title: Therapeutic index of methotrexate depends on circadian cycling of tumour necrosis factor-alpha in collagen-induced arthritic rats and mice.
abstract: OBJECTIVE
  Rheumatoid arthritis is an autoimmune disorder of unknown aetiology. Morning stiffness, a characteristic feature of rheumatoid arthritis, shows a 24-h rhythm. Noticing this rhythm, we hypothesized the presence of a similar rhythm for a rheumatoid arthritis indicator, in addition to dosing-time dependency of the anti-rheumatic effect of methotrexate in arthritis induced by collagen in rats and mice, which reflect the symptomatology of rheumatoid arthritis patients.
  
  
  METHODS
  To measure tumour necrosis factor (TNF)-alpha concentration, blood was taken at different times (2, 6, 10, 14, 18 or 22 h after the light was turned on (HALO)) in collagen-induced arthritic mice. Methotrexate was administered at two different dosing times based on these findings to estimate arthritis.
  
  
  RESULTS
  The arthritis score was significantly lower in the 22 HALO-treated group than in the control and 10 HALO-treated groups in collagen-induced arthritic rats and mice. Plasma TNF-alpha concentrations showed obvious 24-h rhythms, with higher levels at light phase and lower levels at dark phase after rheumatoid arthritis crisis. Arthritis was relieved after administration of methotrexate during the dark phase in synchronization with the 24-h rhythm.
  
  
  CONCLUSIONS
  Our findings suggest that choosing an optimal dosing time associated with the 24-h cycling of TNF-alpha could lead to effective treatment of rheumatoid arthritis by methotrexate.
authors.affiliation: Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan. hide-to@umin.net
authors.forename: Hideto
authors.initials: H
authors.lastname: To
authors.forename: Sadaharu
authors.initials: S
authors.lastname: Irie
authors.forename: Mari
authors.initials: M
authors.lastname: Tomonari
authors.forename: Yuko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitahara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000097:blood; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy*; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D007958:Leukocyte Count; D008727:Methotrexate / Q000008:administration & dosage* / Q000097:blood; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D008727:Methotrexate