonary function, a secondary endpoint of the trial, was not performed. We sought to determine the effect of ACsA, in addition to systemic immunosuppression, on pulmonary function. Methods: From 1998-2001, 58 patients were randomly assigned to inhale either 300 mg of ACsA (28 patients) or placebo aerosol (30 patients) 3 days a week for the first 2 years after transplantation. Longitudinal changes in pulmonary function of ACsA patients were compared to aerosol placebo patients. In another analysis, the rate of decline from 6-month maximum FEV 1 in randomized patients was compared to the rate of decline in patients receiving conventional immunosuppression from the Novartis transplant database (644 patients, 12 centers worldwide, transplanted from 1990-1995). Results: The average duration of ACsA and aerosol placebo was 400 days AE 306 and 433 AE 256, respectively. The change in FEV 1 of ACsA patients (adjusted for Cytomegalovirus (CMV) mismatch and transplant type, followed for a maximum duration of 4.6 years) was superior to the aerosol placebo controls (9.0 AE 71.4 mL=year vs. À107.9 AE 55.3, p ¼ 0.007). The FEF 25-75 decreased by À220.3 AE 117.7 L=(secondÂyear) vs. À412.2 AE 139.2, p ¼ 0.07, respectively. Similarly, percent FEV 1 decline from maximal values was improved in ACsA patients compared to aerosol placebo and Novartis controls (ACsA À0.43 AE 1.12%=year vs. aerosol placebo À4.08 AE 1.4, p ¼ 0.04; ACsA vs. Novartis À4.7 AE 0.31, p ¼ 0.007). Single-lung recipients receiving ACsA showed improvement in FEV 1 compared to Novartis controls (FEV 1 À0.8 AE 1.8%=year vs. À4.94 AE 0.4, p ¼ 0.03) but double-lung recipients showed improvement compared to aerosol placebo controls only (FEV 1 À0.28 AE 1.22%=year vs. À8.53 AE 5.95, p ¼ 0.048). Conclusions: In this single center trial, ACsA appears to ameliorate important pulmonary function parameters in lung transplant recipients compared to aerosol placebo and historical control patients. Single-and double-lung transplant recipients may not respond uniformly to treatment, and ongoing randomized trials in lung transplant recipients using ACsA may help elucidate our findings.

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Dose-related reversal of acute lung rejection by aerosolized cyclosporine.

Cited by 70 publications

References 12 publications

Preservation of post-transplant lung function with aerosol cyclosporin

Preservation of post-transplant lung function with aerosol cyclosporin

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

Inhaled Cyclosporine and Pulmonary Function in Lung Transplant Recipients

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