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.

Identification of a predictive biomarker for the beneficial effect of keishibukuryogan, a kampo (Japanese traditional) medicine, on patients with climacteric syndrome.

Keishibukuryogan (KBG; Guizhi-Fuling-Wan in Chinese) is one of the Kampo (Japanese traditional) medicines used to treat patients with climacteric syndrome. KBG can be used by patients who cannot undergo hormone replacement therapy due to a history of breast cancer. We evaluated whether cytosine-adenine (CA) repeat polymorphism of the estrogen receptor ß gene can be a predictor of the beneficial effect of KBG on climacteric syndrome. We also investigated the relationship between CA repeat polymorphism, the patients' profiles, and the therapeutic effect. We found that CA was an SS, SL, or LL genotype according to the number of repeats. We studied 39 consecutive patients with climacteric disorders who took KBG for 12 weeks. The diagnosis of climacteric disorders was made on the basis of the Kupperman index. KBG significantly improved the patients' climacteric symptoms (i.e., vasomotor symptoms in the patients with the LL genotype and melancholia in the patients with the SL genotype). No relationship between the patients' profiles and CA repeat polymorphism was recognized. CA repeat polymorphism could thus be a potential biomarker to predict the efficacy of KBG in climacteric syndrome, and its use will help to reduce the cost of treating this syndrome by focusing the administration of KBG on those most likely to benefit from it.

A valid approach in refractory glossodynia: a single-institution 5-year experience treating with Japanese traditional herbal (kampo) medicine.

Glossodynia is often refractory to conventional medicine, and there is only limited evidence to guide clinicians in its management. Patients with refractory glossodynia are often introduced to Japanese traditional herbal (Kampo) medicine experts under such circumstances because Kampo medicine has become known in Japan to be effective in treating a wide variety of symptoms refractory to conventional medicine. Herein, we report our single-institution 5-year experience treating patients with Kampo medicine for primary glossodynia that was refractory to conventional medicine. We found that 69.2% of patients reported a beneficial effect of Kampo medicine on glossodynia, and the average onset of improvement was 8.0 ± 7.7 weeks after starting Kampo treatment. The top two frequently used Kampo medicines for glossodynia were seinetsuhokito and mibakuekkito among high responders who showed a decrease of severity by 50% or more. The top four most overlapped herbs among effective Kampo medicines for glossodynia were Glycyrrhiza Root, Ginseng Root, Hoelen, and Atractylodes (lancea) Rhizome, which compose an essential Kampo prescription called shikunshito. Although more research is required to further clarify the effectiveness of Kampo medicine, it has valid efficacy even in cases of glossodynia that remain incurable by conventional treatments.

Neuronal nitric oxide synthase-derived nitric oxide is involved in gastric mucosal hyperemic response to capsaicin in rats.

BACKGROUND AND AIMS: Activation of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin leads to gastric hyperemic response through capsaicin-sensitive sensory nerves and nitric oxide (NO). The aim of the present study is to examine which isoform of nitric oxide synthase (NOS)/NO is involved in the hyperemic response to capsaicin in the rat stomach. METHODS: Gastric mucosal blood flow (GMBF) was measured by laser Doppler flowmetry in rats. The localizations of TRPV1 and neuronal NOS (nNOS) in the rat gastric mucosa were detected by immunohistochemical staining. RESULTS: The nNOS inhibitor N(5)-[imino(propylamino)methyl]-L-ornithine substantially reduced GMBF during capsaicin application, whereas the endothelial NOS (eNOS) inhibitor N(5)-(1-iminomethyl)-L-ornithine did not affect the effect of capsaicin during the application. The nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester apparently inhibited the capsaicin-induced GMBF, while the inducible NOS inhibitor 1400W did not affect GMBF response to capsaicin. The immunohistochemical studies revealed nerve fibers coexpressing TRPV1 and nNOS around blood vessels in the gastric submucosa. CONCLUSION: We demonstrated for the first time that nNOS/NO is involved in gastric hyperemic responses to capsaicin.

Orengedoku-to augmentation in cases showing partial response to yokukan-san treatment: a case report and literature review of the evidence for use of these Kampo herbal formulae.

BACKGROUND: Yokukan-san, a Japanese traditional herbal (Kampo) prescription, has recently gathered increasing attention due to accumulating reports showing its remarkable efficacy in treating a wide variety of diseases refractory to conventional medicine as well as the behavioral and psychological symptoms of dementia. As yokukan-san has become broadly integrated with conventional medicine, augmentation therapy with other Kampo prescriptions has become necessary when the yokukan-san has been only partially efficacious. In this paper, we report three cases in which the addition of orengedoku-to, another Kampo formula, to yokukan-san was remarkably effective. CASES: Case 1 was an 85-year-old man with Alzheimer-type dementia who had become aggressive during the past 2 years. Three milligrams of aripiprazole completely suppressed his problematic behaviors but had to be stopped because of extrapyramidal symptoms. In the second case, a 44-year-old man with methamphetamine-induced psychosis had suffered from serious tardive dystonia for 2 years. No conventional approach had improved his tardive dystonia. The third case was a 29-year-old engineer who often failed to resist aggressive impulses and was diagnosed with intermittent explosive disorder. He was prescribed 5 mg of olanzapine, which did not suppress his extraordinary anger and caused somnolence even though the dose was low. INTERVENTIONS AND OUTCOMES: Yokukan-san was complementarily added to the patients' regular medication and exerted a definitive but partial effect in all cases. The addition of orengedoku-to to yokukan-san exerted the same efficacy as aripiprazole in controlling aggressiveness in Case 1, improved the tardive dystonia by 80% in Case 2, and was completely effective in controlling the patient's aggressive impulses in Case 3. CONCLUSION: Together with empirical evidence demonstrating the effectiveness of both yokukansan and orengedoku-to in reducing irritability, impulsivity, and aggression, these three cases suggest that orengedoku-to augmentation can be an effective option in cases that are partially responsive to yokukan-san treatment.

A case of aromatase inhibitor (anastrozole)-induced side-effects successfully treated with Kampo medicines.

OBJECTIVES: Breast cancer is the fourth most frequent cause of death, and it is currently the most frequent cause of death among Japanese women. As to breast cancer therapy, lengthy hormonal therapy is very important for the treatment and prevention of recurrence. Aromatase inhibitors (AIs) are the initial drug of choice for postoperative adjuvant therapy of breast cancer in Japan. AIs require long-term use and occasionally cause serious side-effects. In this report, the effects of Kampo medicines (Japanese traditional medicines) on AIs-induced side-effects are described. SUBJECT: A 55-year-old woman visited the Kampo outpatient department of Chiba University Hospital for atypical genital bleeding and arthralgia. At the age of 54, she suffered from left breast cancer and underwent left total mastectomy followed by chemotherapy for 6 months. Afterwards, 1 mg/day of anastrozole, one of the AIs, was used for therapy. Three (3) months later, atypical genital bleeding from vaginal mucosa and joint pains of bilateral hands and knees occurred as side-effects of anastrozole. Her attending doctor could only prescribe nonsteroidal external medicine for the inflammation of vaginal mucosa and do close follow-up. However, her symptoms showed no improvement. INTERVENTIONS AND OUTCOME: Her deficiency of both ki (qi) and ketsu (Blood) was diagnosed based on Kampo diagnostics. Juzentaihoto was used for treatment. After taking juzentaihoto for 5 weeks, the atypical genital bleeding disappeared, and she no longer need topical medicine. Because her arthralgia showed no improvement, powdered processed aconitine root was added. After taking 3.0 g/day of this medication, her arthralgia almost completely disappeared. CONCLUSIONS: Controlling the side-effects is a clinical issue from the viewpoint of adherence to drug treatment. Kampo therapy should be considered one of the choices for side-effects in the process of cancer treatment.

A case of mediastinal lymphangioma successfully treated with Kampo medicine.

OBJECTIVE: The authors report a case of mediastinal lymphangioma successfully treated with Kampo medicine. METHODS: A 2-year-old boy with an axillary soft mass consulted our clinic. Physical examination findings were normal except for axillary elastic swelling. The neck and chest magnetic resonance imaging scan (MRI) showed a multilocular mass starting from a cervical lesion and extending above the carina. RESULTS: After 9 months of Kampo administration, MRI showed marked regression of mediastinal lymphangioma. CONCLUSIONS: It was found that Kampo medicine might be safe and effective as an alternative choice of treatment for lymphangiomas.

A case of thalamic pain successfully treated with Kampo medicine.

OBJECTIVE: Thalamic pain, one of the central painful poststroke symptoms, is a severe pain that is often intractable. A case of thalamic pain successfully treated with Kampo medicine is presented. SUBJECT: A 65-year-old woman complained of moderate continuous and paroxysmal severe pain in the right upper and lower limbs after she had suffered from stroke. She also complained of sensory disturbance and intermittent involuntary movement. A magnetic resonance imaging scan of the brain showed an old infarction in the left thalamus. INTERVENTIONS AND OUTCOME: Paroxetine was administered, but it was stopped because of nausea. Etizolam was effective in reducing the pain for only about 30 minutes. Sokeikakketsuto decoction, one of the Kampo medicines, was administered orally on the basis of Kampo diagnostic criteria. Ten (10) days later, the pain had almost disappeared, and the other symptoms had also improved. CONCLUSIONS: This result suggested that Sokeikakketsuto could be an option for the treatment of thalamic pain under certain conditions.

A suspected case of somatoform disorder successfully treated with an herbal medicine.

OBJECTIVE: Subjective physical symptoms, irrespective of whether they are psychosomatic or not, do not always show obvious or reasonable signs in examinations, which often makes the differential diagnosis between somatoform disorders and actual physical disease difficult for psychiatrists. In addition, psychiatrists have few clues as to how to treat diverse "medically unexplained" symptoms. This difficulty has highlighted the need for alternative treatments for somatoform disorders. SUBJECT: A 16-year-old high school baseball player was suffering from coxalgia and was unable to walk without crutches over 6 months. No painkiller was effective, the orthopedist found no remarkable signs in any examinations, and the patient was psychiatrically diagnosed with undifferentiated somatoform disorder. However, conventional therapies such as psychotherapy and selective serotonin reuptake inhibitors were ineffective. INTERVENTIONS AND OUTCOME: The therapeutic strategy was reevaluated from the perspective of Kampo diagnostics and keishikajutsubuto, a traditional Japanese herbal (Kampo) medicine, was chosen to be prescribed, which had a remarkable effect. His leg function improved within 2 weeks, and his pain and need for crutches disappeared in 6 weeks. CONCLUSIONS: Keishikajutsubuto has a different pain-relieving effect from conventional therapies. Kampo medicine thus provides an alternative approach for treating medically unexplained symptoms without strictly distinguishing between physically existing illness and psychologically caused somatoform disorders. Although details regarding the therapeutic mechanisms of Kampo medicine remain unclear and further studies are needed to increase its usefulness in clinical practice, Kampo medicine should be considered as an alternative treatment, especially for somatoform disorders.

Three Cases of Chemotherapy-induced Peripheral Neuropathy Successfully Treated With Therapy Based on Kampo Diagnosis.

Patients undergoing chemotherapy often develop symptoms of neurological side effects such as numbness, pain, and weakness in a stocking-and-glove pattern. Yet few therapies are available to treat this condition. We examined the efficacy of therapy based on Kampo diagnosis in three cases of chemotherapy-induced peripheral neuropathy (CIPN). These patients all had severe cases, and the symptoms of CIPN interfered with their daily lives even after the cessation of the offending drugs. Early cessation of the drug therapy would be ideal, but in some cases where chemotherapies were effective against cancer, CIPN was worsened by prolonged administration. With the initiation of therapy based on Kampo diagnosis, the subjects of these case reports showed marked improvement in their daily activities. The Kampo diagnosis of CIPN is not only Jinkyo, as Tankaku, Kiutsu, and other Kampo clinical conditions can be candidates. We consider that the traditional way of Kampo diagnosis can provide options for the treatment of CIPN.

A new laser ablation system for quantitative analysis of solid samples with ICP-MS.

The laser ablation (LA) method is an effective technique for quantitative analysis. In the present work, a new LA system was developed for the high-sensitivity analysis of metal materials using inductively coupled plasma mass spectrometry (ICP-MS). This system consists of a high-frequency Q-switched laser and 2 scanning mirrors for scanning the ablation spot in an adequately large area of the specimen without vacant spaces. The influence of elemental fractionation (non-stoichiometric generation of vapor species) can be eliminated by repetitive irradiation of this pattern on the same area. Particles generated with an average laser power of 0.6 W with the developed LA system gave intensity and stability substantially similar to that of a 500 microg/ml solution steel sample in solution ICP-MS. The analytical performance of the developed LA-ICP-MS was compared with that of a solution ICP-MS using NIST steel SRMs. The performance of the newly-developed system is comparable to that of conventional solution ICP-MS in both accuracy and precision. The correlation coefficients between the contents and the intensity ratios to Fe were over 0.99 for most elements. The relative standard deviation (RSD) obtained by LA-ICP-MS revealed that this system can analyze iron samples with good precision. The results of ultra trace level analysis of high-purity iron showed that developed LA-ICP-MS is capable of analyzing ppm concentration levels with a 20 - 30 ppb level standard deviation. The detection limit was on the order of 10 ppb for most elements.

TAK1-mediated transcriptional activation of CD28-responsive element and AP-1-binding site within the IL-2 promoter in Jurkat T cells.

We focused on the functional involvement of transforming growth factor-beta-activated kinase 1 (TAK1) in transcriptional regulation of interleukin-2 (IL-2) in T cells. Costimulation of Jurkat cells with 12-O-tetradecanoylphorbol-13-acetate and A23187 leads to a rapid phosphorylation of TAK1 and TAK1-binding protein 1 (TAB1), critical for TAK1 activation. A specific inhibitor of TAK1 blocked production of IL-2. In addition, overexpression of TAK1 and TAB1 induced secretion of IL-2. CD28-responsive element/activator protein-1-binding site (RE/AP) within the IL-2 promoter was a functional target for TAK1. The RE/AP-driven transcription was regulated by TAK1-mediated activation of the c-Jun NH2-terminal kinase, p38 and IkappaB kinase. These results indicate that TAK1 plays a critical role in T cell activation by controlling production of IL-2.

A newly devised formulation for self-medication enhances interferon-gamma production and proliferation of splenic lymphocytes.

A newly devised formulation for self-medication in Toyama, PanaWang, is a new herbal medicine (so called Toyama original brand formulation) developed based on traditional philosophy and scientific evidence. We here tried to examine the effect of oral administration of PanaWang on the balance of type I helper T cells (Th1) and Th2 cells. Splenic lymphocytes from normal mice were stimulated with Concanavalin A (Con A) in vitro and the secretion of Th1- and Th2-type cytokines, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) respectively, was investigated. Con A-induced production of IFN-gamma from spleen cells, but not IL-4, was enhanced by the administration of PanaWang. Increased production of IFN-gamma was also detected in splenic lymphocytes from Th2-predominant BALB/c mice after DNP-immunization, without a change in antigen-specific IgE levels in vivo. Antigen-specific proliferative responses were also increased in lymphocytes from PanaWang-treated mice. These findings raise the possibility that PanaWang has Th1-stimulating activity and induces Th1-predominant immunity.

Juzentaihoto, a Kampo medicine, enhances IL-12 production by modulating Toll-like receptor 4 signaling pathways in murine peritoneal exudate macrophages.

Juzentaihoto (TJ-48), a Kampo medicine, has been reported to affect the immune system. Although toll-like receptors (TLRs) have been identified as receptors of innate immunity, the effects of TJ-48 on TLR signaling pathways have not been thoroughly investigated. Here we evaluated the effects of TJ-48 on TLR4 signaling pathways. Peritoneal exudate macrophages (PEMs) isolated from mice orally administered TJ-48 for 11 days were stimulated with lipopolysaccharide (LPS), a ligand of TLR4, in vitro. Production of IL-12 p40 was significantly augmented in TJ-48-treated PEMs compared with that in vehicle PEMs, without affecting the surface expression of TLR4. Treatment with chemical inhibitors of NF-kappa B and p38 mitogen-activated protein kinases (MAPKs) in vitro inhibited LPS-induced IL-12 production, whereas JNK and ERK inhibitors increased IL-12 production. Immunoblotting with phosphorylation-state specific antibodies demonstrated that TJ-48 differentially affected LPS-induced phosphorylation of NF-kappa B and MAPKs. In PEMs treated with TJ-48, LPS-induced phosphorylation of p65 NF-kappa B and p38 MAPK was augmented, while that of JNK and ERK was attenuated compared with those in vehicle PEMs. These results suggest that selective modulation of the TLR4 signaling pathways by TJ-48 is involved in enhanced production of IL-12 in PEMs.

Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway.

The activation of NF-kappaB has been shown to be regulated by multiple phosphorylations of IkappaBs and the NF-kappaB p65 subunit. Here, we characterized the intracellular signaling pathway leading to phosphorylation of p65 on Ser-536 using a novel anti-phospho-p65 (Ser-536) antibody. The Ser-536 of endogenous p65 was rapidly phosphorylated in response to a wide variety of NF-kappaB stimulants including TNF-alpha in the cytoplasm and rapidly dephosphorylated in the nucleus. The TNF-alpha-but not IL-1beta-induced Ser-536 phosphorylation was severely impaired in murine embryonic fibroblasts derived from traf2-/-traf5-/- mice. Bay 11-7082, an inhibitor of IkappaB phosphorylation, inhibited the TNF-alpha-induced phosphorylation in vivo. In addition, overexpression of TGF-beta-activated kinase 1 (TAK1), IKKalpha and IKKbeta stimulated the phosphorylation, and their dominant negative mutants blocked the TNF-alpha-induced phosphorylation. Moreover, small interfering RNAs (siRNAs) against TAK1, IKKalpha and IKKbeta blocked the phosphorylation of endogenous p65. On the other hand, calyculin-A, a protein phosphatase inhibitor, blocked the dephosphorylation in the nucleus in vivo. These results indicate that similar signaling pathways were utilized for the phosphorylations of IkappaBalpha and p65, which further support the idea that both IkappaB and NF-kappaB are substrates for the IKK complex in the activation of NF-kappaB.