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

Abstract

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

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

“…These results indicate that an increase in aspartic acid is an important mechanism in the action of HJG on cognitive function. Because this part of the analysis used the same female patients as were used for the primary endpoint, the significantly greater improvement in cognitive function at 6 months of these female patients treated with HJG (the difference in change from baseline at 6 months for female participants was 2.90 (90% CI, 0.09 to 5.71, p = 0.090) was shown not to be due to a synergistic effect with AchEI: it was the effect of HJG alone (Kainuma et al, 2022). Aspartic acid is involved in the development of nerves and their activity in the central nervous system.…”

“…The data analyzed in this study was from our previous open-label, randomized, multicenter, control trials ( Kainuma et al, 2020 ; Kainuma et al, 2022 ).…”

“…“Kidney [ ™ ] deficiency” is one of the key pathologies of Kampo medicine, defined as a pattern characterized by an insufficient amount of essential qi of kidney. Hachimijiogan (HJG) is a traditional Japanese (herbal) medicine (Kampo) composed of eight herbs that is prescribed for the treatment of “Kidney [ ™ ] deficiency” ( Terasawa, 1993 ; Kainuma et al, 2022 ). It is effective for various symptoms common to members of the older population, such as numbness, nocturia, lower back pain and coldness in the legs, and is used for cases of impotence, nephritis, diabetes, sciatica, bladder catarrh, lumbago, prostatic hypertrophy, and hypertension ( Nakae et al, 2018 ).…”

“…We previously demonstrated the effectiveness of HJG for AD both in vivo and in vitro : improvement was seen in the spatial memory impairment of AD model rats and in cognitive function via cAMP response element binding protein (CREB) ( Kubota et al, 2017 ; Moriyama et al, 2017 ). Although not conclusive, we reported in a clinical trial that HJG has an adjuvant effect for acetylcholinesterase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of mild AD patients ( Kainuma et al, 2022 ). However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear.…”

“…Although not conclusive, we reported in a clinical trial that HJG has an adjuvant effect for acetylcholinesterase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of mild AD patients (Kainuma et al, 2022). However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear.…”