Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Attentional selectivity,automaticity, and self-efficacy predict simulator-acquired skill transfer to the clinical environment

Introduction

Several studies demonstrated that simulator-acquired skill transfer to the operating room is incomplete. Our objective was to identify trainee characteristics that predict the transfer of simulator-acquired skill to the operating room.

Tween 40-based precipitate production observed on modified chromogenic agar and development of biological identification kit for Malassezia species.

We developed a simple identification kit for nine species of Malassezia (M. furfur, M. slooffiae, M. sympodialis, M. restricta, M. obtusa, M. globosa, M. pachydermatis, M. dermatis, and M. japonica) based on their biological features. This method utilizes Tween 40-based precipitate production on modified chromogenic agar (CHROMagar) Malassezia medium, growth on specific agars (Sabouraud's dextrose agar, Cremophor EL agar, Tween 60-esculin agar), and catalase reactions. This identification kit was verified with 11 type and reference strains of nine Malassezia species. An additional 26 clinical isolates were also successfully identified using the kit and the results were confirmed by molecular biological analysis.     

A novel quinolinone diuretic, M12285, and its activation mechanism through sulfate conjugation.

The diuretic activity of a quinolinone oxime diuretic, M12285, was examined after renal arterial, i.v. and portal injection in rats. M12285 injected into the renal artery at a dose of 1 mg/kg caused no diuretic effect, whereas i.v. and portal injections induced marked diuresis dose dependently. The minimum effective dose with portal injection was lower (1 mg/kg) than that with i.v. injection (3 mg/kg) and the start of the effect was faster with portal injection. These results indicated that some metabolic modification in the liver is necessary for the diuretic activity to appear. Accordingly, we performed in situ rat liver perfusion with M12285 and obtained several metabolites. Renal arterial injection of each fractionated metabolite of M12285 revealed that all the diuretic activity derived from one of these metabolites. From IR and 1H-nuclear magnetic resonance (1HNMR) measurements, the chemical structure of this active metabolite was assumed to be a sulfate-conjugated form of M12285 at the oxime moiety. Based on this tentative chemical structure, we synthesized the oxime sulfate of M12285 (potassium salt, M17000) and confirmed the identity of IR and 1HNMR spectra. Administration of M17000 into the renal artery induced apparent diuresis in a dose-dependent manner in both rats and dogs. These results indicate that the oxime sulfate of M12285 is responsible for the diuretic activity of M12285. Therefore, we synthesized several derivatives of M17000 and confirmed their possible therapeutic value as a novel family of diuretics, namely quinolinone oxime sulfonic acids.     

Aneurysms of the anterior communicating artery and subclavian artery in association with congenital absence of unilateral internal carotid artery]

We encountered a rare case of unilateral internal carotid arterial defect complicated with anterior communicating aneurysm and subclavian artery aneurysm. The patient was a 56-year-old man in whom cerebral angiography and 3D-CTA revealed defects in the right internal carotid artery and the right carotid canal, and an unruptured aneurysm in the anterior communicating artery. In addition, the patient was also found to have an unruptured aneurysm in the right subclavian artery. As both the aneurysms were considered to have a high risk of rupture and such subclavian aneurysms were likely to cause an embolism, radical surgery was performed for each aneurysm. The postoperative course was uneventful, and the patient was discharged without ambulatory limitations. Although the defect in the internal carotid artery is a relatively rare vascular deformity, the incidence of cerebral aneurysm is about 30% in such cases due to the marked hemodynamic stress involved. On the other hand, there have been only two previous case reports of internal carotid arterial defect complicated with a subclavian aneurysm. Moreover, there have been no previous reports of internal carotid arterial defect complicated with both an intracranial aneurysm and a subclavian aneurysm, as observed in the present case. Thus, this case was very rare and is reported here.     

Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity

Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC+CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen alpha1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-alpha production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen alpha1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.     

Time-resolved particle image velocimetry and laser doppler anemometry study of the turbulent flow field of bileaflet mechanical mitral prostheses

Dynamic particle image velocimetry (PIV) was applied to the study of the flow field associated with prosthetic heart valves. The results were compared with those of laser Doppler anemometry (LDA). Anatomically and antianatomically oriented Jyros (JR) and St. Jude Medical (SJM) valves were compared in the mitral position to study the effects of valve design on the downstream flow field. The experimental program used a dynamic PIV system utilizing high-speed, high-resolution video to map the true time-resolved velocity field inside the simulated ventricle. This system was complemented by a study using the more traditional LDA system for comparison. Based on the experimental data, the following general conclusions can be made. High-resolution dynamic PIV can capture true chronological changes in the velocity and turbulence fields. It also produces very detailed velocity and turbulence information comparable to the LDA results. In the vertical measuring plane that passes both the center of the aortic and mitral valves (A-A section), the two valves (the SJM and the JR) show distinct circulatory flow patterns when the valve is installed in the antianatomical orientation. Small differences in valve design can generate noticeable differences, particularly during the accelerating flow phase. The SJM valve maintains a relatively high velocity through the central orifice; the curved leaflets of the JR valve generate higher velocities with a divergent flow during the accelerating and peak flow phases. In the velocity field directly below the mitral valve and normal to the previous measuring plane (B-B section), where characteristic differences in valve design will be visible, symmetrical twin circulations were observed because of the divergent nature of the flow generated by the two inclined half-disks installed in the antianatomical orientation. The SJM valve, with a central downward flow near the valve, is contrasted with the JR valve, which has a peripheral downward circulation with higher, turbulent stresses.     

Seeligeriolysin O, a protein toxin of Listeria seeligeri, stimulates macrophage cytokine production via Toll-like receptors in a profile different from that induced by other bacterial ligands

Seeligeriolysin O (LSO), a member of cholesterol-dependent cytolysins of Listeria seeligeri, exhibits cytokine-inducing activity. In this study, we examined the profile of cytokines expressed in macrophages of mice after stimulation with full-length form of recombinant LSO (rLSO530), C-terminal-truncated protein (rLSO483) and two authentic cytokine-inducing Toll-like receptor (TLR) ligands from bacteria, peptidoglycan (PGN) and LPS. Both rLSO530 and rLSO483 were able to induce IL-12 p40 and IL-12 p70 more strongly in macrophages than PGN or LPS. In contrast, IFN-beta and nitric oxide were induced by LPS but not by rLSO530, rLSO483 or PGN. In the presence of exogenously added IFN-beta, IL-12 p40 and IL-12 p70 production was inhibited after LSO stimulation, but IL-12 p70 production was enhanced after PGN stimulation. Although LSO signaling appeared to be associated with both TLR2 and TLR4, the profile of cytokine production by LSO stimulation was distinct from those by stimulation with PGN or LPS. Thus, it was shown that LSO is a unique bacterial ligand that induces macrophage cytokine production in a manner different from PGN or LPS.     

Gamete development inPlasmodium berghei regulated by ionic exchange mechanisms

Ionic regulation in the induction of exflagellation ofPlasmodium berghei was investigated by culturing the parasites in various isotonic media. Of the salts tested, NaHCO₃ exhibited the highest activity in inducing exflagellation, whereas KHCO₃ showed no activity. In the absence of HCO ₃ ^– , media containing monovalent cation (Na⁺, K⁺, Cs⁺, Rd⁺, choline⁺, lysine⁺, arginine⁺) and Cl^– also induced exflagellation, but their activities were lower than that of NaHCO₃. Anions of Br^– or NO ₃ ^– could be substituted with Cl^–, whereas other anions such as I^–, NO ₂ ^– , SO ₄ ^2– , SCN^–, H₂PO ₄ ^– , or HPO ₄ ^2– failed to induce exflagellation, as did tetramethylammonium-Cl, CaCl₂, MgSO₄, MgCl₂ and sucrose as well. These results suggest that the induction of exflagellation requires the presence of Na⁺ and HCO ₃ ^– or monovalent, membrane-permeable cation and Cl^– in the medium. Measurements of the efflux of H[¹⁴C]O ₃ ^– or Cl^– indicated that these anions were released from the cells into the NaCl or the NaHCO₃ medium, respectively, probably by exchange in HCO ₃ ^– /Cl^–. Determination of intracellular ionic concentrations by electron microscopic X-ray microanalysis of cryopreserved specimens revealed that in the NaHCO₃ medium, external Na⁺ (and probably HCO ₃ ^– ) enters the gametocytes by exchange with internal Cl^– (and probably H⁺), whereas in Cl^–-containing media, external unspecified cation and Cl^– influx by exchange, probably with H⁺ and HCO ₃ ^– . It is therefore suggested that two separate ion exchangers, i.e., Na⁺-dependent HCO ₃ ^– (in)/Cl^–(out) and nonspecific monovalent-cation-dependent Cl^–(in)/HCO ₃ ^– (out) exchangers, are involved in the induction of gametogenesis inP. berghei. Furthermore, the presence of both classes of anion in the medium enhanced exflagellation activity and increased Na⁺ uptake more than did the NaCl or NaHCO₃ medium alone. The apparent synergistic enhancement by two contraactive anion exchangers is consistent with a recycling model of pH_i regulation, in which HCO ₃ ^– and Cl^– are exchanged between the cells and the media, resulting in the acceleration of monovalent cation/H⁺ exchange.This work was supported by a Grant-in-Aid (No. 01570212) from the Ministry of Education, Science and Culture, Japan and the Ohyama Health Foundation, Japan (to FK), and in part by the Medical Research Council, United Kingdom (to RES)