Dosing Time–Dependency of the Arthritis-Inhibiting Effect of Tacrolimus in Mice

Obayashi, K; Tomonari, Mari; Yoshimatsu, Hiromichi; Fukuyama, Ryuji; Ieiri, Ichiro; Higuchi, Shun; To, Hideto

doi:10.1254/jphs.11029fp

Cited by 11 publications

(15 citation statements)

References 40 publications

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“…In the present study, CRP concentrations showed a clear 24-h rhythm with a peak at 22 HALO in accordance with those in CIA and MRL/lpr mice (25,27). Moreover, during MZR (10 mg/kg) given the next day after the first immunization, the arthritis score in the 22 HALO group was half that of the 10-HALO group, and MZR showed a significant dosing-time dependent difference in its antirheumatic effect.…”

Section: Discussionsupporting

confidence: 88%

“…An obvious 24-h rhythm in plasma SAA concentrations, involving higher levels at 2 HALO, was observed in MRL/lpr mice that developed RA (data not shown). Moreover, SAA levels in CIA mice also showed a 24-h rhythm with a peak at 2 HALO in our previous study (27). We reported that therapeutic effects markedly improved in clinical and animal studies by administering MTX and tacrolimus in consideration of the rhythm of the inflammatory response (25 -27).…”

Section: Discussionmentioning

confidence: 71%

“…In a previous study, we measured leukocyte counts in MRL/lpr mice. Leukocytes significantly increased after RA onset and a greater antirheumatic effect was shown at 2 HALO when increasing leukocyte counts were inhibited when tacrolimus was administered at 2 or 14 HALO (27). It has been suggested that inhibiting increased leukocyte counts, which induces an inflammatory response, is one of the options available for the treatment of RA.…”

Section: Discussionmentioning

confidence: 99%

“…Although many requirements must be met to establish a diagnosis of RA, morning stiffness, which shows a 24-hour rhythm with a peak in the early morning, is a characteristic feature of RA (22). Chronotherapy and chronopharmacology in RA was used basically and clinically with glucocorticoids (23,24), methotrexate (MTX) (25,26), and tacrolimus (27). These results clarified that choosing an optimal dosing-time associated with the 24-h rhythm of RA symptoms could lead to an effective treatment for RA.…”

Section: Introductionmentioning

confidence: 99%

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Chronopharmacology of Mizoribine in Collagen-Induced Arthritis Rats

et al. 2012

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Abstract. We previously reported that higher therapeutic effects were obtained in rheumatoid arthritis (RA) patients and RA model animals when the dosing-times of methotrexate and tacrolimus were chosen according to the 24-h rhythms of the inflammatory response. Mizoribine (MZR) is an immunosuppressive agent and is used against RA in the same manner as methotrexate and tacrolimus. In this study, we examined whether a dosing-time dependency of the therapeutic effect of MZR could be detected in collagen-induced arthritis (CIA) rats. To measure C-reactive protein (CRP) and tumor necrosis factor (TNF)-α levels, blood was collected from CIA rats at different times. MZR was administered at two different dosing-times based on these findings and its effects and toxicity were examined. CRP and TNF-α concentrations in blood showed significant 24-h rhythms. The exacerbation of arthritis and excessive increase in leukocytes in CIA rats were markedly lower in the group treated with MZR at the dark phase than those of the group treated with MZR at the light phase. These findings suggest that the therapeutic index of RA therapy may be improved by administering MZR at a time in the day when the inflammatory reaction begins to activate.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chronopharmacology of Mizoribine in Collagen-Induced Arthritis Rats

et al. 2012

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“…Figure 3 shows 24-hour rhythms in TNF-α levels before and after the onset of RA, and dosing time differences in the arthritis score for TAC in mice with CIA. 40 Plasma TNF-α concentrations were found to be markedly higher in mice with CIA than in normal mice. Mice with CIA showed a significant 24-hour rhythm in TNF-α levels, with higher levels in the light phase and lower levels in the dark phase.…”

Section: Tacrolimusmentioning

confidence: 90%

Chronotherapy for rheumatoid arthritis: current perspectives

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2016

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Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology. Morning stiffness, a characteristic feature of RA, shows a 24-hour rhythm. Cytokines, which are considered to play an important role in the pathogenesis of RA, also exhibit a 24-hour rhythm, with a peak in the early morning. These rhythms have been attributed to the endogenous hormone balance and changes in expression levels of clock-related genes. Chronotherapy based on the 24-hour rhythm of RA has been performed using glucocorticoids and disease-modifying antirheumatic drugs. In a previous study, it was reported that modified-release prednisone tablets were administered to patients with RA at night, which demonstrated that the severity of morning stiffness was markedly less than that in patients receiving the standard treatment. Methotrexate (MTX) is the most frequently used RA drug worldwide. In a basic study, cytokines and inflammatory responses in RA model animals showed 24-hour rhythms, based on which MTX was administered and exerted dosing time-dependent antirheumatic effects. Plasma C-reactive protein and cytokine levels also exhibit 24-hour rhythms in patients with RA, with peaks occurring in the early morning. MTX has been shown to markedly inhibit the exacerbation of arthritis in patients with RA when it is administered as inflammatory responses and tumor necrosis factor-α levels begin to increase. Tacrolimus (TAC) is an immunosuppressive agent that is administered to patients who undergo organ transplants. Since one of the mechanisms of action of TAC is the inhibition of inflammatory cytokine production, it is used as an RA therapeutic drug. When TAC was previously administered in the early light or early dark phase to RA model animals, the group treated in the early light phase had notably inhibited increase in arthritis scores compared with that in the early dark phase. The selection of an optimal dosing time associated with 24-hour rhythms in RA symptoms may lead to more effective and safer treatments for RA using glucocorticoids and disease-modifying antirheumatic drugs.

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Role of methotrexate chronotherapy in collagen-induced rheumatoid arthritis in rats

et al. 2016

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AimTo explore the circadian rhythm of serum interleukin (IL)-6 in collagen-induced arthritis (CIA) rats and compare the safety and effectiveness of methotrexate (MTX) administered traditionally and via chronotherapy.MethodsCIA rat models were immunized with bovine type II collagen. Serum IL-6 levels in normal and CIA rats were measured at 2, 6, 10, 14, 18, or 22 h after the light was turned on (HALO). MTX was administered to 6 HALO/18 HALO experimental groups of Wistar rats once daily according to the IL-6 rhythm. The control groups (positive, negative, and normal) were given MTX or an equal volume of phosphate buffered saline (PBS) once a week simultaneously. Arthritis score, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C reactive protein (CRP) levels in the serum were measured by enzyme-linked immunosorbent assay (ELISA). Histological changes in the ankle joint were analyzed.ResultsAfter 6 weeks of treatment, arthritis scores in the experimental group were lower than in the control group. The expression of TNF-α, IL-6, and CRP was lower in the 18 HALO group than in the control or 6 HALO groups. Histopathology scores in the experimental groups were lower than in the control group (p < 0.05).ConclusionThe plasma IL-6 levels in CIA rats were higher than in normal rats and showed significant circadian rhythm. Daily administration of MTX is more potent than weekly administration. The therapeutic index of rheumatoid arthritis (RA) may be improved with MTX therapy based on the IL-6 circadian rhythm.

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Dosing Time–Dependency of the Arthritis-Inhibiting Effect of Tacrolimus in Mice

Cited by 11 publications

References 40 publications

Chronopharmacology of Mizoribine in Collagen-Induced Arthritis Rats

Chronopharmacology of Mizoribine in Collagen-Induced Arthritis Rats

Chronotherapy for rheumatoid arthritis: current perspectives

Role of methotrexate chronotherapy in collagen-induced rheumatoid arthritis in rats

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