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Introduction: Bardoxolone methyl significantly increases estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD). However, the phase 3 study, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events (BEACON), was terminated prematurely because bardoxolone methyl increased the risk for early-onset fluid overload in patients with identifiable risk factors for heart failure (elevated baseline B-type natriuretic peptide levels >200 pg/ml and prior history of hospitalization for heart failure). The Phase 2 Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) study aimed to determine if patients without risk factors can mitigate the risk for fluid overload and whether changes in eGFR with bardoxolone methyl reflect true increases in GFR.Methods: This phase 2, randomized, multicenter, double-blind, placebo-controlled study enrolled patients with type 2 diabetes and stage 3-4 CKD. Patients were randomized 1:1 to bardoxolone methyl (n ¼ 41) or placebo (n ¼ 41) (cohort G3), or 2:1 to bardoxolone methyl (n ¼ 24) or placebo (n ¼ 14) (cohort G4), administered orally once daily for 16 weeks using a dose-titration scheme. The primary efficacy endpoint was change from baseline in GFR measured by inulin clearance at week 16 in the cohort G3.Results: A total of 40 patients were evaluated for the prespecified primary efficacy analysis. Mean change (95% confidence interval [CI]) from baseline in GFR was 5.95 (2.29 to 9.60) and À0.69 (À3.83 to 2.45) ml/min per 1.73 m 2 for patients randomized to bardoxolone methyl and placebo, respectively, with a significant intergroup difference of 6.64 ml/min per 1.73 m 2 (P ¼ 0.008). Increases in the albumin/creatinine ratio were observed in the bardoxolone methyl group vs the placebo group. The most common adverse events ($15% in either group) were viral upper respiratory tract infection, increased alanine aminotransferase, increased aspartate aminotransferase, increased g-glutamyltransferase, and constipation. Peripheral edema was reported by 4 patients receiving bardoxolone methyl and by 1 patient receiving placebo; all events were mild and self-limiting. No patient died or experienced heart failure. The study discontinuation rate was higher in the bardoxolone methyl group (cohort G3, n ¼ 8; cohort G4, n ¼ 7) than the placebo group (cohort G3, n ¼ 1; cohort G4, n ¼ 0). Conclusion:Bardoxolone methyl significantly increased measured GFR, and further investigation is ongoing to evaluate whether it provides clinical benefit without major safety concerns in selected patients with CKD.

ABSTRACT-We investigated itch-associated responses (scratching) to mosquito bites and the role of histamine and mast cells in mosquito-induced itching in mice. Although the first bites of mosquito Aedes albopictus did not increase scratching, repeated bites increased scratching. The response was not diminished even after an interval of 2 months. Similarly, repeated intradermal (i.d.) injections of salivary gland extract (SGE) from Aedes albopictus increased scratching after SGE injection itself and mosquito bites. The scratching peaked within 10 min and almost subsided by 60 min. The opioid antagonist naloxone (1 mg / kg, s.c.) inhibited scratching following SGE injection. Although the non-sedative H 1-histamine-receptor antagonist terfenadine (30 mg/ kg, p.o.) significantly suppressed scratching induced by histamine (100 nmol /site, i.d.) in either naive or mosquito-sensitized mice, it did not affect mosquito-induced scratching in mosquitosensitized mice. Repeated injections of SGE increased scratching in mast cell-deficient (WBB6F1-W /W v ) mice as well as in normal (WBB6F1-+/ +) littermates. Repeated exposure to mosquito bites roughly doubled serum concentrations of total IgE and IgG1, but not IgG2a. Repeated injections of SGE markedly increased plasma extravasation induced by mosquito bites and such an increase was almost completely suppressed by terfenadine (30 mg/ kg, p.o.). The results show the presence of histamine-mediated and histamineindependent mechanisms in cutaneous itching and suggest that histamine probably released from mast cells does not play an important role in itching in immediate allergic reaction. Our murine model of mosquito itching may be useful for studying the mechanisms of immediate allergic itching.

Virus infections are a major cause of chronic obstructive pulmonary disease (COPD) exacerbations. Recently, Toll-like receptor 3 (TLR3) has been demonstrated to react to double-stranded RNA (dsRNA) and to be involved in the immune responses after viral infections. In the present study, we examined whether oxidative stress, which is involved in the pathogenesis of COPD, enhances the responses of TLR3 in airway epithelial cells. The effect of hydrogen peroxide (H 2 O 2 ) on the release of IL-8 from BEAS-2B cells and primary human bronchial epithelial cells after stimulation with polyinosinepolycytidylic acid [poly(I:C)], a synthetic analog of viral dsRNA and a ligand for TLR3, and the signal transduction were examined. One hundred to 150 mM H 2 O 2 significantly potentiated the release of IL-8 from the epithelial cells after stimulation with 10 mg/ml poly(I:C). The H 2 O 2 -augmented IL-8 release was inhibited by treatment with N-acetylcysteine. One hundred micromoles of H 2 O 2 enhanced the translocation of nuclear factor (NF)-kB p65, but not that of interferon regulatory factor-3 (IRF-3), into the nucleus and the NF-kB DNA binding activity after poly(I:C) stimulation, which effect was inhibited not by the silencing of IRF-3 but by MG132, a proteasome inhibitor, or dexamethasone. One hundred micromoles of H 2 O 2 potentiated the TLR3 expression on the airway epithelial cells treated with poly(I:C). These data suggest that oxidative stress augments the response of TLR3 in airway epithelial cells via NF-kB and that this effect might be partly mediated by the enhancement of TLR3 expression. Modulation of this pathway may be a therapeutic target for viral-induced exacerbations of COPD.

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