薬理と治療

Background　Empirical antimicrobial therapy in the treatment of infectious diseases can target both methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, often with a combination of broad-spectrum antimicrobials and vancomycin（VCM）. Recently, it was reported that VCM causes acute kidney injury （AKI）when used in combination with tazobactam -piperacillin（TAZ/PIPC）. While VCM is also used in combination with meropenem （MEPM）and cefepime（CFPM）, there have been no reports of AKI in these groups of patients according to a comparison among these three groups during the same period in Japan. Methods　In this study, we compared the incidence of AKI among the TAZ╱PIPC group, MEPM group, and CFPM group, all of which are used in combination with VCM. The subjects were patients who used the combination of VCM and each antimicrobial from April 2015 to March 2017 in Fukuoka University Hospital. Results　The incidence of AKI was 29.7％ in the TAZ╱PIPC group, which was significantly higher than that in the other groups（P＜0.01）. The average occurrence of AKI was 3.4 days （median: 3 days）after the start of combination therapy. Conclusions　The present findings suggest that when VCM is administered with TAZ╱PIPC in combination, not only should the blood concentration of VCM be noted, but the renal function should also be closely monitored early after the start of administration.

Background　A high incidence of adenocarcinomas in colorectum can be induced by weekly subcutaneous injection of 1,2-dimethylhydrazine in rats. Administration of dextran sulfate sodium subsequent to a single intraperitoneal injection of azoxymethane can induce chronic ulcerative colitis in mice, resulting in an increase in incidence of high-grade dysplasia and adenocarcinomas of colorectum. Thymidylate synthase and thymidine kinase, key enzymes in the de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively, are highly active in rapidly proliferating tissues. Methods　In the present study, we investigated the roles of these enzymes in colorectal carcinogenesis in two experimental animal model series. Results　Well and poorly differentiated adenocarcinomas showed high activity of thymidine kinase in distal colon and high activity of thymidylate synthase in proximal colon in rats, respectively. Colorectal carcinogenesis developed with the increasing duration of chemically induced diarrhea in carcinogen-pretreated mice. On the contrary, sulphasalazine, anti-ulcerative colitis drug, markedly reduced the tumorous regions with high-grade dysplasia in the colorectum of mice. Conclusions　These two isolated animal models may provide valuable insight into the mechanisms involved in colorectal carcinogenesis; i.e. repeated carcinogen exposure or repeated mucosal necrosis-regeneration in ulcerative colitis facilitates colorectal carcinogenesis.

Objective　This study aimed to examine the effects of“Fushi-jiman（gel type）”on the knees, shoulders, and/or waist joints in healthy Japanese adult subjects“. Fushi-jiman（gel type）”contains multiple wild plant components, such as glucosamine hydrochloride, sodium chondroitin sulfate, and boswellia serata extract. Methods　We conducted a randomized, double-blind, placebo-controlled, parallel-group trial from November 1, 2019 to April 3, 2020. The effects of“Fushi-jiman（gel type）”on the knee joints of 66 healthy Japanese adult subjects was examined. Subjects were randomly assigned to groups in which“Fushi-jiman（gel type）”（Fushi-jiman group）or placebo ointment（P group） （n＝33 per group）was applied. Randomization was performed using a computerized random number generator. The“Fushi-jiman（gel type）”or placebo ointment was applied twice per day for four weeks. Changes in the total score for the Japanese Knee Osteoarthritis Measure （JKOM; primary outcome）, other parameters of the JKOM, and subjective symptoms regarding the quality of life were assessed. Results　Data were analyzed with the intention to treat. Each group consisted of 33 subjects. After four-week of intervention, in JKOM, the total score, the visual analog scale of knee pain, and the scores of“General activities”and“Health conditions”significantly improved in the Fushi-jiman group compared to the P group. No adverse events were observed. Conclusions　These results suggest that“Fushi-jiman（gel type）”reduces discomfort in the knee joints of healthy Japanese adults. Trial Registration：UMIN-CTR: UMIN000038450 Foundation：YASOUKOUSO Co., Ltd.

Objectives　In this paper, we designed a randomized double-blind placebo-controlled methodology for verifying the clinical effects of a lotus-root extract as antiallergic components. Accordingly, we will report the therapeutic capabilities of the extract against some kind of eye-and nose-corresponding allergy. Methods　As the test food, a granular powder（3.0 g/package）containing a lotus-root extract （1.70 g）, maltodextrin（1.24 g）and a moisture-proof agent（0.06 g）, was used for oral ingestions of the powder to our test volunteers twice a day（total: 6.0 g powder）for 8 weeks. The control experiment was carried out in the same manner, except ingesting the equal amount of a placebo food. Forty healthy volunteers ranging in age from 20-56（nineteen subjects in their 20 s, nine subjects in their 30 s, seven subjects in their 40 s, and five subjects in their 50 s）participated in our clinical trial equipped with the above︱mentioned methodology. We divided them into two groups（n＝20）: placebo︱control group, 9 men and 11 women（mean age ±SD: 33.5 ±11.5）; and test group, 10 men and 10 women（mean age±SD: 32.7 ±10.8）. To observe the clinical effects derived by continuous consumption of the test food for 8 weeks, we measured possible primary╱secondly endpoints for eye- and nose-corresponding allergy. Results　In order to investigate variations in our volunteersʼ allergic conditions during their continuous consumption of the test food, we compared them to a placebo-control group. To begin with, the nose-related conditions in the test group were better than those in the control group, although no significant difference in the endpoint could be detected. Nevertheless, it was quite obvious that the test-food intake revealed remarkable improvements of our volunteersʼ allergies, especially in eye-related ones（P＜0.05）. All through this trial, there were no subjects who complained about any kind of side effect. Conclusions　We designed a randomized double-blind placebo-controlled methodology, andinvestigated the improvement effects with a lotus-root extract in eye- and nose-related allergic conditions. Our experimental results strongly suggest that daily ingestion of lotus root-derived functional foods can improve some kind of allergic reaction, especially in eye-corresponding one.（ UMIN ID: UMIN000038255）

Objective　We investigated how adding kiwi fruit juice powder to a whey protein drink impacts blood amino acid levels and defecation status. Methods　This 2⊠2 randomized, placebo-controlled, double-blind, crossover trial included healthy Japanese subjects（n＝10）who consumed unspecified protein supplements and defecated 3-5 times a week. They were randomly divided into two groups（n＝5 per group）using a computerized random-number generator. One group consumed a protein drink including the kiwi fruit juice powder（KFJP consumption-period）; the other consumed a protein drink containing a placebo additive（Placebo consumption-period）. The subjects consumed their assigned drink daily over a two-week intervention period followed by a one-week washout period. Study outcomes included evaluation of blood amino acid levels and defecation status. Results　All 10 subjects completed the study. In the KFJP drink-period, the incremental area under the curve（IAUC）of total blood amino acids was significantly higher than the Placebo drink-period（P＜0.05）and a subgroup analysis revealed that the subjects having hard stools initially experienced a significant increase in stool volume two weeks after consuming the KFJP drink（P＜0.05）. No adverse events relating the test drinks were reported. Conclusions　A significant increase in the IAUC of total amino acids was observed for those who ingested whey protein containing kiwi fruit juice powder. Furthermore, subjects reporting hard stools initially, experienced a significant increase in stool volume after two weeks of consuming the whey protein drink containing kiwi fruit juice powder. Trial registration　UMIN-CTR: UMIN000039280 Foundation　NOF CORPORATION

Objectives　We evaluated the effect of Kori-tofu on postprandial hyperglycemia. Methods　Ninety-two healthy subjects ingested the test food（bread containing Kori -tofu）or the control food（not containing Kori-tofu）alternately. Their blood glucose level was measured by a continues measurement device. Results　Postprandial hyperglycemia was observed in 27 subjects. Intake of the test food containing resistant protein significantly suppressed the elevation of blood glucose level in the subjects. Conclusions　Intake of Kori-tofu lead to suppression of postprandial hyperglycemia.

Objective　To investigate the effects of ingestion of collagen tripeptide（CTP）on human arteriosclerosis. Methods　We enrolled 42 subjects with hyperlipidemia, hypertension, and/or the pre-stages of these diseases for this randomized, double-blind, placebo-controlled, parallel-group comparison study. Subjects ingested 3.9 g of either CTP or a placebo once daily for 6 months. Body weight, body mass index （BMI）, blood pressure, blood lipids, liver function, fasting blood sugar（FBS）, pulse wave velocity（PWV）, ankle-brachial pressure index（ABI）, and intima-media thickness（IMT）were recorded pre-ingestion and 6 months after the first dose. Results　Thirty-nine patients completed the study. Almost all had hyperlipidemia （including pre-hyperlipidemia）and about 70％ had hypertension（including pre-hypertension）. Systolic and diastolic blood pressure（SBP and DBP）, triglyceride （TG）levels, and FBS were significantly lower while HDL cholesterol（HDL-C）was significantly higher in the CTP group compared with the placebo group. Although PWV was not significantly different between groups, this parameter improved among subjects in the CTP group with high PWV. Multiple regression analysis revealed ingestion of CTP to be an independent factor affecting SBP, DBP, and, HDL-C, and FBS. Furthermore, TG showed a tendency to be related to ingestion of CTP. Conclusion　Ingestion of CTP contributes to the improvement of multiple risk factors for arteriosclerosis; therefore, CTP could be beneficial as a dietary supplement for the management of arteriosclerosis. （UMIN-ID：000023186）

Background/Objective　This study investigated the effects of maltobionic acid （maltobionic acid syrup）ingestion on bowel movement in healthy Japanese adult women with mild constipation. Methods　This was a randomized, double-blind, placebo-controlled, crossover trial. Twenty healthy Japanese adult women with mild constipation were categorized into three groups: MB syrup 4 g group maltobionic acid syrup 4 g）, MB syrup 2 g group（maltobionic acid syrup 2 g, maltose syrup 2 g）, and Placebo group（maltose syrup 4 g）. Defecation days, stool volume, Constipation Assessment Scale Middle Term version（CAS-MT）, and Bristol stool scale were used to assess the efficacy of the intervention in terms of improving bowel movements. Results　No dropouts or adherence violations occurred during the intervention period, and all 20 subjects completed the study. Compared to placebo intake, continuous ingestion of≥2 g of maltobionic acid syrup（equivalent to≥0.8 g of maltobionic acid）significantly improved bowel movement indicators defecation days, fecal amount, CAS score, and Bristol stool scale score, confirming the efficacy of the intervention. Conclusions　Maltobionic acid is known to be rarely absorbed in the small intestine, reached the large intestine and used by intestinal bacteria which produces short-chain fatty acids and organic acids. As a result, these metabolites were considered to have contributed to the improvement of various defecation indicators by activating intestinal peristalsis.（UMIN-CTRID: 000039225）

Objective　The aim of this study was to evaluate the safety of long-term oral intake of passion fruit seeds extract on healthy subjects. Methods　An open-label study was conducted in 20 healthy subjects（20-64 years old）. The subjects were given the test product（125 mL drink containing 10 mg piceatannol derived from passion fruit seeds extract）3 times per day for 90 days. Physical examination, blood analysis, urinalysis, and a medical questionnaire were examined. Results　11 out of 20 subjects were included in the final analysis. No abnormal changes were observed in physical examination, blood analysis, or urinalysis. No adverse events attributed to the test drink were observed during the study. Conclusions　These results demonstrated that long-term oral intake of drink containing 30 mg piceatannol derived from passion fruit seeds extract was safe.（UMIN-CTR000039098）

Background　Intake of tripotassium citrate, trisodium citrate, and citric acid （hereafter collectively referred to as citrate）are suggested to improve quality of sleep and moods. Objectives　The purpose of this study was to examine the effects of citrate on quality of sleep and mood in healthy people（those who do not have the disease）. Methods　Citrate（3000 mg/day）was continuously ingested for 14 days in Japanese men and women aged 20-65 who were unsatisfied with sleep, and the St. Mary Hospital sleep questionnaire, heart rate, sleep time, and POMS2, etc. as an index of objective and subjective sleep quality were investigated by a randomized, double-blind, placebo-controlled, parallel-group comparative study. Results Compared with the control group, the citrate intake group showed a significant increase in the refreshing degree upon waking up, a significant increase in the total sleep time, a significant decrease in the awakening frequency, and a significant decrease in the pulse rate （comparison between groups）. In addition, there was a significant decrease in the POMS2 fatigue-inertia（FI）score, a significant decrease in the tension-anxiety（TA）score, and a significant decrease in the total mood disturbance（TMD）score in women（comparison between groups）. Conclusions　Oral intake of 3000 mg of citrate╱day was shown to improve sleep quality in healthy adults and mood in healthy adult women.（UMIN000037893）

Objective　To clarify the effects of β-carotene on the symptoms of perennial allergic rhinitis （PAR）in subjects with mild to moderate symptoms, a randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted. Methods　Forty subjects with mild to moderate PAR symptoms were randomly divided into two groups and ingested a mixed vegetable and fruit juice containing β-carotene（β-carotene group）or a placebo juice（placebo group）for 8 weeks. The symptoms of PAR were assessed by Japanese allergic rhinitis standard quality of life questionnaire（JRQLQ）and classification of the severity of allergic rhinitis symptoms. The serum concentrations of β-carotene were measured by HPLC. Results　JRQLQ symptoms scores of“watery eyes”at week 8,“eye symptoms”at week 6 and 8, and“nasal and eye symptoms”at week 6 were significantly lower in β-carotene group than in placebo group. In quality of life（QOL）scores of JRQLQ“, daily life”score at week 8 was also significantly lower in β-carotene group than in placebo group. The serum concentration of β-carotene at week 4 and 8 were significantly higher in β-carotene group than in placebo group. Conclusions　These results suggest that β-carotene could improve nasal and eye symptoms of PAR and QOL in subjects with mild to moderate symptoms. （UMIN ID：UMIN 000034060）

Background　The aim of this study is to determine the effect of a Hydrogen-rich jelly supplement on the sleep quality of healthy female adults. Method　A clinical trial was conducted with 29 female adults who felt stressed but generally healthy randomly assigned to either a Hydrogen rich jelly supplement group, or a placebo group. It was confirmed that sleep quality was enhanced when taking the Hydrogen rich jelly supplement. Result　The intake of Hydrogen-rich jelly supplement had a significant effect on sleep length over 4 weeks. In addition, there was a significant interaction（group×before-and-after test）in hydration level of the skin. Conclusion　Overall, the effect of Hydrogen-rich jelly supplement on sleep length in healthy female adults was observed. Our results may suggest that daily intake of the Hydrogen-rich jelly supplement prevents sleep disturbances by reducing oxidative stress. （UMIN000038533）