Impact of Lycium barbarum polysaccharide on the expression of glucagon-like peptide 1 in vitro and in vivo.

Several studies showed the efficacy of Lycium barbarum polysaccharide (LBP) in diabetic animals and patients with type 2 diabetes mellitus (T2DM). However, the mechanism of LBP in alleviating T2DM based on glucagon-like peptide 1 (GLP1) has not been suitably elucidated. GLP1 is an important peptide that plays a role in blood glucose homeostasis. Inhibition of sodium/glucose cotransporter 1 (SGLT1) can result in a net increase in GLP1 release. We found that LBP could reduce SGLT1 expression. Thus, the effects of LBP on the first- and second-phase secretion of GLP1 were systematically assessed in vitro using STC1 cells and in vivo using diabetic KKAy mice. LBP could induce the first-phase secretion of GLP1 by stimulating calcium ion influx in vitro and by inhibiting alpha-glucosidase activity in vivo. Regulation of Gcg gene expression by modulating the Wnt/ß-catenin and cAMP/Epac pathways, as well as inhibition of alpha-glucosidase activity, was responsible for the second-phase secretion of GLP1. LBP could stimulate GLP1 secretion; however, dipeptidyl peptidase 4 (DPP4) activated by LBP might offset the second-phase secretion of GLP1. Thus, we suggest considering the simultaneous use of LBP and a DPP4 inhibitor to stimulate slow, continuous GLP1 secretion. Further studies are warranted for in-depth mechanistic information.

[Analysis and considerations on revision of instructions for traditional Chinese medicine injections].

According to the notice on revision of the instructions for traditional Chinese medicine injections(TCMIs) issued by the National Medical Products Administration(NMPA) from January 2006 to May 2020, the revised contents in the instructions for 29 varieties involved in the notice were sorted out, and the existing problems in the instructions for TCMIs were analyzed, so as to provide the basis for dynamic revision of the instructions. It was found that the revised items of instructions for 29 varieties all involved adverse reactions, contraindications and precautions, and warnings were added for 82.76% of 29 TCMIs preparations, indicating that all the revised contents were related to safety issues. In addition, 33.33% of the drugs risks mentioned in the precautions were not indicated in the adverse reactions; 82.76% instructions did not indicate drug interactions; 17.24% instructions lacked medication notes for special populations; 48.28% instructions did not indicate traditional Chinese medicine(TCM) syndromes of the main disease; 44.83% instructions did not indicate the type and stage of indication; and 86.21% instructions did not indicate the course of treatment. It could be concluded that the instructions for TCMIs have known risks of drugs that are not fully reflected in adverse reactions and the effective information is not comprehensive. The risk control measures proposed in the precautions need to have aftereffect evaluation and there is a lack of drug interactions and medications for special populations. As an important part of the full life-cycle management of drugs, the revision of instructions for TCMIs should be continuously improved to provide the basis for safe and reasonable application of TCMIs. Based on the above problems, it is proposed that the marketing license holder as the main body of the revision of instructions should actively carry out post-marketing basic and clinical research in accordance with the characteristics of TCM, combine the updated research with the guidance of TCM theory and improve the revision level of instructions for TCMIs to provide the basis for post-marketing evaluation.

[Inhibition effect of active fraction from clove on PI3K/Akt/mTOR signaling pathway to induce apoptosis of human colon cancer HCT116 cells].

To screen the sensitive cell lines of active fraction from clove(AFC) on human colon cancer cells, investigate the effects of AFC on the cells proliferation and apoptosis as well as PI3 K/Akt/mTOR(phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin) signaling pathways involved, and reveal the mechanism of AFC for inducing apoptosis of human colorectal carcinoma cells. Cell counting kit-8(CCK-8) assay was used to detect the cytotoxic effect of different concentrations of AFC. AFC-induced apoptosis was detected by Hoechst 33258 fluorescence staining and Annexin V-FITC/PI double staining. HCT116 cells were treated with AFC with or without pretreatment with insulin-like growth factor-Ⅰ(IGF-Ⅰ), and then the protein expression levels of caspase-3, caspase-9, poly ADP-ribose polymerase(PARP), PI3 K, p-PI3 K, Akt, p-Akt, mTOR and p-mTOR in PI3 K/Akt/mTOR signaling pathway were detected by Western blot. RESULTS:: showed that the most obvious inhibitory effect of AFC was on human colon cancer HCT116 cells, and the optimal AFC treatment time was 48 hours. After AFC treatment, typical apoptotic features such as nuclear chromatin concentration, nuclear fragmentation and apoptotic bodies appeared in a dose-dependent manner. Annexin V-FITC/PI double staining showed that as compared with the control group, 50 and 100 µg·mL~(-1) AFC groups increased the apoptosis rate of HCT116 cells significantly(P<0.001); AFC activated caspase-9, cleaved caspase-3 and cleaved PARP in a concentration-dependent manner. The protein expression levels of cleaved caspase-3/procaspase-3, cleaved PARP/PARP and caspase-9/ß-actin after treatment of AFC(100 µg·mL~(-1)) were significantly different from those in the control group(P<0.001). The relative protein expression of p-PI3 K, p-Akt and p-mTOR decreased in a concentration dependent manner, while Akt and mTOR showed no significant differences among groups. The ratios of p-PI3 K/PI3 K, p-Akt/Akt and p-mTOR/mTOR in the AFC groups(50 and 100 µg·mL~(-1)) were significantly lower than those in the control group(P<0.01). Its combination with IGF-Ⅰ weakened the effect of AFC in inhibiting PI3 K/Akt/mTOR signaling pathway. The ratios of p-Akt/Akt and p-mTOR/mTOR in the AFC+IGF-Ⅰ group were significantly enhanced as compared with the AFC group(P<0.05). Apoptosis-related protein expression levels(cleaved caspase-3 and cleaved PARP) in HCT116 cells treated with AFC+IGF-Ⅰ were also down regulated. As compared with the AFC group, the ratios of cleaved caspase-3/procaspase-3 and cleaved PARP/PARP in the AFC+IGF-Ⅰ group were significantly decreased(P<0.01). In summary, AFC activated caspase-mediated cascades and induced HCT116 cells apoptosis in a dose-dependent manner, which may be associated with the inhibition of the PI3 K/Akt/mTOR signaling pathway.

Nerve coblation for treatment of trigeminal neuralgia: A case report.

BACKGROUND: Trigeminal neuralgia (TN) is a severe type of neuropathic pain which is often inadequately managed using conventional therapies. In this report, we present the first case of TN treated with gasserian ganglion nerve coblation (NC). CASE SUMMARY: A 58-year-old man presented with right facial pain, mostly localized in the right zygomatic zone, alveolar region, and jaws. Similar to acupuncture and shock pain, the pain lasted about five seconds after each attack before resolving unaided. A diagnosis of TN was made, after which treatment with acupuncture therapy and oral carbamazepine was given. However, the pain was not satisfactorily controlled. Subsequently, gasserian ganglion NC of the right trigeminal nerve guided by computed tomography (CT) was performed on the patient. Following this procedure, the right zygomatic, alveolar, submandibular, and cheek pain disappeared completely. The right zygomatic and alveolar areas experienced mild numbness (level II). At 1-, 2-, 3-, and 6-mo follow-ups after surgery, the patient was painless and the numbness score was level I. CONCLUSION: CT-guided gasserian ganglion (NC) is an effective treatment for TN and is associated with less or no postoperative numbness or hypoesthesia in comparison with current standard-of-care approaches.

[Species of Fistular Onion Stalk in Zhouhou Beiji Fang].

Congchi Decoction in Zhouhou Beiji Fang is a prescription commonly used in treating light exterior wind-cold syndrome.Fistular Onion Stalk in the prescription has the effects in inducing sweat and dispelling exogenous evils and accelerating Yang Qi,and has been recorded in many medical books. In addition to be used to treat light exterior wind-cold syndrome,Fistular Onion Stalk is also used extensively and uniquely to treat restlessness after cholera,febrile disease,thoracic obstruction,Yin-Yang toxin syndrome,consumptive disease,bellyache due to spleen Qi deficiency according to Zhouhou Beiji Fang. However,there is still lack of the research on whether Fistular Onion Stalk is derived from shallot or scallion. The authors analyzed the sources of Fistular Onion Stalk in the prescription of Congchi Decoction by consulting ancient books,and studying the plant morphology of shallot,the characteristic and effect of Fistular Onion Stalk and the historical physicians' clinical application of Fistular Onion Stalk,the completion and popularity of Zhouhou Beiji Fang,the ratio of water to medicine of Congchi Decoction and the chemical ingredients of Fistular Onion Stalk. Finally,the authors concluded that Fistular Onion Stalk in the Congchi Decoction refers to Scallion bulbs.

[Expert consensus statement on treatment of type 2 diabetes with Xiaoke Pills in clinical practice].

Xiaoke Pills are Chinese and Western medicine compound preparations with effects of nourishing kidney and Yin,and supplementing Qi and promoting fluid. It is widely used in clinical treatment of type 2 diabetes( Qi and Yin deficiency syndrome),and continuously included in 2010,2013 and 2017 editions of Chinese prevention guide for type 2 diabetes. For the purpose of accurate positioning and rational use in clinic,it is necessary to further define the curative effect,indications,medication precautions and contraindications of Xiaoke Pills,in order to improve medication safety. This consensus was reached by reference of international clinical guidelines and expert consensus approach based on clinical evidence-based evidence,expert experience and standard specification. The evidence-based evaluation was oriented to clinical problems summarized by no less than 200 front-line clinical physicians in two rounds.GRADE system was adopted for quality classification and evaluation of the evidences,and then the nominal group method was used to form consensus recommendations or suggestions. This consensus defined the curative effect advantages,target users,dosage,administration method,contraindications and precautions of Xiaoke Pills,and provided valuable reference for the clinical use of the drug. Thisconsensus still needs to be updated and revised based on new clinical problems and evidence-based evidence in practical application in the future.

[Safety evaluation and risk control measures of Psoralea corylifolia].

Through a systematic and comprehensive study of domestic and foreign literatures and information, this study aims to trace the herbal origin and the toxicity recorded in ancient and current documents, analyze the safety case reports of Psoralea corylifolia and experimental studies on toxicity in recent years, and make a preliminary summary about the clinical characteristics and potential risk factors of cases related to the safety of P. corylifolia and its preparations. The study involved 84 patients in the safety case reports of P. corylifolia. The adverse events were mainly liver damage (55.95%) and light toxic contact dermatitis (38.10%), sugguesting that P. corylifolia may lead to liver damage and photo toxicity. However, reproductive toxicity and renal damage were only reported in animal studies, but not in clinical reports. Because of its complicated ingredients, the toxic components and mechanisms of P. corylifolia have not been clear at present. Therefore, the authors proposed to strictly apply P. corylifolia in clinic, use it rationally and combine it with other medications. Besides, efforts shall be made to strength the guidance for doctors, the safety monitoring of P. corylifolia and relevant preparations, and actively carry out safety-related basic and clinical studies, so as to give a better guidance to safe medication, full exert the efficacy and avoid the medication risk.

[Systematic evaluation for safety of traditional Chinese medicine Areca catechu and its preparations].

The authors systemically evaluated and analyzed the safety of Areca catechu from domestic and foreign literatures about the herbal origin, toxicity recorded in ancient/current documents, safety case reports of clinical A. catechu, experimental studies on toxicity in recent years, and differences of safety risk between edible and medicinal A. catechu. Subsequently, they proposed a preliminary summary about the clinical characteristics and potential risk factors of safety related cases of A. catechu and its preparations. According to the authors, although clinical adverse events of A. catechu were fewer and controllable, clinicians shall stillstrictly standardize its application, and rationally combine it with other herbs, while strengthening fundamental and clinical studies related to safety, so as to give better guidance to safety application of A. catechu in clinic.

[Comprehensive evaluation and risk control measures of Xanthii Fructus].

By retrieving domestic and foreign literatures, the authors provided a systematic review for effects of Xanthii Fructus, toxicity recorded in ancient/current literatures and relevant toxicological experience, and summarized clinical characteristics of clinical cases related to Xanthii Fructus and influencing factors. In addition to liver and kidney injuries as the major side effects of Xanthii Fructus, neurotoxicity and cardio-toxicity of Xanthii Fructus were also common clinical adverse events. However, there have been a few animal experimental studies so far. Oral administration and external application with Xanthii Fructus have often caused skin reactions, even such severe cases as exfoliative dermatitis. The authors suggested standardizing the clinical medication, avoiding to use untreated prescriptions and unprocessed herbs, ensuring the effective and safety use of Xanthii Fructus in strict accordance with the recommended dosage and usage in pharmacopeia, paying attention to the accumulation of safety signals, strengthening studies on toxic substance, toxicity mechanism, and synergy and attenuation effects.

Synthesis and pharmacological evaluations of 4-hydroxycoumarin derivatives as a new class of anti-Staphylococcus aureus agents.

OBJECTIVES: Due to the increasing prevalence of drug-resistant Staphylococcus aureus infection, we develop novel 4-hydroxycoumarin derivatives as antimicrobials. METHODS: The antibacterial activity of 4-hydroxycoumarin derivatives against drug-susceptive S. aureus (ATCC 29213) and methicillin-resistant S. aureus (MRSA) were evaluated using minimal inhibitory concentration (MIC) assay; the activity of favourable compound was further observed using bacterial growth curves assay and in the MRSA infection mice. KEY FINDINGS: Compared with dihydropyran derivatives, compound 1 as one of biscoumarins showed most potent activity with MIC values of 4-8 µg/ml and apparently inhibited the growth rate of S. aureus ATCC 29213 and USA300 strain in concentrations of both 16 and 32 mg/ml. In the mice infected with MRSA USA300, administration of 5 mg/kg compound 1 improved the animal survival rate to 66.7%, and improved the pathological change in lung tissue compared with the infection model animals. No significant cytotoxicity of compound 1 was observed on the umbilical vein endothelial cells (HUVECs) under the concentration of 800 µg/ml. CONCLUSION: Compared with the dihydropyran derivatives, biscoumarins exhibited more promising activity against both drug-sensitive and drug-resistant S. aureus, and it is efficacious in treating MRSA infections in mouse models with a favourable safety in human cells.

["Re-evaluation upon suspected event" is an approach for post-marketing clinical study: lessons from adverse drug events related to Bupleuri Radix preparations].

We revisited the "Xiao Chaihu Decoction event (XCHDE)" occurred in late 1980s in Japan and the Bupleuri Radix related adverse drug reaction (ADR) reports in China After careful review, comparison, analysis and evaluation, we think the interstitial pneumonitis, drug induced Liver injury (DILI) and other severe adverse drug envents (ADEs) including death happened in Japan is probably results from multiple factors, including combinatory use of XCHDE with interferon, Kampo usage under modern medicine theory guidance, and use of XCHD on the basis of disease diagnosis instead of traditional Chinese syndrome complex differentiation. There are less ADE case reports related to XCHD preparation in China compared to Japan, mostly manifest with hypersensitivity responses of skin and perfuse perspiration. The symptoms of Radix Bupleuri injection related ADEs mainly manifest hypersensitivity-like response, 2 cases of intravenous infusion instead of intramuscular injection developed hypokalemia and renal failure. One case died from severe hypersensitivity shock. In Chinese literatures, there is no report of the interstitial pneumonitis and DILI associated with XCHDG in Japan. So far, there is no voluntary monitoring data and large sample clinical research data available. The author elaborated the classification of "reevaluation" and clarified "re-evaluation upon events" included the reaction to the suspected safety and efficacy events. Based on the current status of the clinical research on the Radix Bupleuri preparations, the author points out that post-marketing "re-evaluation upon suspected event" is not only a necessity of continuous evaluation of the safety, efficacy of drugs, it is also a necessity for providing objective clinical research data to share with the international and domestic drug administrations in the risk-benefit evaluation. It is also the unavoidable pathway to culture and push the excellent species and famous brands of TCM to the international market, in that it enhances the pharmaceutical manufactures the ability to control enterprise risk and eliminate the negative impact on traditional Chinese medicine. With the widely used and ADR report concentrated Radix Bupleuri injection as an example, the author provide a new approach to post-marketing clinical research.

[Post-marketing clinical study of traditional Chinese medicine--lessons learned from comprehensive evaluation of Fufang Zaoren capsule].

By comprehensive review and analysis of post-marketing clinical research on the efficacy and safety,we concluded that Fufang Zaoren capsule has certain therapeutic effects for insomnia, although current clinical research design needs improving. The post-marketing clinical studies also showed that it causes several adverse reactions at the recommended doses, such as chills, fever, dizziness, nausea, shortness of breath, chest tightness and palpitations, whereas high doses of Fufang Zaoren capsule can cause delayed extrapyramidal symptoms. Health Canada government website also prompted the L-tetrahydropalmatine in Fufang Zaoren capsule caused liver damage in pregnant women. The authors summarized the risk points, factors and risk control in the clinical use of Fufang Zaoren capsule and also present their perspective on the research status, existing problems and corresponding countermeasures in the post-marketing clinical re-evaluation of traditional Chinese medicine.

[Pharmacovigilance idea should be introduced sufficiently into the safety monitoring and evaluation process of Chinese drugs].

Along with the general improving of public consciousness on drugs' safety and the increasing of new Chinese drugs' manufacture and application, the safety of Chinese drugs has become a more prominent concern and a focus of attention. The scientific identification, analysis and evaluation of this affairs greatly impacts the scientific decision-making for ensuring the public use of drugs in security, also influences the healthy development of Chinese medicine industry. In this paper, the different meanings of "adverse reaction" and "adverse events" of Chinese drugs were introduced from pharmacovigilance idealistic view, and the influencing factors on safety of Chinese drugs were analyzed from the perspective of pharmacovigilance. The authors proposed that "Chinese medicine safety monitoring and evaluation" is a much more practical concept in consistency with the current situation. They pointed out that introducing sufficiently the concept of pharmaco vigilance idea into the safety monitoring and evaluation process is the basis for overall evaluation and effective risk controlling of Chinese drugs.

[Current status and development of monitoring on adverse reaction of traditional Chinese medicine in China].

With the wide usage of traditional Chinese medicine (TCM) and the diversity of its dosage-forms, the reports about adverse reaction (ADR) caused by TCM were gradually increased. As the cradle of TCM with tremendous manufacturing enterprise engaged for this purpose, to establish and perfect the TCM ADR monitoring is the problem that TCM industry should face to. In this paper, the key point of TCM ADR monitoring was made clear by analysing the current situation and the problems presented in TCM ADR monitoring in China, and indicated that the nowday developing goals of TCM ADR monitoring are to establish and perfect the technologic system for TCM ADR monitoring, strengthen the related basic research and enhance international communication and cooperation in this field.