Drug interactions between ALK inhibitors and warfarin with concurrent use of bucolome: a case report.

BACKGROUND: Alectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking. CASE PRESENTATION: We report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2-3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake. Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome. CONCLUSIONS: Close monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.

Utility of a Score for Predicting Glomerular Filtration Rate Overestimation in Patients with Cardiovascular and Renal Diseases and Their Risk Factors.

Objective We recently reported a novel score for the detection of glomerular filtration rate (GFR) overestimation using a creatinine-based equation. We examined the utility of this score in patients with cardiovascular/renal diseases and diabetes mellitus. Methods We enrolled 1,425 patients (65±15 years old; 37% women) who were admitted to our hospital for the management of cardiovascular and renal diseases and their risk factors. Overestimation of the GFR (OE) was defined as a creatinine-based GFR (eGFRcre) ≥120% of the cystatin C-based estimated GFR. The OE score was calculated as the sum of the scores for the body weight, hemoglobin concentration, and blood urea nitrogen (BUN)/serum creatinine (Scr), totaling 1 point if the body weight was <63.0 kg in men or <42.0 kg in women, 1 point if the hemoglobin concentration was <12.4 g/dL in men or <11.0 g/dL in women, and 1 point if the BUN/Scr was >26.5. Results The proportion of patients with OE was 14.2%. The score predicted OE with a sensitivity of 70.8% and a specificity of 99.6%, and the sensitivity was increased in patients ≥75 years old (88.3%) and decreased in diabetics (58.6%). When patients were divided into subgroups by the total score, the frequencies of OE were 8% (59/754), 14% (72/502), 38% (58/151), and 72% (13/18) in patients with scores of 0, 1, 2, and 3, respectively. Conclusion The OE score is useful for detecting elderly cases of cardiovascular and renal diseases in which eGFRcre overestimates the GFR, although its utility is limited in diabetics.

Potential drug-drug interactions in the era of integrase strand transfer inhibitors: a cross-sectional single-center study in Japan.

BACKGROUND: Potential drug-drug interactions (PDDIs) commonly occur because of aging and comorbidities in people living with human immunodeficiency virus (HIV; PLWH). Protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been reported to cause PDDIs in these patients. However, there are few reports of PDDIs in the era of treatment using integrase strand transfer inhibitors. Therefore, we investigated PDDIs in Japanese PLWH receiving antiretroviral drugs (ARVs). METHODS: This was a cross-sectional observational study conducted in Japanese outpatients. All eligible patients who had received ARV therapy for at least 48 weeks were enrolled. The primary endpoint was the incidence of PDDIs detected using the Lexicomp® interface. RESULTS: Of the 71 eligible patients, 51 (71.8%) were prescribed concomitant non-ARV medications. In 21 patients (29.6%), PDDIs with the potential to reduce the effects of ARVs occurred, although the HIV load was suppressed in all cases. Polypharmacy (the use of ≥5 non-ARVs) was observed in 25 patients (35.2%). There was a significantly higher median number of non-ARV medications in the PDDI group than in the non-PDDI group (6 vs. 3, P <  0.001). Furthermore, the proportion of patients on polypharmacy was significantly higher in those with PDDIs than in those without PDDIs (81.0% vs. 26.7%, P <  0.001). CONCLUSIONS: The incidence of PDDIs is relatively high in Japanese PLWH, even in the era of treatment using integrase strand transfer inhibitors. Therefore, it is important for patients and health care providers to be constantly aware of PDDIs associated with ARV treatment.

Japanese Traditional Miso and Koji Making.

Miso is a traditional Japanese seasoning paste produced by fermenting soybeans using the power of koji mold. A recent Japanese cohort study has shown that increased consumption of fermented soybean products is associated with a reduced risk of death in both men and women. In this review, we briefly explain what miso means in the Japanese culture and food industry, varieties of miso available today, and steps involved in miso making. Then, we review early and latest scientific researches in koji mold species, their safety, and beneficial enzymes they produce during fermentation and maturation processes, which play a major part in determining the quality and sensory profile of miso.

[Efficacy and Safety of Linaclotide in Elderly Patients].

The efficacy and safety of linaclotide in elderly patients are poorly understood. Herein, we aimed to assess the efficacy and safety of linaclotide in elderly patients in real-world setting. We retrospectively enrolled consecutive patients who started linaclotide therapy at Sapporo Medical University Hospital from October 1, 2017 to December 31, 2019. The efficacy and safety of linaclotide were examined in relation to various factors, including age (<65 or ≥65 years) and dose (0.25 or 0.5 mg/d). Fifty-two patients were enrolled, 60% of whom were over 65 years old and 40% were female. Thirty-six patients received a linaclotide dose of 0.25 mg/d. The most common side effect was diarrhea, but there was no difference in the incidence of diarrhea between the elderly (64.5%) and non-elderly patients (42.9%, p=0.130). No significant difference was observed with respect to improvement in constipation in the elderly (83.9%) and non-elderly patients (71.4%, p=0.318). Additionally, the difference in efficacy of linaclotide in patients who received a reduced dose (80.6%) vs. those who received the recommended dose (75.0%) was not statistically significant (p=0.719). Multivariate analysis revealed that age, gender, and dose were not associated with diarrhea induced by linaclotide treatment. However, concurrent treatment with constipation-inducing medications [odds ratio (OR) 5.79, p=0.047] and linaclotide monotherapy (OR 11.1, p=0.040) were both risk factors contributing to diarrhea. Linaclotide is effective and safe for use in elderly patients. The incidence of diarrhea may increase when linaclotide is administered alone or concurrently used with medications that cause constipation.

[Association Suvorexant and Ramelteon Use with the Risk of Falling: A Retrospective Case-control Study].

Sedative hypnotics are among the classes of drugs reported to influence falls. However, the effects of the sedative hypnotic drugs, suvorexant and ramelteon, on falls are not well known. Therefore, we conducted this retrospective case-control study to examine the association of the use of these two sedative hypnotics with the risk of falls. Conducted at the Sapporo Medical University Hospital in Japan, our study included 360 patients with fall incidents and 819 randomly selected control patients. Patients in the fall group were significantly older with a lower body mass index, and had a history of falls, disabilities in activities of daily living, cognitive impairment, and delirium. Monovariate analysis revealed that patients in the fall group frequently used ramelteon [odds ratio (OR) 2.38, 95% confidence interval (CI): 1.49-3.81, p<0.001], but rarely used suvorexant (OR 0.66, 95% CI: 0.29-1.39, p=0.317), compared with control patients. Furthermore, multivariate analysis revealed that ramelteon use did not increase the risk of falls (adjusted OR 1.43, 95% CI: 0.82-2.48, p=0.207), whereas suvorexant use significantly decreased the risk of falls (adjusted OR 0.32, 95% CI: 0.13-0.76, p=0.009). Although ramelteon tends to be used in patients at a high risk of falls, it may not increase the risk of falls. In contrast, the use of suvorexant may reduce the risk of falls.

Overestimation of glomerular filtration rate by creatinine-based equation in heart failure patients is predicted by a novel scoring system.

AIMS: Creatinine-based estimated glomerular filtration rate (eGFRcre) has been shown to overestimate the glomerular filtration rate (GFR) when it is compared with cystatin C-based estimated GFR (eGFRcys) in older people. We investigated clinical determinants of GFR overestimation by eGFRcre and developed a score for prediction of GFR overestimation (OE) in heart failure patients. METHODS: We retrospectively examined 244 Japanese heart failure patients (aged 72.2 ± 13.1 years; 48% women) who had no known extrarenal factors that affect serum cystatin C concentration. eGFR OE by eGFRcre was defined as eGFRcre being ≥120% of cystatin C-based eGFR. RESULTS: The proportion of heart failure patients with OE was 14.3%. Patients with OE were older, had lower body weight and total skeletal muscle mass than those in patients without OE. Laboratory examinations showed that hemoglobin concentration was lower, and the ratio of blood urea nitrogen-to-creatinine was higher in patients with OE than in patients without OE. In multivariate regression analysis, body weight (<63.0 kg in men and <42.0 kg in women), hemoglobin level (<12.4 g/dL in men and <11.0 g/dL in women) and ratio of blood urea nitrogen-to-creatinine (>26.5) in addition to skeletal muscle mass were independently associated with OE. A score calculated by using cut-off levels of body weight, hemoglobin concentration and ratio of blood urea nitrogen-to-creatinine predicted OE with a sensitivity of 97.1% and a specificity of 98.1%. CONCLUSION: Overestimation of GFR by eGFRcre is predictable by a novel scoring system, which might be useful for the detection of patients who require cystatin C-based eGFR measurement for accurate assessment of renal function. Geriatr Gerontol Int 2020; 20: 752-758.

Long-term intake of miso soup decreases nighttime blood pressure in subjects with high-normal blood pressure or stage I hypertension.

The present study aimed to investigate the effects of the combination of Marukome Nenrin miso, which has natriuretic effects, and Marukome MK-34-1 miso, which has potent angiotensin converting enzyme inhibitory effects, on blood pressure (BP) in humans. A total of 40 subjects aged 40-69 years with high-normal BP or stage I hypertension were randomly assigned to two groups: 1) the miso group (32 g 2:1 w/w Nenrin and MK-34-1 with 3.8 g salt/day) or 2) the control soy food group (14.4 g soy food with 0.2 g salt/day). The levels of major nutrients were equal in the miso and control food servings, except for the fiber and Na levels, which were higher in the miso food serving. Daytime and nighttime BP were measured with an automated BP monitor. Compared with the soy food intake, miso intake for 8 weeks did not affect daytime clinical BP but significantly decreased nighttime BP without affecting pulse rate (PR). Moreover, miso shifted the nighttime BP profile to lower levels than those at baseline. Soy food intake did not change the nighttime BP profile after 8 weeks. Miso intake also tended to reduce nighttime BP in a subgroup with stage 1 hypertension compared with the results of the soy food group participants and shifted the nighttime BP profile toward lower levels than those recorded at baseline. Miso intake did not influence lipid or glucose metabolism. In conclusion, this is the first report showing that miso reduces nighttime BP in humans. Miso may do so by shrinking the fluid spaces in the body and/or deactivating the adrenergic nervous system.

Newly manufactured Marukome MK-34-1 miso with angiotensin-converting enzyme inhibitory activity and its antihypertensive effects in genetic hypertensive rat models.

We newly manufactured miso rich in angiotensin-converting enzyme (ACE) inhibitory activity (Marukome MK-34-1, shinki miso) and investigated its antihypertensive properties in rat models of genetic hypertension. ACE inhibitory activity was tenfold higher in shinki miso than in commercially available Marukome Nenrin miso (nenrin miso). The inhibitory activity of shinki miso was confined to <3 kDa fractions and was detected in several fractions with high polarity by C18 high-performance liquid chromatography. Systolic blood pressure (SBP) increased age-dependently in stroke-prone spontaneously hypertensive rats (SHRSP/Izm) given a 0.6% (w/v) NaCl solution (salt solution group) that matched the salt content of the miso solutions. This SBP increase was attenuated in both the 5% nenrin and 5% shinki miso solution groups compared to the salt solution group. The reduction in SBP was greater in rats fed shinki than in rats fed nenrin miso. Similarly, in a salt-induced hypertension model with Dahl rats, the 5% nenrin miso solution attenuated the rising SBP observed in the salt solution group. Moreover, combining 5% nenrin miso with 5% shinki miso (2:1, v/v) (awase miso group) significantly decreased the SBP per gram salt intake by 8% compared with the nenrin miso treatment. However, there were no differences in urinary Na excretion between the nenrin and awase miso groups. In conclusion, we produced a new miso with potent ACE inhibitory activity that reduced spontaneous and salt-induced hypertension. These results suggest that salt sensitivity is decreased by the addition of shinki miso to nenrin miso.

Identification of Rice Koji Extract Components that Increase ß-Glucocerebrosidase Levels in Human Epidermal Keratinocytes.

Rice miso contains many ingredients derived from rice koji and has been a valuable source of nutrition since ancient times. We found that the consumption of rice miso led to improvements in the moisture content of cheek stratum corneum, skin viscoelasticity, and skin texture. Further, rice miso extract was found to increase the mRNA expression and activity of β-glucocerebrosidase (β-GCase), an enzyme involved in ceramide synthesis in the stratum corneum, in cultures. In this study, we identified the lipid-derived components of rice koji that increase the β-GCase activity in cultured human epidermal keratinocytes. The methanol fraction of rice koji extract induced an increase in the mRNA expression and activity of β-GCase in keratinocytes. The active fraction of rice koji was found to contain phosphatidic acid (PA) and lysophosphatidic acid (LPA). The total PA concentration in rice koji was 973.9 ng/mg dry weight, which was 17.5 times higher than that in steamed rice. Among the molecular species, PA_18:2/18:2 was the most frequently found. The total LPA concentration in rice koji was 29.6 ng/mg dry weight, and 2-LPA_18:2 was the most frequently found LPA. Since PA and LPA increase the mRNA expression and activity of β-GCase in keratinocytes, they are thought to be the active ingredients in rice koji that increase the β-GCase levels in human epidermal keratinocytes.

Novel antimicrobial activities of a peptide derived from a Japanese soybean fermented food, Natto, against Streptococcus pneumoniae and Bacillus subtilis group strains.

We recently isolated a tumoricidal peptide from Natto, a Japanese traditional fermented food. In the present study, antimicrobial activity of the Natto peptide was examined. The peptide consisted of 45 amino acid residues, and its structure was predicted to be rich in α-helix. It excreted antimicrobial activity only against Streptococcus pneumoniae and Bacillus subtilis group (B. subtilis, Bacillus pumilus, and Bacillus licheniformis). Lesser antimicrobial activity was observed for Streptococcus species other than S. pneumoniae. Hemolysate or hemin was required for the antimicrobial activity of the peptide. The Natto peptide damages the cell membrane of B. subtilis. On the other hand, chain morphology was induced in S. pneumoniae, which is naturally diplococcus, during the early phases of the Natto peptide treatment; following that the cells were rapidly lysed. This suggested that the Natto peptide displayed a novel narrow spectrum of bactericidal activity and inhibited cell separation during cell division of S. pneumoniae.

Adaptive Cross-Resistance to Aminoglycoside Antibiotics in Pseudomonas aeruginosa Induced by Topical Dosage of Neomycin.

BACKGROUND: Topical antimicrobial formulations containing neomycin are commonly used to prevent and treat burn infections. However, Pseudomonas aeruginosa shows rapid acquisition of adaptive resistance to neomycin. This study aimed to evaluate the survival of P. aeruginosa during exposure to neomycin at high concentrations comparable to those used in topical formulations, and to investigate the effect of adaptive resistance to neomycin on the susceptibility to other aminoglycosides. METHODS: Strain IID1130 [neomycin minimal inhibitory concentration (MIC) = 4 µg/ml] was incubated on an agar medium containing neomycin at high concentrations (8-4,096 µg/ml), and growing colonies were macroscopically observed. Acquisition of adaptive resistance was examined for 5 P. aeruginosa strains. Cells were sequentially passaged on agar medium containing neomycin with step-wise increased concentrations (8-2,048 µg/ml). To assess reversion of antibiotic susceptibility, the resulting colonies were repeatedly subcultured on antibiotic-free agar plates. RESULTS: Growing IID1130 colonies were macroscopically detected on a neomycin-containing (2,048 µg/ml) agar plate for 48 h. These cells showed increasing MIC for not only neomycin, but also gentamicin and amikacin; the MIC values were occasionally higher than the breakpoints. When the adapted cells were subcultured on antibiotic-free agar, several passages were required for reversion of susceptibility. CONCLUSIONS: Our findings suggest that P. aeruginosa can survive in the presence of neomycin with a concentration typically used in topical dosage forms, and that the acquired adaptive resistance is persistent and is accompanied by cross-resistance to other aminoglycosides.

Plasma tenofovir trough concentrations are associated with renal dysfunction in Japanese patients with HIV infection: a retrospective cohort study.

BACKGROUND: Plasma tenofovir (TFV) trough concentrations may be relevant for tenofovir disoproxil fumarate (TDF)-induced renal dysfunction. The purpose of this study was to determine the association between plasma TFV trough concentrations and TDF-induced renal dysfunction in Japanese patients with human immunodeficiency virus (HIV) infection. METHODS: A 48-week, retrospective cohort study was performed with Japanese patients with HIV infection who started a TDF-containing combination antiretroviral therapy regimen. Plasma TFV trough concentrations were obtained at steady state. The following variables were included in the analysis: sex, age, body weight, body mass index (BMI), serum creatinine, CD4+ cell count, HIV-RNA, concomitant medications, comorbidities, plasma TFV trough concentrations, and estimated glomerular filtration rate (eGFR). For comparisons of variables, we used Mann-Whitney U tests or Fisher's exact tests. Then, variables associated with renal dysfunction in the univariate analysis were entered into correlation analysis. RESULTS: The analysis included 11 patients. The rate of decrease in eGFR was significantly correlated with body weight (Spearman correlation = -0.645, p = 0.041), BMI (Spearman correlation = -0.682, p = 0.031), and plasma TFV trough concentrations (Spearman correlation = 0.709, p = 0.025). CONCLUSIONS: Despite the small sample size, our findings suggest that higher plasma TFV trough concentrations may cause TDF-induced renal dysfunction. To prevent TDF-induced renal dysfunction, we propose that individual monitoring of plasma TFV trough concentrations should be performed in Japanese patients with HIV infection.

Novel histone deacetylase inhibitors: N-hydroxycarboxamides possessing a terminal bicyclic aryl group.

Utilizing tranexamic acid as a starting material, a series of N-hydroxycarboxamides were synthesized in order to seek new histone deacetylase (HDAC) inhibitors. Further structure optimization involving the replacement of the 1,4-cyclohexylene group with the 1,4-phenylene group yielded the promising HDAC inhibitors which possess a terminal bicyclic aryl amide.