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The aim of this study was to evaluate the safety and effectiveness of rotigotine under daily clinical practice in Parkinson's disease patients.The study was a prospective, non-interventional, observational study targeting patients who were treated with rotigotine for the first time, with a 1-year follow-up period from September 2013 to August 2016.There were 603 patients in the safety population and 599 patients in the effectiveness population. The mean age was 71.6 years, and the age group of ≥65 and ≥80 years accounted for 80% and 18.6% of all patients, respectively. The frequency of adverse drug reaction (ADR) was 34.3%, and common ADRs were application site reaction (20.2%), typical for transdermal patches. However, the majority of patients recovered or was recovering from these ADRs and were non-serious. Although ADRs related to non-motor symptoms of Parkinson's disease were observed, most of them were non-serious. Total scores of the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) (ON-time) significantly decreased from baseline in the effectiveness population. In the analysis of overall improvement in 12 months of post-treatment, ≥70% of patients achieved mild or greater improvement. The safety profiles and improvements in the UPDRS-III score were similar in both the ≥80 years of age group and younger age group.There were no new or notable safety concerns observed, and the effectiveness of rotigotine was suggested in daily clinical practice.

BackgroundThis large-scale post-marketing surveillance study (START study) evaluated the effectiveness and safety of tolvaptan in Japanese liver cirrhosis patients with hepatic edema in real-world clinical settings. Here, we present the final analysis outcomes.MethodsA prospective, multicenter, non-interventional study involving patients who received tolvaptan for the treatment of liver cirrhosis with hepatic edema with an insufficient response to conventional diuretics. The observation period was up to 6 months. Effectiveness evaluation included changes in body weight and clinical symptoms. Safety analysis included evaluation of adverse drug reactions (ADRs).ResultsCase reports of 1111 patients were collected. Of these, 1109 were included in the safety analysis and 1098 in the effectiveness analysis. The mean age was 69.4 ± 11.5 years and 695 (62.7%) patients were male. After tolvaptan treatment, a decrease in body weight from baseline was − 2.6 ± 2.7 kg on day 7 and − 3.8 ± 4.1 kg on day 14. Moreover, clinical symptoms significantly improved over the 14-day treatment. Frequently reported ADRs were thirst (6.6%), hepatic encephalopathy (2.3%), dehydration (1.5%), and hypernatremia (1.2%). A serum sodium level of ≥ 150 mEq/L was reported in five patients (0.5%). Multivariate analyses showed that the baseline blood urea nitrogen (BUN) level (cut-off value: 22.4 mg/dL) was the predictive factor for tolvaptan treatment response.ConclusionsThe results suggest that tolvaptan was effective and well-tolerated in liver cirrhosis patients with hepatic edema. In the real-world clinical setting, tolvaptan provides a useful option for the treatment of hepatic edema.

Tolvaptan, a vasopressin V2 receptor antagonist, is approved in Japan for the treatment of fluid retention in patients with heart failure (HF), and in the United States for hyponatremia. The efficacy and safety of tolvaptan in patients with HF with reduced ejection fraction (HFrEF) have been demonstrated previously. However, its efficacy in patients with HF having preserved (HFpEF) and mid-range (HFmrEF) ejection fraction (EF) remains uncertain. The present subgroup analysis from the post-marketing surveillance SMILE Study aims to explore the efficacy and safety of tolvaptan across the HF subgroups (HFrEF, HFpEF, and HFmrEF).Patients with HF accompanied by fluid retention who received tolvaptan were enrolled. Primary endpoints were: change in body weight, 24-hour urine volume, congestive symptoms, and safety over 14-day treatment. Of the 3,349 patients enrolled, left ventricular EF data were available for 1,741 patients; 45.7% had HFpEF. Tolvaptan treatment resulted in body weight reduction and increases in 24-hour urine volume across the 3 subgroups. Congestive symptoms significantly improved over the 14-day treatment in all subgroups. The frequency of adverse events (AEs) was comparable across the subgroups; thirst was the most common AE.Tolvaptan provides a safe and effective option for treating fluid retention in patients with HFpEF, as well as HFmrEF and HFrEF.

Background In Japan, tolvaptan is indicated for patients with heart failure and volume overload who have inadequate response to other diuretics. In contrast to the USA and Europe, tolvaptan can be used in Japan in patients with normal sodium levels.Methods and Results:In this multicenter, non-interventional, post-marketing surveillance study, prospective data from 3,349 patients treated with tolvaptan over a 5-year period were analyzed to identify benefits and risks. By Day 2 of treatment, 76.9% of evaluable patients had an increase in baseline 24-h urine volume (tolvaptan responders). Mean change in body weight was similar between 7.5 mg and 15 mg dosage groups (-3.6±3.9 kg and -3.7±4.0 kg, respectively). Improvement or disappearance rates for congestive symptoms from baseline to Day 14 ranged from 77.7% for lower limb edema to 51.1% for 3rd sound. Adverse drug reactions were reported in 18.1% of patients, most frequently thirst (8.4%). No case of central pontine myelinolysis was reported. All-cause mortality was significantly lower in patients with improved sodium concentration and increased 24-h urine volume. Conclusions The effectiveness and safety of tolvaptan in real-world clinical settings was confirmed in this large-scale analysis. The 7.5-mg dose was equally as effective as the 15-mg dose and had a better safety profile. Improvements in all-cause mortality were suggested in tolvaptan responders.

Aim Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings. Methods Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure. Results Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were −2.38 kg on day 7 and −3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of ≥146 mEq/L was observed in 12 patients (2.7%). Conclusions In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained.

The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is an aquaretic agent that has been approved for heart failure patients with volume overload in Japan. In this study (SMILE study), we investigated patient characteristics and effectiveness in both a 14 days and shorter treated group (14DS) and 15 days and longer treated group (15DL). The results showed that the patients in the 15DL group had low cardiac output with intensive diuretic administration (ie, diuretic resistance). The congestive symptoms were greatly improved within 14 days of treatment in both the 14DS and 15DL groups. Further improvements in lower limb edema, pulmonary congestion, dyspnea, third sound, and rales after 2 weeks were statistically significant in the 15DL group, but the amount of improvement was subtle and the 15DL group might have consisted of a considerable number of "non-responders". Therefore, identifying "responders" by biomarkers and conducting a prospective randomized study is required to validate our findings.

Augmentation therapy is an option for patients with major depressive disorder who do respond sufficiently to adequate dosages of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, but little is known about application of this strategy in everyday practice.This prospective, multi-center, observational study investigated the effectiveness and safety of aripiprazole augmentation in Japanese patients with inadequate response to conventional antidepressant therapy in real-world clinical practice. The primary endpoint was mean change in the (Japanese version) Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to study end. Safety was assessed by monitoring adverse events.There were 1103 patients in the safety population and 1090 patients in the effectiveness population. Mean change in the MADRS total score at study end was -14.9 ± 12.3 (p .001 vs baseline). The remission rate increased from 34.5% at Month 6 to 43.3% at Month 12, suggesting additional benefit with continued treatment. The type of primary antidepressant (paroxetine, fluvoxamine, sertraline, milnacipran, duloxetine, mirtazapine, or escitalopram) had no influence on the effectiveness of aripiprazole augmentation therapy. A baseline MADRS total score of33 points and an elapsed time of176 days from an episode of depression to the start of aripiprazole treatment increased the likelihood of achieving remission; 24.8% of patients experienced at least one adverse event, but no new safety signals were identified.Aripiprazole augmentation therapy appears to be effective and safe in Japanese patients with depression/depressive symptoms treated in everyday clinical practice, taking into account factors associated with achieving remission.

Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings.Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure.Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were -2.38 kg on day 7 and -3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of ≥146 mEq/L was observed in 12 patients (2.7%).In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained.

The purpose of this study was to investigate the efficacy of alpha-linolenic acid-rich perilla oil emulsion (POE) in a rat model with trinitrobenzenesulfonic acid (TNB)-induced inflammatory bowel disease. Three different isocaloric solutions, which are glucose solution (FF), soybean oil emulsion (SOE) and POE, were infused for 14 days after instillation of TNB. After infusion, total cholesterol and phospholipid concentration in the plasma in the POE group were significantly decreased compared with the FF and SOE groups. Arachidonic acid level in the colonic phospholipids was significantly decreased and eicosapentaenoic acid level was significantly increased in the POE group compared with the FF and SOE groups. Thickness, damage score and leukotriene B4 content in the colon in the POE group were the lowest among the infusion groups. These results suggest that alpha-linolenic acid suppresses the synthesis of leukotriene B4 in the colon by changing the fatty acid composition in the colonic phospholipids and that POE may be effective in the improvement of inflammation in the colon.

The purpose of this study was to investigate the nutritional effect of perilla oil emulsion (POE) in a rat model with inflammatory bowel disease (IBD) induced by 2,4,6-trinitrobenzenesulfonic acid. POE and soybean oil emulsion (SOE) were infused at 20% of nonprotein energy during 7 days' total parenteral nutrition (TPN). After infusion of test solutions, body weight gain and cumulative nitrogen balance in the POE group were significantly higher than those in the fat-free TPN (FF) group after infusion of test solutions. Moreover, those in the POE group were higher than those in the SOE group, but no significant difference was observed between the POE and SOE groups. In the POE group, total cholesterol and phospholipid concentration in the plasma was significantly decreased compared with the FF and SOE groups. Triglyceride concentration in the plasma did not significantly differ between the POE, SOE and FF groups. Plasma lipid peroxide concentration in the POE group was significantly lower than that in the SOE group, but it was not different from the FF group. In fatty acid composition in the plasma total lipids, linoleic acid in the POE and SOE groups and alpha-linolenic acid in the POE group were significantly increased compared with those in the FF group. Arachidonic acid (AA) in the POE and FF groups were significantly decreased compared with that in the SOE group. Otherwise, eicosapentaenoic acid (EPA) in the POE group was significantly increased compared with that in the SOE and FF groups. EPA/AA ratio in the POE group was significantly increased compared with the SOE group. The thickness and damage score of the colon were significantly depressed in the POE group compared with the SOE group. These results suggest that POE has a superior nutritional effect and improves inflammation in the IBD.

生体内におけるα-リノレン酸とリノール酸のエネルギー産生効率を比較するため, 7週齢のSD系雄性ラットを用いて1- [14C] -α-リノレン酸および1- [14C] -リノール酸を静脈内投与し, 呼気中への14CO2排泄量を測定した。1) 呼気中への14CO2排泄量は, α-リノレン酸がリノール酸に比べて有意に高い値を示した。2) 投与後の肝および精巣上体脂肪における放射能残存量は, α-リノレン酸がリノール酸に比べて有意に低い値を示した。以上の結果, 静脈栄養時においてα-リノレン酸は生体内でエネルギー源として利用されやすいことが明らかとなった。

A method of preparing fine emulsified fat particles without glycerol for intravenous nutrition was investigated. The factors assessed were the oil phase ratio, the glucose level of the aqueous phase and the temperature of high-pressure homogenization. The particle size decreased with an increase in the oil phase ratio and it went below 250 nm only in the emulsion with a 50% oil phase ratio. The weight-weighted particle size (dw)/number-weighted particle size (dn) value reflected the particle size distribution. The emulsion with a 50% oil phase ratio had a very narrow distribution of particle sizes and the dw/dn value was below 1.1. With the use of glucose solutions for the aqueous phase, smaller particle sizes and narrower distributions were obtained with increasing glucose concentrations. The controlled temperature of 50 degrees C was appropriate for high-pressure homogenization, producing particles below 160 nm. The rate of the layer separation was a function of particle size. The particle sizes below 180 nm can be expected to suppress the separation of the formulation which consisted of 10.0% soybean oil, 1.2% phospholipids and 5.0% glucose. The stability studies were conducted at 40 degrees C for 3 months and the fat emulsion was stable during storage. These investigations contribute to the preparation of a new caloric source for peripheral parenteral nutrition.

Glucose is usually chosen as the energy source for total parenteral nutrition. However, the optimal glucose : fat ratio for peripheral parenteral nutrition has not been examined sufficiently. We compared glucose : fat ratios in hypocaloric nutrition. Male SD rats were given hypocaloric parenteral nutrition (approx. 190 kcal/kg/d) for 5 d after laparotomy. The hypocaloric solutions used contained 0, 33, 50, 67 or 100% of the non-protein energy in the form of fat. Body weight change, nitrogen balance, organ weights, and hepatic, splenic and plasma biochemistries were assessed. Body weight increase in the 67 and 100% fat groups was significantly greater than that in the 0 % fat group. Nitrogen balance was the same in all groups. Hepatic glycogen content was significantly lower in the 100% fat group than that in the 0 % fat group. The weight of epididymal fat deposits was significantly lower in the 0 % fat group than in the 50 and 67% fat groups. On the other hand, tissue triglyceride content and plasma lipid levels in the 100% fat group were significantly higher than in the 0 % fat group, and were also higher than in the control group. It is suggested that combinations of glucose and fat have sparing effects on body fat and hepatic glycogen. Combinations of glucose and fat as non-protein energy sources were superior to glucose or fat alone for hypocaloric parenteral nutrition.

We investigated the relationship between intravenous energy loading and zinc status in laparotomized rats. One of three test solutions consisting of 3% amino acid, the same amount of electrolytes (excluding zinc) and different concentrations of glucose were infused through the jugular vein for 5 d. The total energy was 109, 191 and 273 kcal/kg/d, respectively. Significantly positive correlations were observed between infusion energy and rat body weight changes (% of initial value) and between infusion energy and cumulative nitrogen balance. Regarding the zinc status, a negative correlation was found between infusion energy and plasma zinc concentration, and a positive correlation was observed between infusion energy and urinary zinc excretion. There was no significant relationship between infusion energy and hepatic zinc content. These results indicate that the zinc requirement might be increased when infusion energy is elevated and the nutritional status is improved. Zinc supplementation in the post-operative period should be considered in light of not only catabolism but also anabolism. Anabolism may be more important than catabolism in regard to zinc metabolism under relatively mild stress.