Liposomal encapsulation enhances and prolongs the anti-inflammatory effects of water-soluble dexamethasone phosphate in experimental adjuvant arthritis
| Autor: | Theodora Katsila, Rolf Bräuer, Steffen Panzner, Margarida Castell, Alexandros P. Siskos, Mieczyslaw Gajda, Dirk Pohlers, Francisco J. Pérez-Cano, Una Rauchhaus, Rebecca Anderson, Raimund W. Kinne, Constantin Tamvakopoulos, Àngels Franch |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
BLOOD
Chemistry Pharmaceutical Arthritis Pharmacology Dexamethasone Leukocyte Count Immunology and Allergy Hypersensitivity Delayed Tissue Distribution Lymphocytes Drug Carriers Dose–response relationship medicine.anatomical_structure 1107 Immunology Injections Intravenous Cytokines Female Drug carrier Life Sciences & Biomedicine Research Article medicine.drug EXPRESSION DELAYED-TYPE HYPERSENSITIVITY Immunology Spleen RATS 1117 Public Health and Health Services Pharmacokinetics Rheumatology White blood cell PEG ratio medicine ETANERCEPT Animals GLUCOCORTICOIDS Science & Technology ANTI-CD4 MONOCLONAL-ANTIBODY Dose-Response Relationship Drug business.industry 1103 Clinical Sciences medicine.disease EFFICACY Arthritis Experimental RHEUMATOID-ARTHRITIS Arthritis & Rheumatology PEGYLATED LIPOSOMES Solubility Rats Inbred Lew Immunoglobulin G Liposomes Macrophages Peritoneal business |
| Zdroj: | Arthritis Research & Therapy |
| Popis: | Introduction The objective of this study was to evaluate the efficacy of intravenous (i.v.) injection of liposomally encapsulated dexamethasone phosphate (DxM-P) in comparison to free DxM-P in rats with established adjuvant arthritis (AA). This study focused on polyethylene glycol (PEG)-free liposomes, to minimize known allergic reactions caused by neutral PEG-modified (PEG-ylated) liposomes. Methods Efficacy was assessed clinically and histologically using standard scores. Non-specific and specific immune parameters were monitored. Activation of peritoneal macrophages was analyzed via cytokine profiling. Pharmacokinetics/biodistribution of DxM in plasma, synovial membrane, spleen and liver were assessed via mass spectrometry. Results Liposomal DxM-P (3 × 1 mg/kg body weight; administered intravenously (i.v.) on Days 14, 15 and 16 of AA) suppressed established AA, including histological signs, erythrocyte sedimentation rate, white blood cell count, circulating anti-mycobacterial IgG, and production of interleukin-1beta (IL-1β) and IL-6 by peritoneal macrophages. The suppression was strong and long-lasting. The clinical effects of liposomal DxM-P were dose-dependent for dosages between 0.01 and 1.0 mg/kg. Single administration of 1 mg/kg liposomal DxM-P and 3 × 1 mg/kg of free DxM-P showed comparable effects consisting of a partial and transient suppression. Moreover, the effects of medium-dose liposomal DxM-P (3 × 0.1 mg/kg) were equal (in the short term) or superior (in the long term) to those of high-dose free DxM-P (3 × 1 mg/kg), suggesting a potential dose reduction by a factor between 3 and 10 by liposomal encapsulation. For at least 48 hours after the last injection, the liposomal drug achieved significantly higher levels in plasma, synovial membrane, spleen and liver than the free drug. Conclusions This new PEG-free formulation of macrophage-targeting liposomal DxM-P considerably reduces the dose and/or frequency required to treat AA, with a potential to enhance or prolong therapeutic efficacy and limit side-effects also in the therapy of rheumatoid arthritis. Depot and/or recirculation effects in plasma, inflamed joint, liver, and spleen may contribute to this superiority of liposomally encapsulated DxM-P. |
| Databáze: | OpenAIRE |
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