薬理と治療

Dapagliflozin highly selectively and reversibly inhibits sodium︱glucose cotransporter 2, a protein involved in renal glucose reabsorption in the proximal tubule. Such an inhibition lowers the renal glucose reabsorption threshold and induces glycosuria, leading to reduction of blood glucose levels in diabetic patients. On the other hand, glycosuria induces osmotic diuresis by increasing osmotic pressure, resulting in decreased body fluid volume, dehydration. The present study examined laboratory values of two phase Ⅲ clinical trials（a 24-week double-blind study and a 52-week long-term safety study）of dapagliflozin conducted in Japan to clarify not only the dapagliflozin-mediated blood glucose lowering effect but also dapagliflozinʼs pharmacological effects comprehensively. We in particular focused on parameters that may need to be paid attention after administration of dapagliflozin in regular clinical practice such as body fluid volume, blood pressure, serum lipids, and renal and hepatic functions. Analyses suggested slight decrease in body fluid volume especially in the acute phase of dapagliflozin administration；however, no clinically significant changes in values related to serum lipids or renal or hepatic functions were observed. Although attention is needed regarding the risk of decreased body fluid volume, particularly during the initial administration period, the present findings demonstrate that dapagliflozin lowers blood glucose levels effectively while delivering additional potential benefits such as weight loss and decreased systolic blood pressure. As long as these pharmacological characteristics are taken into consideration properly, dapagliflozin will be a safe and effective treatment option for diabetes.

Objectives A post︱marketing surveillance was conducted to collect information on the safety and efficacy of long︱term combination therapy of mitiglinide calcium hydrate（GLUFAST(R) Tablet）, a short-acting insulin secretagogue, and a thiazolidine derivative in patients with type 2 diabetes. Methods This surveillance was conducted using a prospective central registration method from July 2009 to June 2012. An observation period was 18 months. Information including the background of patients, concomitant medications, laboratory values and adverse events was collected. Results Adverse drug reactions were observed in 49 （4.6％）out of 1071 patients in the safety analysis set. The most frequent adverse drug reaction was hypoglycaemia, which occurred in 23 cases（2.1％）. There was no increase in the incidence of adverse drug reactions and hypoglycaemia with long︱term combination therapy. HbA1c（NGSP）was 7.75 ±1.25％ at the start of combination therapy, and 6.98±0.97％ and 6.88±1.00％ at 12 and 18 months after starting combination therapy, respectively. The change in HbA1c from the start of combination therapy at 12 and 18 months was －0.72 ±1.07％ and －0.78±1.16％, respectively, with these being significant decreases at both time points（both P＜0.001）. The improvement in blood glucose levels was maintained during 18 months of combination therapy. Conclusions In this surveillance, information on more than 1000 patients treated with this combination therapy was collected and the safety and efficacy were evaluated. No new relevant safety findings were observed during the 18 months of combination therapy period. With regard to efficacy, sustained improvement in blood glucose levels was observed.

The objective of this investigation was to assess the safety and effectiveness of long-term use of pioglitazone╱metformin hydrochloride combination tablets （METACT(R) combination tablets） in type 2 diabetes patients. This investigation was a 12︱months prospective cohort study where the incidence of adverse drug reactions, changes in glycosylated hemoglobin（HbA1c）, and changes in drug adherence were assessed. Of the 1103 patients enrolled, 1084 Case Reports were collected from 196 sites. The incidence of adverse drug reactions was 3.19％ in 1067 safety-evaluable patients. The common adverse drug reactions were oedema peripheral, oedema, and weight increased. Within 905 efficacy-evaluable patients, HbA1c significantly decreased after 12 months of treatment compared with baseline（－0.60±1.190％；mean±SD）. The percentage of patients with high drug adherence rate（≥90％）increased significantly from 78.0％ at the baseline to 89.9％ after 12 months of treatment. To evaluate the influence of the improvement of drug adherence on glycemic control in more detail, subpopulation analysis was performed in patients for whom the doses of pioglitazone and metformin remained unchanged upon the switch and dosages of all diabetes medications including METACT(R) remained the same throughout the treatment, because the glycemic control in these patients was considered to be highly affected by their drug adherence. In these patients, significant decrease in HbA1c was demonstrated throughout the treatment and drug adherence also improved. These results suggested that the reduction in HbA1c could be related to the improvement of drug adherence due to the switch to METACT(R). This investigation demonstrated the safety and effectiveness of the long-term use of METACT(R) combination tablets in the treatment of type 2 diabetes patients in Japan.

Background There is an increasing reported clinical studies demonstrating the potential of collagen peptides（CP）of various origins to improve skin condition. In this study, we used a CP-based multiple nutrients supplement mainly containing fish CP, in combination with proprietary amounts of hyaluronic acid, ceramide, sodium ascorbate and vitamin P（CPMN supplement）, and examined its effects on some skin functions and various skin properties. Methods A randomized, double-blind, placebo-controlled trials was conducted on 66 middle-aged women with subjective dry skin. They were assigned to receive either the CPMN supplement in a daily 5000 mg as CP dose or placebo for 8 weeks. Efficacy was evaluated using values of two epidermal barrier function parameters, viz, stratum corneum hydration（SCH）and transepidermal water loss（TEWL）and questionnaire-based subjective evaluation of 20 and 9 skin properties of the face and whole body, respectively, measured at weeks 4 and 8 of intervention. Results Twenty-nine subjects on CPMN supplement（CPMN group）and 30 on the placebo （placebo group）completed the study protocol and were subjected to efficacy analysis. The SCH value was significantly increased at week 4 compared to baseline（P＜0.01）, although there was no significant between-group difference. Additionally, appreciable efficacy of the CPMN supplement was observed for self-evaluated skin properties. Between-group comparisons of the magnitude of score changes of all evaluated skin properties for the face showed that two properties（skin dryness and skin wetness）, as well as of the mean of aggregate skin properties, improved to significant levels（P＜0.05）and four properties（skin moisture, crowʼs feet, skin looseness at the eye, and skin looseness at the mouth）improved to nearly significant levels（P＜0.1, ＞0.05）at week 8 of intervention. Basically similar improvements of self-evaluated skin properties were also observed for the whole body. Conclusions Although the results are not definitive, our CPMN supplement may have potential for improving skin hydration and some self-evaluated skin properties in middle-aged women with subjective dry skin.

Objectives To evaluate the safety of excessive intake of tea containing quercetin glucosides in healthy adults including obese subjects. Study design A randomized, double-blind, placebo-controlled, parallel-group study. Methods Forty-eight healthy adults aged 20-64 years old with body mass index（BMI）≳ 18.5 and＜30.0 kg╱m2 were randomly assigned into two groups and ingested daily one bottle of the tea containing 0 mg or 330 mg of quercetin glucosides for 4 weeks. Results There were no clinically concerning changes or adverse effects related to the test beverage containing quercetin glucosides in this study. Conclusions These results indicated that the tea containing quercetin glucosides was safe for excessive intake.

Objecive Blueberries contain a lot anthocyanin, and have been considered healthful for eyesight. In the present study, palliative effect of standard alcoholic bilberry extract（SBE）was investigated on accommodative asthenopia compulsory induced by video display terminal （VDT）stress. Methods Placebo-controlled double-blind randomized clinical trial was conducted in 30 Japanese healthy adults（range：20-59 years old）. Volunteers took 160 mg of SBE or placebo daily for 4 weeks. On the first and the last day of the administration, objective and subjective examinations were performed three times：before, prompt after, and 20 minutes after VDT work. They played Tetris game for a half hour on iPhone as deemed VDT work. Accommodation was examined by using TriIRIS(R) C9000. Subjective symptoms were evaluated by means of questionnaire sheet. Results Accommodative function was significantly improved in SBE group compared with controls at 20 minutes after VDT work（P＜0.05）. Subjective complaints of eyestrain were also restorative both before（P＜0.05）and 20 minutes after（P＜0.01）VDT task among SBE users compared with controls. Conclusions Oral intake of qualified SBE saved eyestrain both objectively and subjectively when abusing eyes. It suggests that SBE may reduce eye fatigue caused by computers and smartphones.

Objective L-Cysteine has been reported as a preventative or antidote for some of the negative effects of liver damage. On the other hands, L-Cystine is a dimeric amino acid formed by the oxidation of two L-Cysteine residues that covalently link to make a disulfide bond. Therefore, we hypothesized that L-Cystine may function in a similar way to L-Cysteine. In this study, we evaluated the effect of hepatoprotective of L-Cystine on liver injury animal model. Methods Acute liver injury was induced by injection of carbon tetrachloride into the intraperitoneally, after the administration of L-Cystine to Sprague-Dawley rats. The hepatic damage was evaluated by the plasma levels of aspartate aminotransferase（AST）, alanine aminotransferase（ALT）and total bilirubin（T-Bil）.Results The administration of L-Cystine was suppressed the increase in the plasma levels of AST, ALT and T︱Bil. Conclusions The present study suggested that the administration of L-Cystine have the protective effect on carbon tetrachloride-induced hepatic damage.

Bisphosphonates can cause chemical ulcerations in the esophagus in some patients. The postulated pathophysiological mechanism of underlying ulcer formation due to bisphosphonate tablets use is direct mucosal irritation. An 83-year-old woman who had been treated for osteoporosis and vertebral fractures was admitted to Tsuboi hospital owing to complain of tarry stools since two days. The patient had anemia and was malnourished. Five days before manifestation of these symptoms, the patient had taken risedronate with a full glass of water, after which she had remained upright for 30 minutes. At admission endoscopy showed severe circumferential ulceration of the distal esophagus close to the esophagogastric mucosal junction. She was treated with an intravenous proton-pump inhibitor, and received a blood transfusion. After her recovery, a large hiatal hernia of the esophagus was noted on barium studies. A longer duration of high pressure zone in the esophageal hiatal hernia leads to a disturbance of peristalsis, which may have prolonged the contact time of risedronate tablets on the esophageal mucosa. This case suggests that we should exercise caution when using bisphosphonates in patients with hiatal hernias of the esophagus.