The efficacy and safety, including arrhythmia and sudden death, 1 2 of intravenous methylprednisolone pulse (IVMP) therapy in patients with Kawasaki disease (KD) are uncertain. We conducted a control study in KD patients with persistent or recurrent fever (>37.5˚C) 48 hours after a single infusion of initial intravenous immunoglobulin (IVIG) 2 g/kg. At enrolment (day 1), the subjects were randomised to receive IVMP (30 mg/kg/day of methylprednisolone for three days), or additional IVIG (2 g/kg). Heparin was also continuously infused (15-20 units/kg/h) in the IVMP group. The study was halted prematurely because of adverse effects of IVMP when 22 patients were recruited; they accounted for 13% of KD patients treated with initial IVIG. The antipyretic effect of IVMP was superior to that of additional IVIG on day 2 (p = 0.02, repeated measures analysis), but not on day 3 and later (fig 1). The fraction of febrile patients was significantly lower in the IVMP group until day 3 (1/11 v 8/11, p , 0.001, Fisher exact test), but not on day 4 and later (6/11 v 6/11). Coronary artery dimensions and the prevalence of coronary artery lesions (2/11 v 3/11) were similar in the two groups. Regarding adverse effects, sinus bradycardia and hyperglycaemia occurred more often in the IVMP group (table 1). Hypertension occurred in 91% of the IVMP group, but the fraction did not differ significantly, probably due to the small sample size. All of the adverse effects were transient. There were no convulsions, gastrointestinal symptoms, infection, malignant arrhythmia, or sudden death in any subjects. KD patients refractory to initial IVIG should be treated with additional IVIG, 3 4 because IVMP induced faster but temporary resolution of fever and more adverse effects. Further investigations with steroid therapy are necessary to determine the indication and the appropriate dose in KD.
This study aimed to determine the effects of intravenous methylprednisolone pulse (IVMP) therapy on cytokine levels in patients with acute Kawasaki disease (KD) unresponsive to initial intravenous immunoglobulin (IVIG) therapy. Fifteen KD patients unresponsive to initial IVIG, 2 g/kg/day, were randomized to receive IVMP (n = 7), 30 mg/kg/day for 3 days or additional IVIG (n = 8), 2 g/kg/day, and plasma cytokine levels were compared. The fraction of febrile patients was significantly lower in the IVMP group than in the additional IVIG group on day 2 (0/7 vs. 3/8, p = 0.03), but not on day 4 and later (3/7 vs. 4/8, p = 1.00) because of recurrent fever. The prevalence of coronary lesions was similar between the two groups (2/7 vs. 2/8, p = 1.00). The ratios of plasma levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 to those at enrollment (defined as day 1) were significantly lower in the IVMP group on day 4 (0.50 +/- 0.27 vs. 1.01 +/- 0.46, 0.53 +/- 0.39 vs. 0.93 +/- 0.44, p = 0.02 and 0.045, respectively), but not on day 7 (0.54 +/- 0.34 vs. 0.88 +/- 0.39, 0.76 +/- 0.39 vs. 0.61 +/- 0.17, p = 0.07 and 0.83, respectively). The ratios of interleukin-2 receptor, interleukin-6, and vascular endothelial cell growth factor to those at enrollment did not differ significantly between the two groups. In conclusion, for KD patients unresponsive to initial IVIG, IVMP suppresses cytokine levels faster, but subsequently similarly, compared with additional IVIG.
Background:The need to promote novel drug development for advanced biliary tract cancer (ABTC) has emphasised the importance of determining whether various efficacy end points can act as surrogates for overall survival (OS).Methods:We conducted a literature search of randomised trials of first-line chemotherapy for ABTC and investigated correlations between efficacy end points and OS using weighted linear regression analysis. The ratios of the median OS, median progression-free survival (PFS), response rate, and disease control rate in each trial were used to summarise treatment effects. The surrogate threshold effect (STE), which was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS, was calculated.Results:Seventeen randomised trials with 36 treatment arms were identified, and a sample size of 2148 patients with 19 paired arms was analysed. The strongest correlation between all evaluated efficacy end points was observed between median OS and median PFS ratios (r2=0.66). In trials with gemcitabine-containing therapies and targeted agents, the r2-values were 0.78. The STE was estimated at 0.83 for all trials and 0.81 for trials with gemcitabine-containing therapies, and was not calculated for trials with targeted agents.Conclusions:The median PFS ratio correlated well with the median OS ratio, and may be useful for planning a clinical trial for novel drug development.
The response to warfarin is highly variable among individuals and such variability is likely to have some genetic basis. We evaluted the effect of VKORC1 polymorphisms on warfarin response among Japanese, taking advantage of its unique population structure in which CYP2C9 *2 and *3 alleles are relatively rare. Thirty-one patients (12-34 years old; median, 22) on warfarin were recruited from a pediatric cardiology clinic. Genotyping of the C>T polymorphism at position 1173 in intron 1 of VKORC1 revealed that 26 patients (84%) were T/T homozygotes at nucleotide 1173, whereas 5 (16%) were C/T heterozygotes. Complete linkage disequilibrium was observed between the 1173C > T polymorphism and another polymorphism, the 3730G > A, in the 3' untranslated region. The C/T heterozyogtes at the 1173C > T polymorphism tended to require more warfarin than the T/T homozygotes, when adjusted for international normalized ratio (p = 0.003). Both the 1173C > T polymorphism and the 3730G > A polymorphism are likely to be inert from a functional standpoint. Rather, based on the complete linkage disequilibrium between 1173C > T and 3730G > A polymorphisms, we suspect that the actual change that defines the relative resistance to warfarin may be present in the proximity of these two polymorphisms.
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