Research article
Separating therapeutic efficacy from glucocorticoid side-effects in rodent arthritis using novel, liposomal delivery of dexamethasone phosphate: long-term suppression of arthritis facilitates interval treatment
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* Corresponding author: Steffen Panzner steffen.panzner@novosom.com
1 Novosom AG, Weinbergweg 22, D-06120 Halle/Saale, Germany
2 Aurigon Life Science GmbH, Bahnhofstrasse 9-15, D-82327 Tutzing, Germany
Arthritis Research & Therapy 2009, 11:R190 doi:10.1186/ar2889
Published: 15 December 2009Abstract
Introduction
Glucocorticoids have extensively been used in the treatment of rheumatoid arthritis and other inflammatory diseases. However, their side-effects remain the major limitation in clinical use and an improved therapeutic index is needed.
Methods
Therapeutic efficacy and persistence of free and liposomal dexamethasone phosphate (DXM-P) were determined in mouse collagen-induced arthritis. For regimens with equal therapeutic benefit, the side-effect profiles were analysed over time with respect to collagen breakdown, suppression of the hypothalamus-pituitary-adrenal (HPA) axis, changes in blood glucose levels and the haematological profile. In addition, the presence of drug was monitored in plasma.
Results
Liposomal DXM-P, but not free drug, resulted in a persistent anti-inflammatory effect. Comparable clinical benefit was achieved with a single administration of 4 mg/kg liposomal DXM-P or daily administrations of 1.6 mg/kg free drug for at least 7 days. For the liposomal form, but not for the free form, we observed a limitation of the suppression of the HPA axis in time and an absence of the drug-induced gluconeogenesis.
Conclusions
Liposomal DXM-P, but not free DXM-P, achieves therapeutic persistence in mouse collagen-induced arthritis, which results in drug-free periods of therapeutic benefit. The physical absence of drug after day 2 is associated with a reduction of the typical glucocorticoid side-effects profile. Liposomal DXM-P thereby has an improved therapeutic window.