Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

Search method for inhibitors of Staphyloxanthin production by methicillin-resistant Staphylococcus aureus.

Staphyloxanthin, a yellow pigment produced by methicillin-resistant Staphylococcus aureus (MRSA), is a virulent factor escaping from the host immune system. A new screening method for inhibitors of staphyloxanthin production by MRSA was established using paper disks. By this screening method, inhibitors of staphyloxanthin production were selected from the natural product library (ca. 300) and from actinomycete culture broths (ca. 1000). From the natural product library, four known inhibitors of lipid metabolism, cerulenin, dihydrobisvertinol, xanthohumol and zaragozic acid, were found to inhibit staphyloxanthin production; however, typical antibiotics used clinically, including vancomycin, had no effect on staphyloxanthin production. From actinomycete culture broths, two known anthraquinones, 6-deoxy-8-O-methylrabelomycin and tetrangomycin, were found to inhibit staphyloxanthin production by MRSA in the paper disk assay. These results suggested that this screening method is useful and effective to find compounds targeting staphyloxanthin production, leading to a new type of chemotherapeutics against MRSA infection.

Event-related potentials in patients with adult attention-deficit/hyperactivity disorder versus schizophrenia.

Event-related potentials (ERPs) such as Nd, N2b, and P300 in an attentional task and an auditory oddball task were compared among 54 adult AD/HD patients, 43 schizophrenic patients (SZ), and 40 healthy age-matched volunteers (HC). It is known that Nd, N2b, and P300 reflect selective attention, voluntary attention, and cognitive context updating respectively. The peak amplitude of P300 was significantly lower in the adult AD/HD and SZ groups than in the HC group. The peak latencies of late Nd, N2b, and P300 were significantly longer in the SZ group than in the HC and adult AD/HD groups. Thus, attenuated amplitude and prolonged latency of various ERP components in the SZ group suggest the possibility of impairment of basic mechanisms underlying cognitive processing. Unlike the SZ group, the adult AD/HD group exhibited reduced amplitude of P300 but not prolonged latency. These findings suggest the existence of a different type of cognitive dysfunction in the adult AD/HD group, which might be closely related to attentional function.

A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer.

PURPOSE: Curcumin, a plant-derived natural polyphenol, could be a promising anti-cancer drug and shows synergic effects with cytotoxic agents. We evaluated the safety and feasibility of combination therapy using curcumin with gemcitabine-based chemotherapy. METHODS: Gemcitabine-resistant patients with pancreatic cancer received 8 g oral curcumin daily in combination with gemcitabine-based chemotherapy. The primary endpoint was safety for phase I and feasibility of oral curcumin for phase II study. RESULTS: Twenty-one patients were enrolled. No dose-limiting toxicities were observed in the phase I study and oral curcumin 8 g/day was selected as the recommended dose for the phase II study. No patients were withdrawn from this study because of the intolerability of curcumin, which met the primary endpoint of the phase II study, and the median compliance rate of oral curcumin was 100% (Range 79-100%). Median survival time after initiation of curcumin was 161 days (95% confidence interval 109-223 days) and 1-year survival rate was 19% (4.4-41.4%). Plasma curcumin levels ranged from 29 to 412 ng/ml in five patients tested. CONCLUSIONS: Combination therapy using 8 g oral curcumin daily with gemcitabine-based chemotherapy was safe and feasible in patients with pancreatic cancer and warrants further investigation into its efficacy.