Low doses of dexamethasone constantly delivered by autologous erythrocytes slow the progression of lung disease in cystic fibrosis patients
Introduction
Cystic fibrosis (CF) is one of the most common and serious inherited disorders associated with considerable morbidity and high-case fatality. Lung disease is the major cause of morbidity in CF, being characterized by persistent bacterial infection leading to inflammation and long-term lung damage (bronchiectasis), respiratory failure, and death [1], [2]. Persistent airway inflammation begins at a very early stage in these patients [3] and continues throughout life. Controlling the inflammatory process early in the course of disease may limit the damaging effects of excessive inflammation, thus delaying the progression of pulmonary deterioration and potentially decreasing morbidity and mortality. Glucocorticoid drugs have been studied as potential agents for long-term anti-inflammatory therapy in CF patients [4]. Although oral glucocorticoids are associated with reduced progression of pulmonary disease, the risk of clinically significant adverse effects (such as growth retardation, glucose abnormalities, and cataract formation) [5] limits long-term therapy. However, whether these risks balance the benefits of improved lung function for patients in which respiratory failure represents a major cause of death is still unclear. Furthermore, it has been reported that a reduced concentration of oral glucocorticoids is associated with minimal complications [6]. A recent assessment of the effectiveness of oral steroids in the Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trial register [7] suggested that oral glucocorticoids appear to slow the progression of lung disease and recommended a risk–benefit analysis of low-dose glucocorticoids. Engineered erythrocytes have been proposed as drug delivery systems [8], [9], [10], [11], [12], [13], [14], and previous experience [15], [16], [17] has demonstrated that the nondiffusible pro-drug dexamethasone 21-phosphate (Dex 21-P) can be entrapped in human erythrocytes where it is slowly dephosphorylated to the corresponding diffusible glucocorticoid analogue dexamethasone. We have evaluated in a group of CF patients the safety and efficacy of very-low doses of glucocorticoids administered encapsulated in autologous red blood cells (RBCs) once every 4 weeks for 15 months. The results obtained are summarized in this paper.
Section snippets
Study subjects
The goal of the clinical trial was to evaluate the safety and efficacy of the administration of low doses of corticosteroid in CF patients taking an advantage of the use of autologous erythrocytes loaded with Dex 21-P to obtain a slow delivery of dexamethasone in circulation. For the study, we recruited 17 CF patients homozygous for ΔF508 deletion [18], ranging from 12 to 26 years. Inclusion criteria for patients enrolment included the following: forced expiratory volume in 1 s (FEV1) at least
Dexamethasone 21-P encapsulation in CF patient erythrocytes
Dex 21-P was encapsulated in erythrocytes of CF patients processing 50 ml of blood samples by a loading procedure as reported by Magnani et al. [16]. At the end of the procedure, 82 ± 8 ml of suspension of RBCs at 9.96 ± 2% hematocrit was obtained with a cell recovery of 43 ± 5%. To evaluate the safety of the procedure, autologous erythrocytes loaded with increasing amounts of drug (1.19–14.5 mg) were administered to eight different patients. The different amounts of Dex 21-P in RBCs were
Discussion
Anti-inflammatory therapy is a strategy for treating CF pulmonary disease because it is directed at one of the primary pathophysiologic mechanisms responsible for progressive lung damage [19]. Several targets for anti-inflammatory therapy are available; however, efforts are focused on reducing local neutrophil infiltrations, and consequently, glucocorticoids are major candidates [20]. Also, if oral glucocorticoids are associated with reduced progression of pulmonary disease, the risk of
Acknowledgements
We thank the patients and physicians of the “Bambino Gesù” Hospital in Rome (Italy) for their invaluable collaboration. Moreover, we thank DIDECO (Italy) for providing the “Red Cell Loader”. We thank Prof. Andrea De Gaetano (Institute of Biomathematics, University of Urbino, Urbino, Italy) for his helpful consultation. This work was partially supported by the Italian Ministry of Health, the National Research Council, the Target Project on Biotechnology, and FIRB funds (COD. RBNE 01TBTR),
References (22)
- et al.
A multicenter study of alternate day prednisone in patients with cystic fibrosis
J. Pediatr.
(1995) - et al.
Cystic fibrosis: state of the art
Am. J. Respir. Crit. Care Med.
(1996) - et al.
Cystic Fibrosis
(1993) - et al.
Current understanding of the inflammatory process in cystic fibrosis: onset and etiology
Pediatr. Pulmonol.
(1997) - et al.
Corticosteroid treatment in cystic fibrosis
Arch. Dis. Child.
(1993) - et al.
Risks of alternate-days prednisone in patients with cystic fibrosis
Pediatrics
(1991) - et al.
Oral steroids for cystic fibrosis
Cochrane Database Syst. Rev.
(2000) - et al.
Enzyme loading of erythrocytes
Proc. Natl. Acad. Sci. U. S. A.
(1973) - et al.
Improved oxygen delivery to tissues and iron chelator transport through the use of lysed and resealed red blood cells: a new perspective on Cooley's anemia therapy
Ann. N. Y. Acad. Sci.
(1985) - et al.
Conversion of encapsulated 5-fluoro-2′-deoxyuridine 5′-monophosphate to the antineoplastic drug 5-fluoro-2′-deoxyuridine in human erythrocytes
Proc. Natl. Acad. Sci. U. S. A.
(1988)
Increased glucose metabolism by enzyme-loaded erythrocytes in vitro and in vivo normalization of hyperglycemia in diabetic mice
Biotechnol. Appl. Biochem.
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