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Aim: 5‐Fluorouracil/folinic acid and oxaliplatin plus bevacizumab (FOLFOX + BV) is a standard chemotherapy regimen for metastatic colorectal cancer (mCRC). This study was aimed at evaluating the preventive effects of shakuyakukanzoto against oxaliplatin‐induced neurotoxicity associated with FOLFOX + BV administration. Methods: In this single‐arm, open‐label, phase II clinical trial, we enrolled patients with previously untreated, histologically confirmed mCRC from six hospitals in Japan who were aged 20 years and older and had an Eastern Cooperative Oncology Group performance status of 0–1. The patients received shakuyakukanzoto 2.5 g thrice daily, orally, until disease progression and/or unacceptable toxicity was noted. The primary endpoint was the incidence of neurotoxicity following oxaliplatin administration at a dose of 500 mg/m2. Neurotoxicity was evaluated according to the Neurotoxicity Criteria of Debiopharm (DEB‐NTC). The trial was registered in the UMIN Clinical Trials Registry of Japan (UMIN000001853). Results: Forty‐one non‐pretreated mCRC patients were included between April 2009 and September 2013. At an oxaliplatin dose of 500 mg/m2, neurotoxicity of DEB‐NTC grade 1–2 developed in 25.0% of patients; no patient had DEB‐NTC grade 3 neurotoxicity. The most common grade 3/4 adverse events were neutropenia (34.1%), hypertension (24.4%), and fatigue (9.8%). The response rate of the 38 patients with measurable lesions was 55.2%. The median progression‐free and overall survival was 14.9 and 35.2 months respectively. Conclusion: Shakuyakukanzoto substantially reduced oxaliplatin‐induced neurotoxicity without negatively affecting tumor response or survival in FOLFOX + BV‐treated patients with CRC. [ABSTRACT FROM AUTHOR]

Abstract Introduction/aims Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS. Methods This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). Discussion The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life. Trial registration This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

Aim: Chemotherapy for cancer patients induces peripheral neuropathic pain as a refractory side effect. We reported that the prophylactic repeated oral administration of a traditional herbal medicine, shakuyakukanzoto (SKT), peripherally inhibited paclitaxel‐induced mechanical allodynia in mice. In the present study, we therefore developed external gel forms of SKT and the major constituent paeoniflorin (PF), and evaluated their effects on paclitaxel‐induced mechanical allodynia in mice. Methods: A single intraperitoneal injection of paclitaxel was given to mice. SKT or PF external gel (SKT‐Gel or PF‐Gel) was topically applied to the right planar surface twice daily for 13 days. Mechanical allodynia was evaluated by the von Frey filament test. Results: The prophylactic repeated topical application of SKT‐Gel or PF‐Gel on the right planar surface inhibited the exacerbation of paclitaxel‐induced mechanical allodynia. However, the prophylactic repeated topical application of external base gel (BS‐Gel) on the left planar surface in the same mice treated with paclitaxel did not affect the allodynia. Conclusion: Prophylactic repeated topical applications of SKT‐Gel and PF‐Gel locally inhibited the exacerbation of paclitaxel‐induced mechanical allodynia. These gels were useful for the control of paclitaxel‐induced peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

Abstract Background Muscle soreness after exercise, called delayed-onset muscle soreness (DOMS), may cause significant changes in muscle function and may increase the risk of sports injuries. Therefore, various therapeutic strategies have been studied to help recovery after exercise. Jakyakgamcho-tang (JGT) is a widely prescribed herbal medicine to treat muscle pain and cramps in traditional Eastern medicine. The aim of this study is to evaluate the effect of JGT for reducing pain and improving muscle damage after exercise. Methods This study is a randomized, double-blind, placebo-controlled, crossover design clinical trial. A total of 30 healthy male adults will be recruited. Subjects who voluntarily wish to participate in this study will be hospitalized for 4 days. On the first day, the subjects will perform a standardized treadmill exercise for 1 h to induce DOMS. After the exercise, the subjects will take either JGT or a placebo for 3 days. After a more than 1 week wash-out period, the subjects will repeat the same process with the other drug. Pain intensity, calf circumference, and pain threshold will be measured as outcome measures. Blood tests and blood pressure will be measured as safety assessments. In addition, blood tests for muscle damage and inflammation markers, such as creatine kinase, interleukin-6, and C-reactive protein, will be analyzed. Discussion This will be the first trial to assess the effect of JGT on exercise-induced muscle soreness. Our findings will provide valuable data to determine the clinical effects of JGT on DOMS. Trial registration Clinical Research Information Sevice, KCT0003457. Registered on 29 January 2019.

Introduction: Shakuyakukanzoto (SKT), a Kampo medicine, has been shown to alleviate paclitaxel-induced neuropathic pain in several studies. This report presents a case in which SKT was successfully used to treat vincristine/vinblastine-induced neuropathic pain. Case presentation: A patient received anticancer drugs for almost 3 years to treat a low-grade recurrent cerebellar glioma. Two cycles of combination therapy with carboplatin and vinblastine and 12 cycles of carboplatin and vincristine were administered, followed by vinblastine monotherapy. The patient began to experience tingling oral pain on the second day after first injection of carboplatin and vinblastine. Three months after the initiation of chemotherapy, vinblastine was replaced with vincristine. The patient suffered severe hiccups. SKT was administered thrice daily to prevent hiccups. Thereafter, hiccups disappeared, and the oral pain was also relieved. SKT markedly improved the patient's quality of life during chemotherapy. Discussion: The findings of previous studies showing an analgesic effect of SKT for chemotherapy-induced neuropathic pain by paclitaxel were consistent with the present result using vincristine/vinblastine. Vinca alkaloids inhibit spindle function by targeting microtubules to arrest cellular mitosis, similar to paclitaxel. Conclusion: SKT had analgesic effects on oral neuropathic pain induced by vinca alkaloids, which have a similar mechanism of action as paclitaxel. [ABSTRACT FROM AUTHOR]

Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) show excessive peristalsis, and antispasmodic agents may be useful therapeutic agents. There are few reports on the use of Kampo medicines for the treatment of IBS-D. Shakuyakukanzoto (SKT) is a Kampo medicine that is effective against abdominal pain. We examined the relationship between SKT and intestinal peristalsis in an animal model and a prospective study. In the animal model, SKT and its components were administered from the serosal side of the colon and colonic peristalsis was evaluated using intraluminal pressure and spatiotemporal mapping before and after the administration of SKT and its components. In this clinical trial, we used abdominal ultrasonography (US) to obtain long-axis images of the sigmoid colon of 11 patients. The frequency of intestinal peristalsis was measured using US in five patients with SKT and six patients without medication after the ingestion of a test meal. The primary outcome was the frequency of peristalsis. The Clinical Trial Registry Website (Trial No. UMIN-CTR; UMIN000051547). In the animal model, peony did not suppress peristalsis frequency, but SKT (p = 0.005) and glycyrrhiza (p = 0.001) significantly suppressed peristalsis frequency compared with saline and peony. Among the glycyrrhiza components, glycycoumarin and isoliquiritigenin suppressed the peristalsis frequency compared to dimethyl sulfoxide (control) (p = 0.001, 0.01, respectively). In a clinical trial, peristalsis was significantly suppressed after oral administration in patients taking SKT (p = 0.03). Administration of SKT was found to inhibit colonic peristalsis, with glycicumarin and isoliquiritigenin being particularly relevant among its components.

Background: Muscle soreness after exercise, called delayed-onset muscle soreness (DOMS), may cause significant changes in muscle function and may increase the risk of sports injuries. Therefore, various therapeutic strategies have been studied to help recovery after exercise. Jakyakgamcho-tang (JGT) is a widely prescribed herbal medicine to treat muscle pain and cramps in traditional Eastern medicine. The aim of this study is to evaluate the effect of JGT for reducing pain and improving muscle damage after exercise.Methods: This study is a randomized, double-blind, placebo-controlled, crossover design clinical trial. A total of 30 healthy male adults will be recruited. Subjects who voluntarily wish to participate in this study will be hospitalized for 4 days. On the first day, the subjects will perform a standardized treadmill exercise for 1 h to induce DOMS. After the exercise, the subjects will take either JGT or a placebo for 3 days. After a more than 1 week wash-out period, the subjects will repeat the same process with the other drug. Pain intensity, calf circumference, and pain threshold will be measured as outcome measures. Blood tests and blood pressure will be measured as safety assessments. In addition, blood tests for muscle damage and inflammation markers, such as creatine kinase, interleukin-6, and C-reactive protein, will be analyzed.Discussion: This will be the first trial to assess the effect of JGT on exercise-induced muscle soreness. Our findings will provide valuable data to determine the clinical effects of JGT on DOMS.Trial Registration: Clinical Research Information Sevice, KCT0003457. Registered on 29 January 2019. [ABSTRACT FROM AUTHOR]

Abstract Background In chemotherapy, the full round of treatment must be completed as scheduled to achieve the strongest therapeutic effect. However, peripheral neuropathy, a severe side effect of the chemotherapeutic agent paclitaxel, can force the premature discontinuation of treatment. As some kampo practitioners have suggested that it may be possible to counteract such side effects, we analyzed the effects of Kamishoyosan, Shakuyakukanzoto, and Goshajinkigan in an in vitro model of paclitaxel-induced peripheral neuropathy. Methods Paclitaxel-treated PC12 cells were assessed for neurite length and performed Western blot analysis for growth-associated protein-43 (GAP-43) and light neurofilament protein (NF-L) levels in the presence of nerve growth factor (NGF); they were re-assessed, with additional testing for acetylcholinesterase levels, after application of one of the kampo. We also compared phosphorylation of extracellular signal-regulated kinase (Erk)1/2 and Akt via Western blot analysis. About effect of kampo to anticancer efficacy, we confirmed cell cytotoxicity in A549 cells using MTT assay. Results Addition of Kamishoyosan or Shakuyakukanzoto, but not Goshajinkigan, significantly improved neurite length and GAP-43 and NF-L levels from paclitaxel-treated PC12 cells, relative to those of only NGF-treated PC12 cells. The promoting effect of Kamishoyosan and Shakuyakukanzoto in neurite outgrowth is confirmed when NGF promoted neurite outgrowth, and it was inhibited partially when Erk1/2 and Akt were blocked by Erk1/2 inhibitor or Akt inhibitor alone. Furthermore, neurite outgrowth induced by TJ24 and TJ68 was inhibited more strongly when Erk1/2 inhibitor and Akt inhibitor were treated at the same time. NGF with Kamishoyosan or Shakuyakukanzoto promoted the proportion of phosphorylated Erk1/2 and phosphorylated Akt compare with NGF only. On the other hand, Kamishoyosan or Shakuyakukanzoto didn’t influence cytotoxicity of paclitaxel in A549 cells. Conclusions Kamishoyosan or Shakuyakukanzoto promotes neurite outgrowth with NGF via increasing the proportion of phosphorylated Erk1/2 and phosphorylated Akt in PC12 cells. The effect applies to recovery from paclitaxel-induced axonal involvement and might promote recovery from paclitaxel-induced neuropathy without influence of anticancer effect of paclitaxel.

Oxaliplatin-induced peripheral neuropathy characterized especially as cold dysesthesia is a major dose-limiting side effect of the drug and is very difficult to control. In the present study, we examined whether the traditional herbal formulation Shakuyakukanzoto (SKT: 芍藥甘草湯Sháo Yào Gān Cǎo Tāng) could relieve oxaliplatin-induced cold dysesthesia in mice. The inhibitory mechanisms were also investigated. Repetitive administration of SKT (0.1–1.0 g/kg) starting from the day after oxaliplatin injection inhibited cold dysesthesia in a dose-dependent manner. Our previous report has shown that the mRNA expression of transient receptor potential melastatin 8 (TRPM8), characterized as a cold-sensing cation channel, is increased in the dorsal root ganglia of mice treated with oxaliplatin. In addition, TRPM8 antagonist TC-I 2014 (10 and 30 mg/kg) also attenuated cold dysesthesia in oxaliplatin-treated mice. Taken together, it is suggested that TRPM8 is involved in the cold dysesthesia induced by oxaliplatin. Repetitive administration of SKT inhibited the mRNA expression of TRPM8 induced by oxaliplatin in the dorsal root ganglia. These results suggested that prophylactic repetitive administration of SKT is effective in preventing the exacerbation of oxaliplatin-induced cold dysesthesia by inhibiting the mRNA expression of TRPM8 in the dorsal root ganglia.

ABSTRACT: Case: A 73‐year‐old woman with a history of generalized tetanus and hypertension developed localized tetanus. Daisaikoto (DST) was used to control spasming of cervical muscles given the symptom of tenderness observed on both sides of her abdomen, kyokyo‐kuman. All symptoms except for cheek discomfort were improved. On day 7, shakuyakukanzoto (SKT) was given to control the residual symptoms. Outcome: Residual symptoms improved after treatment with DST and SKT. Conclusion: DST can be used for the management of muscle spasms in localized tetanus, based on the oriental medical syndromes. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim The influence of angiotensin II receptor blockers ( ARB) on licorice-induced pseudoaldosteronism remains unclear and the antihypertensive drug selection of prescribers, when they encounter hypokalemia and hypertension in licorice-treated patients, has not been surveyed. Methods We examined the occurrence of hypokalemia, concomitant drugs, and treatment for hypokalemia and hypertension in 42, 26 and 27 patients prescribed the licorice-containing traditional Japanese kampo medicines shakuyakukanzoto ( SKT; containing 6 g licorice/day), rikkunshito ( RKT; 1 g licorice/day), and goshajinkigan ( GJG; without licorice), respectively. Results Seven (16.7%; P < 0.05) of 42 patients treated with SKT more than 4 weeks developed hypokalemia. This rate was significantly higher than that in the GJG group as a negative control. Only one (3.8%) of 26 patients treated with RKT developed hypokalemia. None of the five patients who received simultaneous SKT and mineralocorticoid receptor ( MR) antagonists developed hypokalemia. In contrast, four (57.1%) of seven patients who developed hypokalemia were treated with simultaneous SKT and ARB. Conclusion MR antagonists may be useful for both the prevention and treatment of pseudoaldosteronism, while ARB may not be. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Peripheral neuropathy is the major dose-limiting side-effect of paclitaxel. We examined whether the traditional herbal formulation shakuyakukanzoto ( SKT) inhibited paclitaxel-induced mechanical allodynia and peripheral nerve activity in mice, and identified the site at which SKT exerted its effects. Methods The mice received i.p. injections of paclitaxel. SKT was given orally once daily from the day after the injection of paclitaxel. Mechanical allodynia in the hind paw was evaluated using a von Frey filament. The activity of the saphenous nerve was recorded electrophysiologically, using a bipolar electrode. Results A single i.p. injection of paclitaxel induced mechanical allodynia, which peaked on day 14. Prophylactic repetitive SKT treatment attenuated paclitaxel-induced mechanical allodynia. The paclitaxel-treated mice had increased spontaneous and von Frey filament-induced firing of the saphenous nerve. These increased nerve firings were inhibited by repetitive SKT treatment. Conclusion Prophylactic repetitive SKT treatment inhibited paclitaxel-induced mechanical allodynia and peripheral nerve activity. Moreover, SKT inhibited paclitaxel-induced spontaneous nerve firing, and thus, SKT may be effective for spontaneous pain (including also numbness). Thus, SKT prevents neuropathic dysesthesia through a peripheral action. [ABSTRACT FROM AUTHOR]

Shakuyakukanzoto (SKT) is a kampo medicine composed of equal proportions of Glycyrrhizae radix ( G. radix) and Paeoniae radix ( P. radix). A double-blind study reported that SKT significantly ameliorated painful muscle cramp in cirrhosis patients without the typical severe side effects of muscle weakness and central nervous system (CNS) depression. Previous basic studies reported that SKT and its active components induced relaxation by a direct action on skeletal muscle and that SKT did not depress CNS functions; however, why SKT has a lower incidence of muscle weakness remains unknown. In the present study, we investigated which components are absorbed into the blood of rats after a single oral administration of SKT to identify the active components of SKT. We also investigated the effects of SKT and its components on the twitch contraction induced by physiological Ca release. Our study demonstrated that SKT and five G. radix isolates, which are responsible for the antispasmodic effect of SKT, did not inhibit the twitch contraction in contrast to dantrolene sodium, a direct-acting peripheral muscle relaxant, indicating that the mechanisms of muscle contraction of SKT and dantrolene in skeletal muscle differ. These findings suggest that SKT does not reduce the contractile force in skeletal muscle under physiological conditions, i.e., SKT may have a low risk of causing muscle weakness in clinical use. Considering that most muscle relaxants and anticonvulsants cause various harmful side effects such as weakness and CNS depression, SKT appears to have a benign safety profile. [ABSTRACT FROM AUTHOR]

Background/Aims: Topical epinephrine application to the duodenal papilla reduces spasm of the sphincter of Oddi and prevents acute pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). Shakuyakukanzoto (TJ-68) has an inhibitory effect on muscle contraction. Therefore, TJ-68 potentially allows the relaxation of the sphincter of Oddi, which can aid in the prevention of post-ERCP pancreatitis. Methods: Thirty-six patients planned for ERCP were divided into TJ-68 (n = 17) and control groups (n = 19). In the TJ-68 group, the TJ-68 solution was endoscopically sprayed directly onto the duodenal papilla of patients. To assess the effects of TJ-68, serum amylase levels were measured at 1 h and 1 day after ERCP and symptoms were evaluated. Results: The serum amylase levels at 1 h after ERCP were 273.6 ± 212.0 IU/l in the TJ-68 group and 428.7 ± 281.6 IU/l in the control group, showing a statistically significant difference (p = 0.036). The serum amylase levels at 24 h after ERCP were 230.0 ± 182.7 IU/l in the TJ-68 group and 497.4 ± 514.0 IU/l in the control group (p = 0.011). Post-ERCP pancreatitis was observed in 0 and 4 patients (21.1%) in the TJ-68 and control groups, respectively, which was not statistically significant (p = 0.11). Conclusion: Direct TJ-68 solution application to the duodenal papilla significantly inhibited the elevation of serum amylase levels. However, the preventive effect regarding post-ERCP pancreatitis was not confirmed in this study. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Shakuyakukanzoto (SKT) composed of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix) has been traditionally used in Japan, Korea and China as an antispasmodic drug for the treatment of skeletal muscle cramps and intestinal cramps. Aim of this study: To evaluate the antispasmodic activity of SKT and its two components, as well as to identify the key constituents of the components which mediate this effect in skeletal muscles in vivo. Materials and methods: An experimental cramp model was constructed to evaluate the effects of peripherally-acting muscle relaxants on electrically-induced cramps under physiological conditions. This was accomplished by surgically isolating the motor supply to the gastrocnemius muscle in an anesthetized rat and delivering electrical stimuli to an isolated tibial nerve to induce tetanic contractions. We first tested dantrolene, a well-known peripherally-acting relaxant, to determine the sensitivity and reliability of our experimental model. We then evaluated the effects of SKT, P. radix, G. radix, and the eight active constituents of G. radix against tetanic contractions. Results: We found that dantrolene (10 and 30mg/kg, i.d.) rapidly and significantly inhibited tetanic contractions (P<0.01) irrespective of dose. SKT (0.5, 1.0, and 2.0g/kg, i.d.) and G. radix (0.5 and 1.0g/kg, i.d.) also significantly inhibited tetanic contractions (P<0.01) but in a dose-dependent manner owing to the actions of six of the eight active constituents in G. radix (liquiritin apioside, liquiritigenin, isoliquiritin apioside, isoliquiritigenin, glycycoumarin, and glycyrrhetinic acid, 20μmol/kg, i.v.). These constituents, which include flavonoids, a triterpenoid, and a courmarin derivative, demonstrated temporal variations in their inhibitory activity. In contrast, P. radix (0.5 and 1.0g/kg, i.d.) did not show a statistically significant antispasmodic effect in our study; however, we previously found that it had a significant antinociceptive effect. Conclusions: Our findings show that SKT inhibits tetanic contractions in vivo and that G. radix is the main antispasmodic component due to the actions of its active constituents, thus supporting the traditional use of SKT. We further propose that SKT containing the antispasmodic G. radix and antinociceptive P. radix is a pharmaceutically elegant option for muscle cramps as treatment requires a two-pronged approach, i.e., inhibition of hyperexcitable skeletal tissues and modulation of the pain accompanying cramps. [Copyright &y& Elsevier]

Shakuyakukanzoto (SKT) has long been used for the treatment of muscle cramps. A typical and well-known adverse effect of SKT is licorice-induced pseudoaldosteronism with symptoms of hypokalemia and hypertension. Herein, we report two cases of severe hypokalemia due to SKT-induced pseudoaldosteronism. Both patients were female, over 80 years old and with a history of prolonged SKT usage. Symptoms related to pseudoaldosteronism resolved soon after SKT stoppage with spironolactone. SKT-induced pseudoaldosteronism should be considered in elderly patients with hypokalemia and hypertension. [ABSTRACT FROM AUTHOR]

Background: In chemotherapy, the full round of treatment must be completed as scheduled to achieve the strongest therapeutic effect. However, peripheral neuropathy, a severe side effect of the chemotherapeutic agent paclitaxel, can force the premature discontinuation of treatment. As some kampo practitioners have suggested that it may be possible to counteract such side effects, we analyzed the effects of Kamishoyosan, Shakuyakukanzoto, and Goshajinkigan in an in vitro model of paclitaxel-induced peripheral neuropathy., Methods: Paclitaxel-treated PC12 cells were assessed for neurite length and performed Western blot analysis for growth-associated protein-43 (GAP-43) and light neurofilament protein (NF-L) levels in the presence of nerve growth factor (NGF); they were re-assessed, with additional testing for acetylcholinesterase levels, after application of one of the kampo. We also compared phosphorylation of extracellular signal-regulated kinase (Erk)1/2 and Akt via Western blot analysis. About effect of kampo to anticancer efficacy, we confirmed cell cytotoxicity in A549 cells using MTT assay., Results: Addition of Kamishoyosan or Shakuyakukanzoto, but not Goshajinkigan, significantly improved neurite length and GAP-43 and NF-L levels from paclitaxel-treated PC12 cells, relative to those of only NGF-treated PC12 cells. The promoting effect of Kamishoyosan and Shakuyakukanzoto in neurite outgrowth is confirmed when NGF promoted neurite outgrowth, and it was inhibited partially when Erk1/2 and Akt were blocked by Erk1/2 inhibitor or Akt inhibitor alone. Furthermore, neurite outgrowth induced by TJ24 and TJ68 was inhibited more strongly when Erk1/2 inhibitor and Akt inhibitor were treated at the same time. NGF with Kamishoyosan or Shakuyakukanzoto promoted the proportion of phosphorylated Erk1/2 and phosphorylated Akt compare with NGF only. On the other hand, Kamishoyosan or Shakuyakukanzoto didn't influence cytotoxicity of paclitaxel in A549 cells., Conclusions: Kamishoyosan or Shakuyakukanzoto promotes neurite outgrowth with NGF via increasing the proportion of phosphorylated Erk1/2 and phosphorylated Akt in PC12 cells. The effect applies to recovery from paclitaxel-induced axonal involvement and might promote recovery from paclitaxel-induced neuropathy without influence of anticancer effect of paclitaxel.

Oxaliplatin-induced peripheral neuropathy characterized especially as cold dysesthesia is a major dose-limiting side effect of the drug and is very difficult to control. In the present study, we examined whether the traditional herbal formulation Shakuyakukanzoto (SKT: Sháo Yào Gān Cǎo Tāng) could relieve oxaliplatin-induced cold dysesthesia in mice. The inhibitory mechanisms were also investigated. Repetitive administration of SKT (0.1-1.0 g/kg) starting from the day after oxaliplatin injection inhibited cold dysesthesia in a dose-dependent manner. Our previous report has shown that the mRNA expression of transient receptor potential melastatin 8 (TRPM8), characterized as a cold-sensing cation channel, is increased in the dorsal root ganglia of mice treated with oxaliplatin. In addition, TRPM8 antagonist TC-I 2014 (10 and 30 mg/kg) also attenuated cold dysesthesia in oxaliplatin-treated mice. Taken together, it is suggested that TRPM8 is involved in the cold dysesthesia induced by oxaliplatin. Repetitive administration of SKT inhibited the mRNA expression of TRPM8 induced by oxaliplatin in the dorsal root ganglia. These results suggested that prophylactic repetitive administration of SKT is effective in preventing the exacerbation of oxaliplatin-induced cold dysesthesia by inhibiting the mRNA expression of TRPM8 in the dorsal root ganglia.