Hidetoshi Watari

New Treatment for Alzheimer's Disease, Kamikihito, Reverses Amyloid-β-Induced Progression of Tau Phosphorylation and Axonal Atrophy

Aims. We previously reported that kamikihito (KKT), a traditional Japanese medicine, improved memory impairment and reversed the degeneration of axons in the 5XFAD mouse model of Alzheimers disease (AD). However, the mechanism underlying the effects of KKT remained unknown. The aim of the present study was to investigate the mechanism by which KKT reverses the progression of axonal degeneration. Methods. Primary cultured cortical neurons were treated with amyloid beta (Aβ) fragment comprising amino acid residues (25–35) (10 μM) in an in vitro AD model. KKT (10 μg/mL) was administered to the cells before or after Aβ treatment. The effects of KKT on Aβ-induced tau phosphorylation, axonal atrophy, and protein phosphatase 2A (PP2A) activity were investigated. We also performed an in vivo assay in which KKT (500 mg/kg/day) was administered to 5XFAD mice once a day for 15 days. Cerebral cortex homogenates were used to measure PP2A activity. Results. KKT improved Aβ-induced tau phosphorylation and axonal atrophy after they had already progressed. In addition, KKT increased PP2A activity in vitro and in vivo. Conclusions. KKT reversed the progression of Aβ-induced axonal degeneration. KKT reversed axonal degeneration at least in part through its role as an exogenous PP2A stimulator.

Diosgenin-Rich Yam Extract Enhances Cognitive Function: A Placebo-Controlled, Randomized, Double-Blind, Crossover Study of Healthy Adults

Diosgenin, a yam-derived compound, was found to facilitate the repair of axonal atrophy and synaptic degeneration and improve memory dysfunction in a transgenic mouse model of Alzheimer’s disease (AD). It was also found to enhance neuronal excitation and memory function even in normal mice. We hypothesized that diosgenin, either isolated or in an extract, may represent a new category of cognitive enhancers with essential activities that morphologically and functionally reinforce neuronal networks. This study aimed to investigate the effects of a diosgenin-rich yam extract on cognitive enhancement in healthy volunteers. For this placebo-controlled, randomized, double-blind, crossover study, 28 healthy volunteers (age: 20–81 years) were recruited from Toyama Prefecture, Japan, and was randomly assigned to receive either a yam extract or placebo. Preliminary functional animal experiments indicated that an oil solvent mediated the most efficient distribution of diosgenin into the blood and brain after oral administration, and was a critical factor in the cognitive benefits. Therefore, test samples (placebo and yam extract) were prepared with olive oil and formulated as soft capsules. The intake period was 12 weeks, and a 6-week washout period separated the two crossover intake periods. The Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test was used for neurocognitive assessment, and the adverse effects were monitored through blood testing. Diosgenin-rich yam extract consumption for 12 weeks yielded significant increases in total RBANS score. Among the 12 individual standard cognitive subtests, diosgenin-rich yam extract use significantly improved the semantic fluency. No adverse effects were reported. The diosgenin-rich yam extract treatment appeared to safely enhance cognitive function in healthy adults.

Patient safety incident reports related to traditional Japanese Kampo medicines: medication errors and adverse drug events in a university hospital for a ten-year period

BackgroundKampo medicine is traditional Japanese medicine, which originated in ancient traditional Chinese medicine, but was introduced and developed uniquely in Japan. Today, Kampo medicines are integrated into the Japanese national health care system. Incident reporting systems are currently being widely used to collect information about patient safety incidents that occur in hospitals. However, no investigations have been conducted regarding patient safety incident reports related to Kampo medicines. The aim of this study was to survey and analyse incident reports related to Kampo medicines in a Japanese university hospital to improve future patient safety.MethodsWe selected incident reports related to Kampo medicines filed in Toyama University Hospital from May 2007 to April 2017, and investigated them in terms of medication errors and adverse drug events.ResultsOut of 21,324 total incident reports filed in the 10-year survey period, we discovered 108 Kampo medicine-related incident reports. However, five cases were redundantly reported; thus, the number of actual incidents was 103. Of those, 99 incidents were classified as medication errors (77 administration errors, 15 dispensing errors, and 7 prescribing errors), and four were adverse drug events, namely Kampo medicine-induced interstitial pneumonia. The Kampo medicine (crude drug) that was thought to induce interstitial pneumonia in all four cases was Scutellariae Radix, which is consistent with past reports. According to the incident severity classification system recommended by the National University Hospital Council of Japan, of the 99 medication errors, 10 incidents were classified as level 0 (an error occurred, but the patient was not affected) and 89 incidents were level 1 (an error occurred that affected the patient, but did not cause harm). Of the four adverse drug events, two incidents were classified as level 2 (patient was transiently harmed, but required no treatment), and two incidents were level 3b (patient was transiently harmed and required substantial treatment).ConclusionsThere are many patient safety issues related to Kampo medicines. Patient safety awareness should be raised to prevent medication errors, especially administration errors, and adverse drug events in Kampo medicine.

Cytosolic aspartate aminotransferase, a direct binding protein of kamikihito, regulates axon growth

Alzheimers disease (AD) is the most common cause of dementia. The aim of this study was to identify the direct binding proteins of kamikihito (KKT), a traditional Japanese Kampo medicine used as an anti‐AD drug.

Comparing the effects of kamikihito in Japan and kami-guibi-tang in Korea on memory enhancement: working towards the development of a global study.

Traditional medicine is widely used in East Asia, and studies that demonstrate its usefulness have recently become more common. However, formulation‐based studies are not globally understood because these studies are country‐specific. There are many types of formulations that have been introduced to Japan and Korea from China. Establishing whether a same‐origin formulation has equivalent effects in other countries is important for the development of studies that span multiple countries. The present study compared the effects of same‐origin traditional medicine used in Japan and Korea in an in vivo experiment. We prepared drugs that had the same origin and the same components. The drugs are called kamikihito (KKT) in Japan and kami‐guibi‐tang (KGT) in Korea. KKT (500 mg extract/kg/day) and KGT (500 mg extract/kg/day) were administered to ddY mice, and object recognition and location memory tests were performed. KKT and KGT administration yielded equivalent normal memory enhancement effects. 3D‐HPLC showed similar, but not identical, patterns of the detected compounds between KKT and KGT. This comparative research approach enables future global clinical studies of traditional medicine to be conducted through the use of the formulations prescribed in each country. Copyright

Non-alcoholic fatty liver disease satisfactorily treated with traditional Japanese kampo medicine

An obese 17‐year‐old male patient with right hemiparesis secondary to cerebral infarction presented for kampo treatment. The hemiparesis and resultant lack of exercise had led to an increase in bodyweight. Serum alanine aminotransferase (ALT) was elevated and abdominal ultrasound identified fatty liver. The patient was diagnosed with non‐alcoholic fatty liver disease (NAFLD). Aspirin and tocopherol acetate (vitamin E), previously prescribed, were continued, and kampo medicines were prescribed.

A Case of Recurrent Drug-induced Liver Injury Caused by the Incidental Readministration of a Kampo Formula Containing Scutellariae Radix

A 67-year-old woman experiencing coughing visited a clinic and was prescribed drugs, including shosaikoto extract, for 4 days. She subsequently suffered from liver injury, but her condition improved after the discontinuation of all medications. Approximately 1 year later, she experienced fatigue, consulted another clinic, and received saikokeishikankyoto extract for 21 days. She subsequently suffered liver injury again. Both shosaikoto and saikokeishikankyoto contain Scutellariae Radix. This case is thought to be one of recurrent drug-induced liver injury caused by the incidental readministration of a Kampo formula containing Scutellariae Radix. An awareness of adverse drug events caused by Kampo formulas, especially those containing Scutellariae Radix, is essential.

Traditional Japanese formulas tokishakuyakusan and ogikenchuto suppress dermal sclerosis in bleomycin-induced murine scleroderma

Systemic scleroderma is a connective tissue disease of unknown etiology characterized by fibrosis of the skin and internal organs. There are few effective treatments for this disease. In this study, we examined the effectiveness of the traditional Japanese medicines keishibukuryogan (KBG), tokishakuyakusan (TSS), and ogikenchuto (OKT) in treating systemic scleroderma.