title: Microbubble-enhanced ultrasound exposure promotes uptake of methotrexate into synovial cells and enhanced antiinflammatory effects in the knees of rabbits with antigen-induced arthritis.
abstract: OBJECTIVE
  To evaluate whether microbubble-enhanced ultrasound (US) treatment promotes the delivery of methotrexate (MTX) into synovial cells and the enhanced antiinflammatory effects of intraarticular MTX therapy in a rabbit arthritis model.
  
  
  METHODS
  Arthritis was induced in both knees of 53 rabbits by immunization with ovalbumin. MTX including a microbubble agent was then injected into the left and right knee joints, and the right knees were exposed to US (MTX+/US+ group), while the left knees were not (MTX+/US- group). The knee joints were evaluated histologically in 7 rabbits at 5 time points up to day 56. Quantitative gene expression of interleukin-1beta (IL-1beta) in synovial tissue was measured on days 7 and 28. Eight rabbits were used for the measurement of MTX concentration in synovial tissue 12 hours after treatment. To evaluate the effect of microbubble-enhanced US treatment in the absence of MTX, only the microbubble agent was injected into the left and right knee joints of 10 rabbits with or without US exposure, and these animals were evaluated histologically on days 7 and 28.
  
  
  RESULTS
  The MTX concentration in synovial tissue was significantly higher in the MTX+/US+ group than in the MTX+/US- group. Synovial inflammation was less prominent in the MTX+/US+ group compared with the MTX+/US- group, judging from the results of the histologic evaluation and the gene expression levels of IL-1beta in synovial tissue. It also appeared that microbubble-enhanced US exposure itself did not affect inflammation.
  
  
  CONCLUSIONS
  Microbubble-enhanced US exposure promoted the uptake of MTX into synovial cells, which resulted in enhancement of the antiinflammatory effects of the intraarticular MTX injection. These results suggest that application of this technique may have clinical benefit.
authors.affiliation: Osaka University Medical School, Suita, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakaya
authors.forename: Tominaga
authors.initials: T
authors.lastname: Shimizu
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Isobe
authors.forename: Keiji
authors.initials: K
authors.lastname: Tensho
authors.forename: Takahiro
authors.initials: T
authors.lastname: Okabe
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Nawata
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Kunio
authors.initials: K
authors.lastname: Takaoka
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Wakitani
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D045423:Microbubbles; D009994:Osmolar Concentration; D010047:Ovalbumin / Q000276:immunology; D011817:Rabbits; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D014465:Ultrasonics
chemical_list: D000893:Anti-Inflammatory Agents; D010047:Ovalbumin; D008727:Methotrexate