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.

Abstract

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.

• Authors: Una Rauchhaus, Franz Werner Schwaiger, Steffen Panzner
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 11 Issue 6 Pg. R190 ( 2009) ISSN: 1478-6362 [Electronic] England
• PMID: 20003498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Liposomes
• Dexamethasone

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage, adverse effects, pharmacokinetics)
• Arthritis, Experimental (drug therapy)
• Dexamethasone (administration & dosage, adverse effects, pharmacokinetics)
• Hypothalamo-Hypophyseal System (drug effects)
• Liposomes
• Male
• Mice
• Mice, Inbred DBA
• Pituitary-Adrenal System (drug effects)
• Rats
• Rats, Wistar