Aconitine - A promising candidate for treating cold and mechanical allodynia in cancer induced bone pain.

BACKGROUND AND AIMS: Patients suffering from cancer induced bone pain (CIBP) have a poor quality of life that is exacerbated by the lack of effective therapeutic drugs. Monkshood is a flowering plant that has been used in traditional Chinese medicine where it has been used to relieve cold pain. Aconitine is the active component of monkshood, but the molecular mechanism for how this compound reduces pain is unclear. METHODS AND RESULTS: In this study, we employed molecular and behavioral experiments to explore the analgesic effect of aconitine. We observed aconitine alleviated cold hyperalgesia and AITC (allyl-isothiocyanate, TRPA1 agonist) induced pain. Interestingly, we found aconitine directly inhibits TRPA1 activity in calcium imaging studies. More importantly, we found aconitine alleviated cold and mechanical allodynia in CIBP mice. Both the activity and expression of TRPA1 in L4 and L5 DRG (Dorsal Root Ganglion) neurons were reduced with the treatment of aconitine in the CIBP model. Moreover, we observed aconiti radix (AR) and aconiti kusnezoffii radix (AKR), both components of monkshood that contain aconitine, alleviated cold hyperalgesia and AITC induced pain. Furthermore, both AR and AKR alleviated CIBP induced cold allodynia and mechanical allodynia. CONCLUSIONS: Taken together, aconitine alleviates both cold and mechanical allodynia in cancer induced bone pain via the regulation of TRPA1. This research on the analgesic effect of aconitine in cancer induced bone pain highlights a component of a traditional Chinese medicine may have clinical applications for pain.

Water extract of Notopterygium incisum alleviates cold allodynia in neuropathic pain by regulation of TRPA1.

ETHNOPHARMACOLOGICAL RELEVANCE: Neuropathic pain can be debilitating and drastically affects the quality of life of those patients suffering from this condition. The Chinese herb Notopterygium incisum Ting ex H.T. Chang has long been used to disperse "cold". One under examined clinical feature of neuropathic pain is sensitivity to cold. Patients with neuropathic pain or arthritis usually describe a worsening of symptoms during the winter. AIMS OF THIS STUDY: We proposed to test the hypothesis that Notopterygium incisum has a positive effect on the cold sensitivity found in neuropathic pain. MATERIALS AND METHODS: In this study, we established chronic constriction injury (CCI) and cisplatin induced neuropathic pain mice models. Behavioral experiments and physiological examination methods were employed to investigate the effect of water extract of Notopterygium incisum (WN) on cold pain. RESULTS: We found WN reduced cold pain and allyl isothiocyanate (AITC, Transient Receptor Potential A1 (TRPA1 agonist)) induced pain. WN inhibited AITC induced calcium response in HEK 293 cells transfected with TRPA1 and dorsal root ganglion (DRG) neurons. Moreover, we found that oral administration of WN reduced cold allodynia and mechanical allodynia caused by (CCI) and cisplatin induced neuropathic pain. We also observed that oral administration of WN decreased responses to AITC in DRG neurons as well as expression of TRPA1 in the WN treated neuropathic pain model. CONCLUSIONS: The present study provide evidence that Notopterygium incisum alleviates cold allodynia in CCI and cisplatin induced neuropathic pain mouse models. WN alleviated neuropathic pain induced cold allodynia via directly modulating TRPA1. Our findings identify WN as a promising candidate for treating neuropathic pain that highlights a new mechanism of Notopterygium incisum on 'disperse cold'.

Ligustrazine mitigates chronic venous disease-induced pain hyperalgesia through desensitization of inflammation-associated TRPA1 activity in DRG.

ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrazine, an important active ingredient extracted from Ligusticum chuanxiong hort, has been widely used to cure cardiovascular diseases and exerts an analgesic effect. AIMS OF THIS STUDY: The aim of this study is to investigate whether ligustrazine mitigates chronic venous disease (CVeD)-induced pain and to explore its underlying mechanisms. MATERIALS AND METHODS: A mouse model of CVeD was established by vein ligature. Ligustrazine was administered intraperitoneally to CVeD mice for a single injection (20 mg/kg, 100 mg/kg, and 200 mg/kg) or once a day for three weeks (100 mg/kg and 200 mg/kg), and TRPA1 overexpressed HEK 293 cells were treated with ligustrazine (600 µM) in the presence of mustard oil (100 µM) for 2 min. Patch clamp and calcium imaging were used to measure the inhibitory response of ligustrazine on DRG neurons and TRPA1 transfected HEK293 cells. RESULTS: The present results showed that mice receiving vein ligature surgery exhibited obvious pain hypersensitivity to mechanical, cold and thermal stimuli, whereas ligustrazine significantly reversed the pain hyperalgesia in CVeD mice. Furthermore, ligustrazine desensitized transient receptor potential ankyrin 1 (TRPA1) activity in the dorsal root ganglion (DRG) neurons, resulting in suppressing the DRG neuronal excitability in the CVeD mice. However, ligustrazine could not directly inhibit the response of TRPA1 transfected HEK293 cells to mustard oil. Strikingly, ligustrazine restricted the macrophage infiltration and decreased the mRNA levels of Interleukin-1ß (IL-1ß) and NOD-like receptor protein 3 (NLRP3) in the DRG neurons of the CVeD mice. CONCLUSIONS: The present study provided evidence that ligustrazine alleviated pain hypersensitivity to mechanical, cold and thermal stimuli in CVeD mice. Ligustrazine could weaken the activity of TRPA1 in the DRG to mitigate CVeD-induced pain hyperalgesia mainly through inhibition of inflammation. Our findings identify that ligustrazine may be a new therapeutic agent for the treatment of CVeD-induced pain.

A Mouse Model of Cancer Induced Bone Pain: From Pain to Movement.

Cancer induced bone pain (CIBP) occurs in patients with advanced osteosarcoma or metastasized bone tumors that can negatively affects the patient's quality of life. However, motor impairment in CIBP is still understudied. To improve the quality of life of patients with CIBP, the study of CIBP induced movement impairment is of particular importance. Here, we presented a model of metastatic cancer induced bone pain caused by an allograft of Lewis lung cancer cells. In this method, we injected Lewis lung cancer cells into the femoral medulla cavity and recorded the pain behavior and motor behavior after CIBP surgery. We observed enhanced pain after the initial surgery. Interestingly, we found the latency on rotarod was significantly reduced concomitant with tumor growth and pain. This result indicated that the motor coordination and balance were severely impaired in CIBP. We also found the pain and motor behavioral differences in models that severed the patellar ligament vs. maintaining the patellar ligament. These findings provide a novel clue for further investigating the mechanisms responsible for the generation and development of CIBP.

[A multi-center, double-blind, placebo-controlled, randomized trial for effect of Longxue Tongluo capsule in treatment of patients of atherosclerotic thrombotic cerebral infarction with blood-stasis syndrome in convalescence].

To evaluate the effectiveness and safety of Longxue Tongluo capsule on patients of atherosclerotic thrombotic cerebral infarction convalescence with blood-stasis syndrome, a double-blind, randomized controlled, multi-center clinical trial was conducted. A total of 160 eligible patients were randomly divided into treatment group and control group, with 80 patients in each group, and all of them were orally given Troxerutin pill(three pills each time, three times daily). Longxue Tongluo capsule was applied in the treatment group, while placebo was applied in the control group(two capsules each time, three times daily) for 4 weeks. Main outcomes were measured by ITT analysis. The neurological function deficits scale showed a decrease of 5.17±2.60 in the treatment group, while 4.31±2.31 in the control group, with significant differences between the two groups(P<0.05); the reduction rate in the treatment group (37.2±15.8)% was significantly higher than that in the control group (29.9±15.3)%(P<0.05). In terms of the comprehensive curative effect by ITT, the effective rates in the treatment and control group were 31.6% and 13.5%, respectively(P<0.05). With respect to the efficacy of traditional Chinese medicine syndrome by ITT, the total effective rate of the treatment group was significantly higher than the control group 88.2% vs 68.9%, P<0.05. Three cases of adverse events occurred in this study, including 1 case of diarrhea in treatment group and 2 cases of skin itch and upper respiratory infection in control group. In conclusion, Longxue Tongluo capsule is effective and safe in the treatment of patients of atherosclerotic thrombotic cerebral infarction convalescence with blood-stasis syndrome, and can effectively alleviate the patients' nerve function defect degree and invalidism, with a good effect on blood stasis syndrome.

A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia.

AIM: To compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia. METHODS: The trial which was conducted at 13 centers in China during 2011-2013 included a 2-week run-in and a 24-week treatment period. A total of 504 eligible participants with gout and with serum urate ≥ 480 µmol/L were randomly assigned 1 : 1 : 1 to febuxostat 40 mg/day, febuxostat 80 mg/day and allopurinol 300 mg/day groups. The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 µmol/L. RESULTS: The primary efficacy endpoint was reached by 33.5% of subjects taking febuxostat 80 mg/day, 22.5% of those taking febuxostat 40 mg/day and 17.0% of those taking allopurinol 300 mg/day (P < 0.001 for the comparison between febuxostat 80 mg/day and allopurinol 300 mg/day groups; P = 0.216 for the comparison between febuxostat 40 mg/day and allopurinol 300 mg/day groups). The incidence of gout flare was relatively high in each group during the first 8 weeks and gradually decreased thereafter. There was no statistically significant difference between the three groups (P > 0.05). The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities. CONCLUSIONS: Febuxostat 80 mg/day had superior urate-lowering efficacy to that of febuxostat 40 mg/day or allopurinol 300 mg/day, which was comparable in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated.

[Clinical study on naoxintong capsule for stroke recovery of Qi-deficiency and blood-stasis syndrome].

OBJECTIVE: To study the efficacy and safety of Naoxintong capsule treatment of stroke recovery with Qi-deficiency and blood-stasis syndrome (cerebral infarction), and to compared the non-inferiority analysis with the positive drug Tongxinluo capsule. METHOD: Taking Tongxinluo capsules as control, randomized, double-blind, controlled, multi-center clinical experiments were studied. The evaluating indexes included the decrease of integral value of stroke patients, changes in traditional Chinese medicine, the improvement of the patient viability status (disability level), Chinese stroke scale (CSS), activities of daily living (DAL) scale and barthel index (BI ) points. RESULT: The total effect of the two groups, Chinese and other symptoms, showed no significant statistical significance. CONCLUSION: Naoxintong capsule stroke recovery, with Qi-deficiency and blood-stasis syndrome (cerebral infarction) has a therapeutic effect, and more secure.

TCM treatment of rheumatoid arthritis by supplementing the kidney and invigorating the blood circulation.

The therapeutic effects in treating the intermediate and late rheumatoid arthritis by supplementing the kidney and invigorating blood circulation were observed. In the 43 cases of the treatment group, No. 2 Qu Feng Shi Ling capsules and Fenbid were prescribed, while in the 39 cases of the control group Lei Gong Teng Tablets and Fenbid were given. The results showed that the total effective rate in the treatment group was more satisfactory than that in the control (P<0.05 or P<0.01). With less toxic effects, the former could better improve the local swelling and lower the blood viscosity.