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.

Therapeutic Potential of Two Derivative Prescriptions of Rokumijiogan, Hachimijiogan and Bakumijiogan against Renal Damage in Nephrectomized Rats.

Background: Hachimijiogan (HJG) and Bakumijiogan (BJG), two derivative prescriptions of Rokumijiogan (RJG), were selected to investigate their renoprotective potential in the 5/6 nephrectomized (5/6Nx) rat model. Methods: Rats were treated with HJG and BJG orally at 150 mg/kg body weight/day once daily for 10 weeks after resection of 5/6 of the renal volume, and their renoprotective effects were compared with 5/6Nx vehicle-treated and sham-operated control rats. Results: Improvements in renal lesions, glomerulosclerosis, tubulointerstitial injury, and arteriosclerotic lesions estimated by histologic scoring indices in the HJG-treated group were compared with those in the BJG-treated group. HJG- and BJG-treated groups ameliorated the renal function parameters. Elevated levels of renal oxidative stress-related biomarkers were reduced, while decreased antioxidant defence systems (superoxide dismutase and the glutathione/oxidized glutathione ratio) were increased in the HJG-treated group rather than the BJG-treated group. In contrast, BJG administration significantly reduced expression of the inflammatory response through oxidative stress. The HJG-treated group showed a decrease in inflammatory mediators through the JNK pathway. To gain a deeper understanding of their therapeutic action, the effects of the main components detected in HJG and BJG were evaluated using the LLC-PK1 renal tubular epithelial cell line, which is the renal tissue most vulnerable to oxidative stress. Corni Fructus and Moutan Cortex-originated compositions afforded important protection against oxidative stress induced by peroxynitrite. Conclusions: From our described and discussed analyses, it can be concluded that RJG-containing prescriptions, HJG and BJG are an excellent medicine for chronic kidney disease. In the future, appropriately designed clinical studies in people with chronic kidney disease are necessary to evaluate the renoprotective activities of HJG and BJG.

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.

Combination therapy with tamsulosin and traditional herbal medicine for lower urinary tract symptoms due to benign prostatic hyperplasia: A double-blinded, randomized, pilot clinical trial.

OBJECTIVES: To evaluate the efficacy and safety of tamsulosin and Hachimijiogan or Ryutanshakanto in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. METHODS: A prospective, randomized, double-blind method was used to determine the efficacy and safety of the combination or placebo at baseline and 4, 8, and 12 weeks of study. The International Prostate Symptom Score, quality of life index, complete voiding diary, and National Institutes of Health-Chronic Prostatitis Symptom Index were studied. Uroflowmetery and postvoid residual urine volume were measured and compared. Laboratory tests including prostate-specific antigen were performed. RESULTS: In all groups, International Prostate Symptom Score and quality of life showed improvement, but no significant differences were shown among the groups. Prostate volume increased after treatment, and uroflowmetric parameters showed improvements after treatment without significance among the three groups. The total score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant improvement in all groups, without significant differences among the groups. Only the pain sub-score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant decrease in the tamsulosin with Ryutanshakanto group compared to the control group. A total of 11 adverse reactions occurred, but they were mild and not related to the study drugs. CONCLUSION: Ryutanshakanto can provide pain relief in patients with chronic prostatitis and chronic pelvic pain syndrome. If more research is conducted, Hachimijiogan and Ryutanshakanto may be applied as add-on treatments in patients with storage symptoms with alpha-blocker monotherapy.

Use of Hachimijiogan in Treatment for Cold/Pain Allows Gradual Dose Reduction of Antihypertensives / 日本東洋医学雑誌

The indications of hachimijiogan formulation include lower limb pain, low back pain, edema, fatigue, coldness, and accompanying symptoms of hypertension. In this study, hachimijiogan was administered to patients who complained of symptoms of coldness, pain, etc., and the subsequent blood pressure was observed. Changes in hachimijiogan, a powder pill formulation of crude drugs, were observed in 12 patients aged 45 years or older, with an average age of 71 years. Various symptoms of jinkyo, blood pressure, and laboratory findings were examined. Coldness and pain improved significantly after 3 months. Of the 9 patients who wanted to take hachimijiogan for more than 9 months, 8 were treated with antihypertensive drugs. Among them, 4 underwent an antihypertensive dose reduction by 9 months, and 3 received angiotensin receptor antagonists, and 1 received a Ca antagonist. The systolic pressure before treatment with hachimijiogan averaged 127 mmHg, and after 9 months it was stable at 128 mmHg despite drug dose reduction. In patients with antihypertensive drugs, the long-term use of hachimijiogan may facilitate dose reduction and protection of the vascular endothelium protection. The usefulness of hachimijiogan in the aging society was suggested.

Two Cases of Successful Treatment With Hachimijiogan for Irregular Menstruation.

Hachimijiogan (HJG), a Kampo prescription medication composed of eight crude drugs, has been used for treatment of climacteric disturbance and irregular menstruation. In the Japanese pharmaceutical market, HJG pills consisting of a powdered mixture of these crude drugs are available, as well as a water extract preparation. In this study, two cases of successful treatment with HJG pills are reported. Case 1 was a 37-years-old woman who had irregular menstruation that had previously been treated with HJG extract granules for 3 months; however, her symptoms were not improved. Subsequent treatment with HJG pills at a dose of 40 pills/day for 10 months led to slight improvement of her menstrual cycle, and at a dose of 60 pills/day, her menstrual cycle was normalized. Case 2 was a 29-years-old woman who had irregular menstruation for more than 5 years and was previously treated with HJG extract granules, which led to slight improvement of her symptoms. Her menstrual cycle improved slightly after 9-months treatment with HJG pills at a dose of 40 pills/day and was normalized at a dose of 60 pills/day. This study suggests that the HJG crude drug preparation is more effective than the HJG extract preparation in some cases.

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate ketamine-induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model.

AIM: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. METHODS: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. RESULTS: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-ß1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. CONCLUSION: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.

Effectiveness of Kampo Medicine for the Patients with Idiopathic Sensorineural Hearing Loss / 日本東洋医学雑誌

We administered Japanese Kampo medicine for seven patients with Grade 3 or more idiopathic sensorineural hearing loss who could not be administered enough amounts of steroids for some reasons. They all exhibited deficiency patterns, and which were all dual deficiency patterns of qi and yin. All patients were administered hochuekkito and hachimijiogan. Six patients were cured, and one patient was recovered.

Three Cases of Dry Nose Successfully Treated with Hachimijiogan or Rokumigan / 日本東洋医学雑誌

Few reports currently exist demonstrating that Kampo medicine is effective for dry nose. Here, we describe three cases of dry nose that were successfully treated with hachimijiogan or rokumigan. The chief complaints of the three cases differed. Dry nose was the second or third most troublesome symptom. The three cases had kidney deficiency and its typical symptom of abdominal numbness in common. Upon administration of hachimijiogan or rokumigan, dry nose improved promptly, along with the improvement of kidney deficiency. In addition, it became easier for all three cases to breathe. According to “Pu ji fang”, dry nose is ascribed to wind-­heat or kidney deficiency. The kidney is considered to control the reception of qi inhaled by the lungs. Taken together, we speculate that dry nose of the three cases were due to kidney deficiency, because treatment with hachimijiogan or rokumigan improved their dry nose along with the improvement of their kidney defi­ciency as well as their breathing which suggests the improvement of the reception of qi inhaled by the lungs. Hachimijiogan or rokumigan is shown to be effective for dry nose in the patients with kidney deficiency.

Three Cases of Meniereʼs Disease in the Elderly SuccessfullyTreated with Kampo Medicine / 日本東洋医学雑誌

We report three closely watched cases of intractable Meniere's disease in the elderly that were successfully treated with Kampo medicine. Case 1 is a 75-year-old female. At the time of the 4th Meniere's attack, we gave her western medicines such as isosorbide, but she had a significant hearing loss. Then, we administered hachimijiogan extract granules, and her hearing level improved and she had been free of Meniere's attack for 23 months. Case 2 is a 78-year-old male. We diagnosed as bilateral Meniere's disease and treated him with western medicines such as isosorbide. In September of year X, his hearing level in the left ear worsened despite the treatment, so we prescribed hachimijiogan extract granules. After the treatment, we found the patient's hearing improved and nystagmus decreased gradually. He has also been free of Meniere's attack for 9 months. Case 3 is a 70-year-old male. He had repeated episodes of vertigo in spite of the administration of western medicines. After we prescribed shimbuto extract granules, vertigo attack and nystagmus disappeared. He has been relieved from Meniere's attack for 8 months. These cases indicate that Kampo therapy is one of the useful therapeutic options for intractable Meniere's disease in the elderly.

Twenty Cases of 20 Women Treated with a Regimen of Herbal Medicine According to the Treatment Stage of in vitro Fertilization or Microinsemination / 日本東洋医学雑誌

This report describes 20 women who underwent in vitro fertilization or microinsemination while receiving a regimen of herbal medicine, of which contents varied according to the treatment stage. Until the ova were harvested, in order to promote maturation, patients were treated with hachimijiogan for reinforcing kidney yang, and keishibukuryogan for removing blood stasis. Following this, during the period between harvesting and implantation, they were treated either exclusively with unkeito for warming meridians, dissipates cold, and replenishes blood, or with unkeito in combination with keishibukuryogan. Following implantation, they were treated with tokishakuyakusan to induce uterine relaxation. The treatment regimen was determined based on traditional herbal evidence of infertile patient's blood stasis and kidney deficiency. We adjusted applied dose depending on the conditions of patients. Fourteen of the 20 women tested positive for pregnancy; 10 of them carried to term, whereas in 4 of them, the pregnancy ended in abortion or miscarriage. Anti-Müllerian hormone concentration, endometrial thickness, estimated follicle count, recovered ova count, fertilized ova count, and numbers of ova to reach the early-embryo stage and blastocyst stage were compared between the continuing pregnancy and the non-pregnancy groups. Improvements were observed in all values after combined use of traditional herbal medicines, except in the case of endometrial thickness, and significant differences appeared in recovered ova count and fertilized ova count. These observations suggest that a regimen of herbal medicine adapted to the various stages of in vitro fertilization may be a useful complementary therapy during pregnancy.

The Traditional Japanese Herbal Medicine Hachimijiogan Elicits Neurite Outgrowth Effects in PC12 Cells and Improves Cognitive in AD Model Rats via Phosphorylation of CREB.

Hachimijiogan (HJG) is a traditional herbal medicine that improves anxiety disorders in patients with dementia. In this study, we tested the hypothesis that HJG exerts neurotrophic factor-like effects to ameliorate memory impairment in Alzheimer disease (AD) model rats. First, we describe that HJG acts to induce neurite outgrowth in PC12 cells (a rat pheochromocytoma cell line) like nerve growth factor (NGF) in a concentration-dependent manner (3 µg/ml HJG, p < 0.05; 10-500 µg/ml HJG, p < 0.001). While six herbal constituents of HJG, Rehmannia root, Dioscorea rhizome, Rhizoma Alismatis, Poria sclerotium, Moutan bark, and Cinnamon bark, could induce neurite outgrowth effects, the effect was strongest with HJG (500 µg/ml). Second, we demonstrated that HJG-induced neurite outgrowth was blocked by an inhibitor of cAMP response element binding protein (CREB), KG-501 (10 µM, p < 0.001). Moreover, HJG was observed to induce CREB phosphorylation 20-90 min after treatment (20 min, 2.50 ± 0.58-fold) and CRE-mediated transcription in cultured PC12 cells (500 µg/ml, p < 0.01; 1000 µg/ml, p < 0.001). These results suggest a CREB-dependent mechanism underlies the neurotrophic effects of HJG. Finally, we examined improvements of memory impairment following HJG treatment using a Morris water maze in AD model animals (CI + Aß rats). Repeated oral administration of HJG improved memory impairment (300 mg/kg, p < 0.05; 1000 mg/kg, p < 0.001) and induced CREB phosphorylation within the hippocampus (1000 mg/kg, p < 0.01). Together, our results suggest that HJG possesses neurotrophic effects similar to those of NGF, and can ameliorate cognitive dysfunction in a rat dementia model via CREB activation. Thus, HJG could potentially be a substitute for neurotrophic factors as a treatment for dementia.

The Effect of Hachimi-Jio-Gan (Ba-Wei-Di-Huang-Wan) on the Quality of Life in Patients with Peripheral Arterial Disease - A Prospective Study Using Kampo Medicine.

Objective: To assess whether Hachimi-jio-gan (HJG), a preparation of Kampo medicine (traditional Japanese medicine), improves quality of life (QOL) in patients with peripheral arterial disease (PAD). Materials and Methods: Among the patients with PAD being followed in the Department of Cardiovascular Surgery at Tokyo Medical University Hachioji Medical Center, those with intermittent claudication (IC) and in stable condition regarding PAD severity were registered. We registered the patients from April 2014 to March 2015. We administered HJG extract for 6 months to the patients. The primary endpoint was Walking Impairment Questionnaire (WIQ) score, which was approved as an indicator of QOL of the patient with PAD. We assessed WIQ score both before and after administration of the HJG. Results: We analyzed 14 patients. WIQ items of pain, distance, and speed improved significantly. Furthermore, the median of the total score of WIQ improved significantly from 162.5 points to 308.0 points. All patients showed improvement in the total score and 7 patients out of 14 patients (50%) showed a remarkably effective improvement in score of more than 100 points. Conclusion: HJG might improve the QOL in patients with IC due to PAD.

Efficacy of Japanese traditional (Kampo) medicine for treating chemotherapy-induced peripheral neuropathy: A retrospective case series study.

AIM: To investigate Japanese traditional (Kampo) medicine's effectiveness on cancer chemotherapy-induced peripheral neuropathy (CIPN), we carried out this retrospective study. METHODS: By searching our outpatient database of 3154 patients who consulted our outpatient clinic of Japanese-Oriental (Kampo) Medicine at Chiba University Hospital from November 2005 to December 2010, a total of 281 patients diagnosed with cancer were identified. Twenty-four patients out of the 281 patients identified met the following three conditions and were eligible for further investigation of the effectiveness of Kampo treatment: At least one course of cancer chemotherapy had been administered; numbness and pain appeared after the chemotherapy; and CIPN was diagnosed before they were given Kampo treatment. RESULTS: The 24 patients included 6 males and 18 females and ranged in age from 39 to 86 (mean 61.2 ± 11.5) years old. Kampo formulas were individually chosen by Kampo expert doctors based on Kampo-specific diagnostics. Beneficial outcomes were obtained by Kampo treatment in 20 out of the 24 cases (83.3%). Nine out 20 cases had a major response (the numbness and pain showed improvement or reduction by 50% or more), with 7 of 9 cases showing a more than 70% symptom reduction. Eleven out of 20 cases showed a minor response (less than 50% symptom reduction), and 4 out of the 24 cases had no beneficial response. The most frequently used formula was goshajinkigan (GJG), followed by hachimijiogan (HJG) and keishibukuryogan. Thirteen of the 24 cases (54.2%) were prescribed aconite root-containing formulas including GJG and HJG. Aconite root has "warming" effects and ameliorates pain and numbness; 21 out of 24 cases (87.5%) in total used warming formulas such as aconite root-containing formulas to reduce CIPN. CONCLUSION: Our current study suggested that Kampo formulas chosen based on Kampo-specific diagnostics could be for treating CIPN that is refractory to conventional medicine.

Application of a quantitative (1)H-NMR method for the determination of paeonol in Moutan cortex, Hachimijiogan and Keishibukuryogan.

Quantitative (1)H-NMR ((1)H-qNMR) was applied to the determination of paeonol concentration in Moutan cortex, Hachimijiogan, and Keishibukuryogan. Paeonol is a major component of Moutan cortex, and its purity was calculated from the ratio of the intensity of the paeonol H-3' signal at δ 6.41 ppm in methanol-d 4 or 6.40 ppm in methanol-d 4 + TFA-d to that of a hexamethyldisilane (HMD) signal at 0 ppm. The concentration of HMD was corrected with SI traceability by using potassium hydrogen phthalate of certified reference material grade. As a result, the paeonol content in two lots of Moutan cortex as determined by (1)H-qNMR was found to be 1.59 % and 1.62 %, respectively, while the paeonol content in Hachimijiogan and Keishibukuryogan was 0.15 % and 0.22 %, respectively. The present study demonstrated that the (1)H-NMR method is useful for the quantitative analysis of crude drugs and Kampo formulas.

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate cyclophosphamide-induced ongoing bladder overactivity and acidic adenosine triphosphate solution-induced hyperactivity on rats prestimulated bladder.

ETHNOPHARMACOLOGICAL RELEVANCE: Ba-Wei-Die-Huang-Wan (BWDHW) is the traditional Chinese medicine formula containing eight ingredients, namely Rehmannia glutinosa (Gaetn.) DC., root, steamed & dried; Cornus officinalis Siebold & Zucc., fructus, dried; Dioscorea oppositifolia L., root, dried; Alisma plantago-aquatica, subsp. orientale (Sam.) Sam., tuber, dried; Poria cocos (Fr.) Wolf., sclerotium, dried; Paeonia×suffruticosa Andrews, bark, dried; Cinnamomum cassia (Nees & T.Nees) J. Presl, bark, dried; Aconitum carmichaeli Debeaux, lateral root, dried & processed. It has been used for diabetes and urinary frequency treatments. AIM OF THE STUDY: We investigate effects of BWDHW on cyclophosphamide (CYP)-induced ongoing bladder overactivity and acidic adenosine triphosphate (ATP) solution-induced hyperactivity on rat's prestimulated bladder. MATERIAL AND METHODS: Female Wistar rats were injected with intraperitoneal CYP (100mg/kg) or saline respectively. Rats were treated with BWDHW (90mg/kg/day) or vehicle for the next five days. After treatments animals were evaluated both in metabolic cage model and then by cystometry. Acidic ATP solution (5mM, pH 3.3) was instilled to provoke bladder hyperactivity. Bladder mucosa and muscle proteins were assessed by Western blotting. RESULTS: As compared to the controls, the CYP group showed significantly decreased mean cystometric intercontractile interval and increased micturition frequency, whereas the CYP/BWDWH group did not. The CYP group had significant protein overexpression in mucosal M2, M3, P2X2, and P2X3 receptors as well as detrusor M2 and M3 receptors. However, the CYP/BWDWH group had insignificant changes from controls. In the provoking test, the control/BWDHW and CYP/BWDHW groups were less affected by acidic ATP stimulation of intercontractile interval changes than the control group. Compared to the control group, the control/BWDHW group showed significantly lower mucosal P2X3 protein expression and the CYP group showed significant mucosal TRPV1 protein upregulation after the provoking test. CONCLUSION: BWDHW treatment can ameliorate CYP-induced ongoing bladder overactivity and suppress mucosal P2X2, P2X3, M2, and M3 receptor protein overexpression, as well as detrusor M2 and M3 receptor protein overexpression. BWDHW pretreatment can reduce acidic ATP solution-provoked hyperactivity by preventing TRPV1 receptor overexpression in CYP-treated bladder mucosa and inhibiting P2X3 receptor overexpression in naïve bladder mucosa.

<b>Two Cases of Stress-induced Chronic Cough Successfully Treated with H</b><b>achimijiogan</b> / 日本東洋医学雑誌

<p>In Kampo, respiratory symptoms are treated with prescriptions related not only to “lung”, but also other parenchymatous viscera. We report 2 patients whose stress-induced chronic cough was ameliorated by <i>hachimijiogan</i>. Case 1 was a 25-year-old female who was working under stressful circumstances at her company and reported an oppressive feeling in the chest. She was initially prescribed <i>hangekobokuto </i>because of a feeling that something was stuck in the pit of her stomach on abdominal examination, but her cough did not get better. As she also noted a dull feeling in her back ; she was switched to <i>hachimigan</i>, and her cough disappeared. Case 2 was 42-year-old female who suffered from depression, sore throat and an obstructive feeling in the throat ; she had been receiving infertility treatment for several years. <i>Hangekobokuto </i>and <i>bakumondoto </i>showed insufficient effect on her persistent cough. Her coughing stopped when she was prescribed <i>hachimigan </i>for back pain. Neither of these patients showed lack of resistance of the lower abdomen on abdominal examination.<br>Chronic <i>ki </i>(qi) stagnation under stressful conditions may cause <i>ki </i>deficiency, especially kidney deficiency. The symptom of stress-induced cough in our cases was considered to be due to kidney deficiency, and therefore <i>hachimijiogan</i>, but not <i>hangekobokuto</i>, was effective. The short duration of the complaints and relatively young age (20-40's) of the patients may account for the absence of the typical abdominal sign of kidney deficiency. Back stiffness and pain may also be important signs for cough due to kidney deficiency.</p>

Clinical efficacy and tolerability of two Japanese traditional herbal medicines, Hachimi-jio-gan and Gosha-jinki-gan, for lower urinary tract symptoms with cold sensitivity.

We evaluated the efficacy and tolerability of Hachimi-jio-gan (HJG; ba wèi dì huáng wán) and Gosha-jinki-gan (GJG; jì sheng shèn qì wán), two traditional Japanese medicines, in 60 patients with lower urinary tract symptoms (LUTS) having cold sensitivity unresponsive to α1-blockers or antimuscarinic drugs. All patients received a mixture of HJG or GJG for 12 weeks in addition to α1-blockers or antimuscarinic drugs as add-on therapy. International Prostate Symptom Score, International Prostate Symptom Score-Quality of Life, Benign Prostatic Hyperplasia Impact Index, and the number of nocturnal voids were statistically much improved. However, there was no change in maximal urinary flow rate and post-void residual urine. Urinary 8-hydroxy-2-deoxyguanosine was statistically greatly improved from baseline after treatment in the HJG group compared to the GJG group. Adverse reactions were observed in 8.3% of patients, but all reactions were mild. Both HJG and GJG mixtures can serve as safe and effective potential therapeutic alternatives in patients with LUTS and cold sensitivity unresponsive to α1-blockers or antimuscarinic drugs. Additionally, HJG mixture was found to have anti-oxidative activity, and therefore further long-term clinical investigations are needed to examine its anti-aging effects in addition to its effect on urinary symptoms.

Effects of Hachimijiogan, a Kampo powder, on epididymidis sperm characteristics in healthy male rats.

Purpose: Hachimijiogan (HJG, Rehmannia Eight Formula), a kidney-replenishing Kampo formula, is clinically known to be effective in the treatment of male infertility with oligozoospermia. The purpose of this study was to evaluate the effect of HJG on the epididymal sperm characteristics and related serum hormone changes in rats in an attempt to determine its mechanism. Methods: Male Wistar-Imamichi rats (233.4 ± 5.2 g, nine weeks old) were assigned randomly to four groups (n = 6 for each group). Apart from one control group treated with distilled water, the other groups were administered HJG consecutively for 9-11 days with doses of 250, 500 and 1,000 mg/kg. After the last administration the caude epididymides were quickly removed under anesthesia for assessing sperm characteristics. Additionally, the testes, seminal vesicles, prostate and adrenal glands were removed surgically and their wet weights measured. Results: Results showed that HJG increased sperm numbers and motility as well as the weights of seminal vesicles and adrenal glands at lower doses. Moreover, HJG decreased serum levels of testosterone and luteinizing hormone while increasing follicle-stimulating hormone levels. Conclusions: Our findings may support the conclusion that a lower dosage of HJG has an effect on improving local spermatogenous environments by activating adrenal functions and/or promoting local androgen activity.

<b>Effect of Hachimijiogan for Male Lower Urinary Tract Symptoms</b> / 日本東洋医学雑誌

We evaluated the effect of hachimijiogan in 30 cases of anticholinergic agent and α-blocker resistant LUTS. International Prostate Symptom Scores (IPSS), QOL scores, Benign Prostatic Hyperplasia Impact Index (BII) scores and urinary 8-OHdG of the patients were statistically much improved. This study demonstrated improvement in urinary symptoms, urinary QOL and oxidative stress, in LUTS resistant to anticholinergic agents and α-blockers. Further long-term studies will be needed not only in urinary symptoms, but also in effect as an anti-aging medicine.