Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC sorafenib and AUC N-oxide , respectively). Inter-group comparison revealed that AUC N-oxide and AUC ratio (AUC N-oxide /AUC sorafenib ) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC N-oxide and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC N-oxide : 2.0 μg•day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC N-oxide ≤ 2.0 μg•day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.

Tottori University research result repository タイトル Title Shape selectivity in toluene disproportionation into para-xylene generated by chemical vapor deposition of tetramethoxysilane on MFI zeolite catalyst

The lattice Boltzmann method for multi-component immiscible fluids is applied to simulations of the behaviour of a drop in a square pipe flow for various Reynolds numbers of 10 < Re < 500, Weber numbers of 0 < We < 250 and viscosity ratios of h = 1/5, 1, 2 and 5. It is found that, for low Weber numbers, the drop moves straight along a stable position on the diagonal line of the pipe section, and it moves along the centre axis of the pipe for larger Weber numbers. We obtain the boundary of the two different behaviours of the drop in terms of Reynolds number, Weber number and viscosity ratio.

Enhancement of oral absorption of food allergens by non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, is considered an exacerbating factor in the development of food allergies. In this study, we examined the effect of aspirin on oral sensitization to and absorption of the egg-white allergen ovalbumin (OVA) in rats. The absorption of OVA was evaluated by measuring the plasma concentration of OVA after oral administration by gavage. To evaluate oral sensitization to OVA, plasma levels of immunoglobulin (Ig) E and IgG1 antibodies (Abs) specific to OVA were determined by enzyme-linked immunosorbent assay after initiation of sensitization. High-dose aspirin (30 mg/kg) increased oral OVA absorption and plasma levels of OVA-specific IgE and IgG1 Abs compared with those observed in vehicle-treated rats. In contrast, low-dose aspirin (3 mg/kg) exerted no changes in either absorption or sensitization. Spermine, an absorption enhancer, increased the oral absorption of OVA to nearly the same extent as high-dose aspirin, whereas the plasma levels of OVA-specific IgE and IgG1 Abs exhibited no significant differences between spermine- and vehicle-treated rats. Among the NSAIDs, diclofenac and indomethacin increased sensitization to OVA, similar to high-dose aspirin, but meloxicam exerted no effects on Ab levels. In conclusion, we showed that high-dose aspirin enhanced oral sensitization to OVA. Our study suggests that enhanced oral sensitization to OVA cannot be ascribed to increased absorption of OVA from the intestinal tract. Although the mechanisms underlying this enhancement of sensitization are still controversial, our study suggests that modification of cytokine production due to impairment of the intestinal barrier function and inhibition of cyclooxygenase-1 activity by aspirin may be involved.

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