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Intra-articular treatment of inflammatory arthritis with microsphere formulations of methotrexate: pharmacokinetics and efficacy determination in antigen-induced arthritic rabbits

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Abstract

Introduction

Methotrexate (MTX) encapsulated microspheres release MTX in the joint in a slow, controlled manner following intra-articular injection in healthy rabbits. The objective of this study was to determine the pharmacokinetics of MTX and to evaluate the efficacy following intra-articular treatment of MTX-loaded microspheres in an antigen-induced inflammatory arthritis rabbit model.

Methods

Arthritis was induced in both knee joints of rabbits using ovalbumin. Rabbits were intra-articularly treated with MTX solution or MTX microspheres and plasma concentrations of MTX were determined in the first 8 h following intra-articular treatment. Rabbits were killed 14 days following treatment and histological analysis of rabbit joints was conducted to determine efficacy.

Results

Arthritis was successfully induced in the joints of rabbits with the observation of histopathological features resembling rheumatoid arthritis. No significant differences were detected between MTX solution and MTX microspheres treated groups compared to phosphate buffered saline (control) animals.

Conclusions

MTX microspheres effectively delivered the drug to the intra-articular space. However, a high degree of inter-animal variability, the severity of the disease induced and insufficient length of the observation period were suggested to be possible causes for the lack of therapeutic responses to MTX-loaded microspheres treatment.

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Acknowledgments

The authors would like to thank Ms. Carol Reno and Ms. Ruth Seerattan at the Faculty of Medicine, University of Calgary for their assistance with animal studies. This study was supported by a grant from the Canadian Arthritis Network Center of Excellence (HMB) and a grant from The Arthritis Society (DAH) who is the Calgary Foundation-Grace Glaum Professor in Arthritis Research.

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Authors and Affiliations

  1. Nanomedicine Research Center, National Health Research Institutes, No. 35, Keyan Road, Zhunan Twoan, 350, Miaoli County, Taiwan, ROC

    Linda S. Liang

  2. McCaig Institute for Bone and Joint Health, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, T2N 4N1, Canada

    Paul T. Salo & David A. Hart

  3. Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada

    Helen M. Burt

Authors
  1. Linda S. Liang
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  2. Paul T. Salo
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  3. David A. Hart
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  4. Helen M. Burt
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Correspondence to Helen M. Burt.

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Responsible Editor: J. A. Di Battista.

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Liang, L.S., Salo, P.T., Hart, D.A. et al. Intra-articular treatment of inflammatory arthritis with microsphere formulations of methotrexate: pharmacokinetics and efficacy determination in antigen-induced arthritic rabbits. Inflamm. Res. 58, 445–456 (2009). https://doi.org/10.1007/s00011-009-0009-7

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  • DOI: https://doi.org/10.1007/s00011-009-0009-7

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