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Digoxin (DX) is mainly excreted unchanged in the urine. In patients undergoing hemodialysis (HD patients), the relative contribution of hepatic elimination is increased. DX is a substrate of OATP1B3 (SLCO1B3), expressed on the sinusoidal membranes of hepatocytes in humans. Therefore, we investigated the relationship between SLCO1B3 gene polymorphisms and the value of trough concentration-to-dose ratio (C/D ratio) of DX in HD patients. We investigated two deletion polymorphisms in complete linkage disequilibrium (-28 to -11 and -7 to -4) and two SNPs in complete linkage disequilibrium (T334G and G699A). Blood was sampled 62-72 hours after the oral administration of DX. The C/D ratio of DX was lower in patients with the deletion allele than in those homozygous for the insertion allele, and was lower in patients with the 334T/669G allele than in those homozygous for the 334G/699A allele, although the differences were not statistically significant. The C/D ratio of DX was significantly higher in patients with homozygous for the insert-variant allele (median: 121.8 (ng/mL)/(mg/week/kg), range: 92.5-259.4 (ng/mL)/(mg/week/kg) than in others (median: 93.4 (ng/mL)/(mg/ week/kg), range: 66.5-154.3 (ng/mL)/(mg/week/kg)). In conclusion, the insert-variant allele of the OATP1B3 gene may increase the C/D ratio of DX in HD patients.

AbstractBackgroundTerpenoids have gained attention as therapeutic agents for skeletal muscle atrophy owing to their various physiological activities. In this study, we screened four terpenoids for their therapeutic potential against muscle atrophy in cultured cells and evaluated the effectiveness of betulinic acid in two disuse muscle atrophy models.MethodsC2C12 cells were used as the skeletal muscle model in cell culture experiments. Betulinic acid (100 mg/kg, twice daily) was administered to two different mouse models of muscle atrophy (established using the sciatic denervation and casting methods) for 7 days.ResultsIn myotube experiments, the mRNA expression of atrogin‐1 and myostatin was significantly suppressed by betulinic and ursolic acids (P < 0.05). In the differentiation phase of C2C12 myotubes, the mRNA expression levels of myoD and myogenin were significantly increased by betulinic acid (P < 0.05). In addition, apelin and irisin were also significantly increased by betulinic acid (P < 0.05 and 0.01, respectively). Consequently, betulinic acid was administered to the aforementioned muscle atrophy models. Betulinic acid did not inhibit the decrease in skeletal muscle weight observed in the denervation model. However, it significantly inhibited the decrease in tibialis anterior (TA) and extensor digitorum longus (EDL) weights and grip strength observed in the cast‐immobilized skeletal muscle atrophy model (TA: Cast + Veh vs. Cast + Bet = 42.6 ± 1.0 vs. 46.0 ± 0.8 mg, P < 0.01; EDL: Cast + Veh vs. Cast + Bet = 9.0 ± 0.4 vs. 11.3 ± 0.5 mg, P < 0.01; grip strength: Cast + Veh vs. Cast + Bet = 222 ± 4.8 vs. 245 ± 3.6 g, P < 0.05). In addition, betulinic acid administration partially inhibited the decrease in skeletal muscle cross‐sectional area.ConclusionsBetulinic acid alleviated muscle atrophy in the cast model of muscle atrophy and has therapeutic potential for the treatment of immobilized disuse skeletal muscle atrophy.

[Background, Purpose] Metronidazole (MNZ), vancomycin (VCM), and fidaxomicin (FDX) are standard therapeutic drugs against Clostridioides difficile infection (CDI). MNZ resulted in lower clinical cure rate compared with VCM. Detail information about antibacterial activities of the drugs and reasons for MNZ inferiority are not clear. Therefore, we evaluated the in vitro antibacterial activities, and measured fecal concentrations in CDI mouse models. [Method] Minimum inhibitory concentration (MIC) against seven strains of C. difficile were determined. Time-kill curves and post-antibiotic effect (PAE) were determined against C. difficile ATCC®43255. In addition, fecal concentrations in CDI mouse models were measured. [Results] MNZ, VCM, and FDX geometric mean MIC were 0.91, 1.81, and 0.34 µg/mL, respectively. MNZ exhibited concentration-dependent and rapid antibacterial activities at low concentrations ranged from 0.5 to 2.0 µg/mL. On the other hands, VCM and FDX exhibited time-dependent and slow antibacterial activities at high concentrations ranged from 0.5 to 32 µg/mL. MNZ showed the shortest PAE (1.9 h). In addition, maximal fecal concentration of MNZ (21.7 µg/g) was significantly lower than that of VCM (222.7 µg/g) at the dose of 40 mg/kg. [Conclusion] MNZ exhibited noteworthy antibacterial activities against C. difficile. However, MNZ PAE was short, and the fecal exposure was significantly small. We think the two characteristics are responsibility for the MNZ inferiority in clinical cure rate.

[Introduction]Fluconazole is anti-fungal agent widely used to prophylaxis and treatment. In the ECIL6 Guidelines, it is recommended that the dose of FLCZ for treatment should be established as ≥10 to 15 mg/mL, which is a trough level. We report a patient in whom a specific interval was required until the blood concentration of FLCZ reached a steady state.[Case]The patient was a 50-year-old male. To treat acute lymphocytic leukemia, remission induction and consolidation therapies were performed. After remission was achieved, umbilical cord blood transplantation was conducted. On Day 18, graft survival was confirmed. A blood culture test on Day 27 detected yeast-like fungus. Micafungin (MCFG) at 150 mg, used for empiric therapy, was switched to liposomal amphotericin B (L-AMB) at 3 mg/kg. On Day 36, renal hypofunction was noted, and L-AMB was switched to MCFG at 150 mg. On Day 65, there was a decrease in the β-D-glucan level from ≥600 to 375.2 pg/mL, and MCFG at 150 mg was switched to FLCZ at 200 mg. On Day 71, the trough level of FLCZ was 21.0 mg/mL, and its concentration 2 hours after administration was 24.4 mg/mL. The β-D-glucan level was 232.1 pg/mL. On Day 79, the trough and 2-hour levels of FLCZ were 30.6 and 32.1 mg/mL, respectively, and the β-D-glucan level was 167.6 pg/mL. On Day 85, the trough level of FLCZ was 38.4 mg/mL, and the β-D-glucan level was 161.4 pg/mL. Subsequently, blood culture was negative, and FLCZ administration was continued until Day 229. During the administration period, the creatinine clearance ranged from 33.0 to 45.9 mL/min.[Discussion]The half-life of FLCZ is approximately 30 hours. Its clearance depends on the renal function. In the present case, a target trough level was achieved in the early phase, but the blood concentration of FLCZ increased with the prolongation of the administration period. Therefore, the appearance of central nervous toxicity must be considered. In the future, it may be necessary to establish individualized, optimized FLCZ dosimetry in accordance with the renal function for the optimal use of FLCZ.

Clostridioides difficile (C. difficile) colitis and pseudomembranous colitis are known as healthcare-associated intestinal infections. In this study, the incidence of C. difficile colitis and pseudomembranous colitis was investigated using the Japanese Adverse Drug Event Report (JADER). Using JADER data between April 2004 and September 2017, the patient who developed C. difficile colitis and pseudomembranous colitis were investigated. During the study period, 375 cases of C. difficile colitis and 903 cases of pseudomembranous colitis were reported. The numbers of reported cases of both C. difficile colitis and pseudomembranous colitis were largest in those in their 70s, accounting for 24.7% and 25.6%, respectively. Patients in their 60s-90s comprised the majority of all patients with both C. difficile colitis and pseudomembranous colitis. Both C. difficile colitis and pseudomembranous colitis were caused by antibiotics in many patients, and signals of all antibiotics were detected. In C. difficile colitis, signals of immunosuppressants, corticosteroids, and alkylating drugs were also detected among drugs other than antibiotics. For pseudomembranous colitis, the use of molecularly targeted drugs, antimetabolic drugs, and corticosteroids was reported other than antibiotics. Using JADER, we revealed risk factors for the development of C. difficile colitis and pseudomembranous colitis, and firstly revealed that molecularly targeted drugs other than antibiotics could also be potential risk factors. Our findings may be useful for the early detection of drug-induced C. difficile colitis and pseudomembranous colitis.