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.
BACKGROUND
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.
Rauchhaus
Una
U
Novosom AG, Weinbergweg 22, D-06120 Halle/Saale, Germany. una.rauchhaus@web.de
Schwaiger
Franz Werner
FW
Panzner
Steffen
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001169:Arthritis, Experimental / Q000188:drug therapy*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008081:Liposomes; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010913:Pituitary-Adrenal System / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D008081:Liposomes; D003907:Dexamethasone