Ventral posteromedial nucleus of the thalamus gates the spread of trigeminal neuropathic pain.

BACKGROUND: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. METHODS: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. RESULTS: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. CONCLUSION: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

Hyperexcitation of ovBNST CRF neurons during stress contributes to female-biased expression of anxiety-like avoidance behaviors.

Corticotropin releasing factor (CRF) network in the oval nucleus of bed nuclei of the stria terminalis (ovBNST) is generally indicated in stress, but its role in female-biased susceptibility to anxiety is unknown. Here, we established a female-biased stress paradigm. We found that the CRF release in ovBNST during stress showed female-biased pattern, and ovBNST CRF neurons were more prone to be hyperexcited in female mice during stress in both in vitro and in vivo studies. Moreover, optogenetic modulation to exchange the activation pattern of ovBNST CRF neurons during stress between female and male mice could reverse their susceptibility to anxiety. Last, CRF receptor type 1 (CRFR1) mediated the CRF-induced excitation of ovBNST CRF neurons and showed female-biased expression. Specific knockdown of the CRFR1 level in ovBNST CRF neurons in female or overexpression that in male could reverse their susceptibility to anxiety. Therefore, we identify that CRFR1-mediated hyperexcitation of ovBNST CRF neurons in female mice encode the female-biased susceptibility to anxiety.

Activation of free fatty acid receptors, FFAR1 and FFAR4, ameliorates ulcerative colitis by promote fatty acid metabolism and mediate macrophage polarization.

OBJECTIVE: To investigate the mechanism of action of fatty acid receptors, FFAR1 and FFAR4, on ulcerative colitis (UC) through fatty acid metabolism and macrophage polarization. METHODS: Dextran sulfate sodium (DSS)-induced mouse model of UC mice was used to evaluate the efficacy of FFAR1 (GW9508) and FFAR4 (GSK137647) agonists by analyzing body weight, colon length, disease activity index (DAI), and histological scores. Real-time PCR and immunofluorescence analysis were performed to quantify the levels of fatty acid metabolizing enzymes and macrophage makers. FFA-induced lipid accumulation in RAW264.7 cells was visualized by Oil Red O staining analysis, and cells were collected to detect macrophage polarization by flow cytometry. RESULTS: The combination of GW9508 and GSK137647 significantly improved DSS-induced UC symptoms, caused recovery in colon length, and decreased histological injury. GW9508 + GSK137647 treatment upregulated the expressions of CD206, lipid oxidation enzyme (CPT-1α) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) but downregulated those of CD86, lipogenic enzymes (ACC1, FASN, SCD1), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). Combining the two agonists decreased FFA-induced lipid accumulation and increased CD206 expression in cell-based experiments. CONCLUSION: Activated FFAR1 and FFAR4 ameliorates DSS-induced UC by promoting fatty acid metabolism to reduce lipid accumulation and mediate M2 macrophage polarization.

Phosphatidic acid interacts with an HD-ZIP transcription factor GhHOX4 to influence its function in fiber elongation of cotton (Gossypium hirsutum).

Upland cotton, the mainly cultivated cotton species in the world, provides over 90% of natural raw materials (fibers) for the textile industry. The development of cotton fibers that are unicellular and highly elongated trichomes on seeds is a delicate and complex process. However, the regulatory mechanism of fiber development is still largely unclear in detail. In this study, we report that a homeodomain-leucine zipper (HD-ZIP) IV transcription factor, GhHOX4, plays an important role in fiber elongation. Overexpression of GhHOX4 in cotton resulted in longer fibers, while GhHOX4-silenced transgenic cotton displayed a "shorter fiber" phenotype compared with wild type. GhHOX4 directly activates two target genes, GhEXLB1D and GhXTH2D, for promoting fiber elongation. On the other hand, phosphatidic acid (PA), which is associated with cell signaling and metabolism, interacts with GhHOX4 to hinder fiber elongation. The basic amino acids KR-R-R in START domain of GhHOX4 protein are essential for its binding to PA that could alter the nuclear localization of GhHOX4 protein, thereby suppressing the transcriptional regulation of GhHOX4 to downstream genes in the transition from fiber elongation to secondary cell wall (SCW) thickening during fiber development. Thus, our data revealed that GhHOX4 positively regulates fiber elongation, while PA may function in the phase transition from fiber elongation to SCW formation by negatively modulating GhHOX4 in cotton.

MLatom 3: A Platform for Machine Learning-Enhanced Computational Chemistry Simulations and Workflows.

Machine learning (ML) is increasingly becoming a common tool in computational chemistry. At the same time, the rapid development of ML methods requires a flexible software framework for designing custom workflows. MLatom 3 is a program package designed to leverage the power of ML to enhance typical computational chemistry simulations and to create complex workflows. This open-source package provides plenty of choice to the users who can run simulations with the command-line options, input files, or with scripts using MLatom as a Python package, both on their computers and on the online XACS cloud computing service at XACScloud.com. Computational chemists can calculate energies and thermochemical properties, optimize geometries, run molecular and quantum dynamics, and simulate (ro)vibrational, one-photon UV/vis absorption, and two-photon absorption spectra with ML, quantum mechanical, and combined models. The users can choose from an extensive library of methods containing pretrained ML models and quantum mechanical approximations such as AIQM1 approaching coupled-cluster accuracy. The developers can build their own models using various ML algorithms. The great flexibility of MLatom is largely due to the extensive use of the interfaces to many state-of-the-art software packages and libraries.

Pharmacoeconomics of ivabradine in the treatment of CHF in the context of “Quadruple Therapy” / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of ivabradine in the treatment of chronic heart failure （CHF） in the context of “Quadruple Therapy” from the perspective of the health system. METHODS Based on real-world cohort data， the Markov model was constructed according to the natural progression of CHF， with a cycle time of 3 months， a study timeframe of 20 years， and a discount rate of 5%. Using quality-adjusted life year （QALY） and incremental cost-effectiveness ratios （ICER） as the output indexes， the cost-utility analysis was used to evaluate the cost-effectiveness of ivabradine in combination with the “Quadruple Therapy” regimen， compared with the “Quadruple Therapy” regimen for the treatment of CHF， and the robustness of the results of the base analysis was verified by univariate sensitivity analysis and probabilistic sensitivity analysis. RESULTS The results of the base analysis showed that the ICER of ivabradine combined with the “Quadruple Therapy” regimen was 165 065.54 yuan/QALY， compared with the “Quadruple Therapy” regimen， which was lower than the willingness-to-pay （WTP） threshold （257 094 yuan/QALY） based on 3 times of China’s gross domestic product （GDP） per capita in 2022. The results of the univariate sensitivity analysis showed that the discount rate had the greatest impact on the robustness of the model. The probabilistic sensitivity analysis showed that the probability that the ivabradine combined with the “Quadruple Therapy” regimen was cost-effective under the WTP threshold in this study was 59.50%. CONCLUSIONS When using 3 times China’s 2022 GDP per capita （257 094 yuan/ QALY） as the WTP threshold， the combination of ivabradine and the “Quadruple Therapy” regimen for treating CHF is cost- effective.

The transcription factor ERF108 interacts with AUXIN RESPONSE FACTORs to mediate cotton fiber secondary cell wall biosynthesis.

Phytohormones play indispensable roles in plant growth and development. However, the molecular mechanisms underlying phytohormone-mediated regulation of fiber secondary cell wall (SCW) formation in cotton (Gossypium hirsutum) remain largely underexplored. Here, we provide mechanistic evidence for functional interplay between the APETALA2/ethylene response factor (AP2/ERF) transcription factor GhERF108 and auxin response factors GhARF7-1 and GhARF7-2 in dictating the ethylene-auxin signaling crosstalk that regulates fiber SCW biosynthesis. Specifically, in vitro cotton ovule culture revealed that ethylene and auxin promote fiber SCW deposition. GhERF108 RNA interference (RNAi) cotton displayed remarkably reduced cell wall thickness compared with controls. GhERF108 interacted with GhARF7-1 and GhARF7-2 to enhance the activation of the MYB transcription factor gene GhMYBL1 (MYB domain-like protein 1) in fibers. GhARF7-1 and GhARF7-2 respond to auxin signals that promote fiber SCW thickening. GhMYBL1 RNAi and GhARF7-1 and GhARF7-2 virus-induced gene silencing (VIGS) cotton displayed similar defects in fiber SCW formation as GhERF108 RNAi cotton. Moreover, the ethylene and auxin responses were reduced in GhMYBL1 RNAi plants. GhMYBL1 directly binds to the promoters of GhCesA4-1, GhCesA4-2, and GhCesA8-1 and activates their expression to promote cellulose biosynthesis, thereby boosting fiber SCW formation. Collectively, our findings demonstrate that the collaboration between GhERF108 and GhARF7-1 or GhARF7-2 establishes ethylene-auxin signaling crosstalk to activate GhMYBL1, ultimately leading to the activation of fiber SCW biosynthesis.

Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection.

Tick-borne encephalitis virus (TBEV) is an important tick-borne pathogen that poses as a serious public health concern. The coverage and immunogenicity of the currently available vaccines against TBEV are relatively low; therefore, it is crucial to develop novel and effective vaccines against TBEV. The present study describes a novel strategy for the assembly of virus-like particles (VLPs) by co-expressing the structural (core/prM/E) and non-structural (NS2B/NS3Pro) proteins of TBEV. The efficacy of the VLPs was subsequently evaluated in C57BL/6 mice, and the resultant IgG serum could neutralize both Far-Eastern and European subtypes of TBEV. These findings indicated that the VLP-based vaccine elicited the production of cross-subtype reactive antibodies. The VLPs provided protection to mice lacking the type I interferon receptor (IFNAR-/-) against lethal TBEV challenge, with undetectable viral load in brain and intestinal tissues. Furthermore, the group that received the VLP vaccine did not exhibit significant pathological changes and the inflammatory factors were significantly suppressed compared to the control group. Immunization with the VLP vaccine induced the production of multiple-cytokine-producing antiviral CD4+ T cells in vivo, including TNF-α+, IL-2+, and IFN-γ+ T cells. Altogether, the findings suggest that noninfectious VLPs can serve as a potentially safe and effective vaccine candidate against diverse subtypes of TBEV.

Synthesis and Antifungal Activity of Novel L-Menthol Hydrazide Derivatives as Potential Laccase Inhibitors.

To discover novel laccase inhibitors as potential fungicides, twenty-six novel L-menthol hydrazide derivatives were designed and synthesized. In the in vitro antifungal assay, most of the target compounds displayed pronounced antifungal activity against Sclerotinia sclerotiorum, Fusarium graminearum, and Botryosphaeria dothidea. Especially, the EC50 of compounds 3 b and 3 q against B. dothidea was 0.465 and 0.622 mg/L, which was close to the positive compound fluxapyroxad (EC50 =0.322 mg/L). Scanning electron microscopy (SEM) analysis showed that compound 3 b could significantly damage the mycelial morphology of B. dothidea. In vivo antifungal experiments on apple fruits showed that 3 b exhibited excellent protective and curative effects. Furthermore, in the in vitro laccase inhibition assay, 3 b showed outstanding inhibitory activity with the IC50 value of 2.08 µM, which is much stronger than positive control cysteine and PMDD-5Y. These results indicated that this class of L-menthol derivatives could be promising leads for the discovery of laccase-targeting fungicides.

Analysis of PRAME immunocytochemistry in 109 acral malignant melanoma in situ.

AIMS: Preferentially expressed antigen in melanoma (PRAME) recently is a reliable immunohistochemistry (IHC) marker for distinguishing melanoma from other lesions. However, there are few articles focused on PRAME use in acral malignant melanoma, the most common type in Asians. This study investigated PRAME IHC expression in a large series of acral malignant melanoma in situ to add to the body of clinical knowledge. METHODS: PRAME IHC was performed in unequivocal cases of primary acral lentiginous melanoma in situ (ALMIS), subungual melanoma in situ (SMIS) and acral recurrent nevi as the control. PRAME tumour cell percentage positivity and intensity were expressed as categorised in a cumulative score by adding the quartile of positive tumour cells to intensity labelling. The final IHC expression was interpreted as negative (0-1), weak (2-3), moderate (4-5) or strong (6-7). RESULTS: In 91 ALMIS patients, 32 cases (35.16%) were strong, 37 (40.66%) were moderate and 22 (24.18%) were weak. In 18 SMIS patients, strong positivity of PRAME was observed in 4 (22.22%) cases, moderate in 10 (55.56%) and weak in the remaining 4 (22.22%). No melanoma sample was negative for PRAME. By comparison, only 2 of the 40 acral recurrent nevi cases were positive. CONCLUSIONS: Our study supports the ancillary value of PRAME for diagnosing ALMIS and SMIS with high sensitivity and specificity.

Huangqin Decoction ameliorates ulcerative colitis by regulating fatty acid metabolism to mediate macrophage polarization via activating FFAR4-AMPK-PPARα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula chronicled in Shang Han Lun, is safe and effective for treatment of ulcerative colitis (UC). AIM OF THE STUDY: To investigate the effect of HQD against dextran sulfate sodium (DSS)-induced UC mice by regulating gut microbiota and metabolites, and further explore the mechanism of fatty acid metabolism on macrophage polarization. MATERIALS AND METHODS: Based on 3% dextran sulfate sodium (DSS)-induced UC mice model, clinical symptoms observation (body weight, DAI, and colon length) and histological inspection were used to evaluate the efficacy of HQD and fecal microbiota transplantation (FMT) from HQD-treated mice. The gut microbiota and metabolites were detected by 16S rRNA sequencing and metabolomics analysis. The parameters of fatty acid metabolism, macrophage polarization, and FFAR1/FFAR4-AMPK-PPARα pathway were analyzed by immunofluorescence analysis, western blotting, and real-time PCR. Then, the effects of FFAR1 and FFAR4 on macrophage polarization were examined by agonists based on LPS-induced RAW264.7 cell model. RESULTS: The results showed that FMT, like HQD, ameliorated UC by improving weight loss, restoring colon length, and reducing DAI scores and histopathological scores. Besides, HQD and FMT both enhanced the richness of gut microbiota, and modulated intestinal bacteria and metabolites to achieve a new balance. Untargeted metabolomics analysis revealed that fatty acids, especially long-chain fatty acids (LCFAs), dominated in HQD against DSS-induced UC by regulating the gut microenvironment. Further, FMT and HQD recovered the expression of fatty acid metabolism-related enzymes, and simultaneously activated FFAR1/FFAR4-AMPK-PPARα pathway but suppressed NF-κB pathway. Combined with cell experiment, HQD and FMT promoted macrophage polarization from M1 toward M2, which were well associated with anti-inflammatory cytokines and combined with the activated FFAR4. CONCLUSIONS: The mechanism of HQD against UC was related to regulating fatty acid metabolism to mediate M2 macrophage polarization by activating the FFAR4-AMPK-PPARα pathway.

Design, synthesis and antifungal evaluation of novel nopol derivatives as potent laccase inhibitors.

BACKGROUND: To explore further potential natural product-based antifungal agents, a series of novel nopol-based carboxamide and hydrazide derivatives containing a natural pinene structure were designed, synthesized, and evaluated for their inhibitory activities against seven phytopathogenic fungi and oomycetes. RESULTS: The bioassay results indicated that some compounds exhibited good inhibitory activities against Gibberella zeae, Sclerotinia sclerotiorum, and Phytophthora capsici. Among them, compound 3h displayed excellent in vitro activities against G. zeae, with EC50 values of 1.09 mg L-1 , which was comparable with the commercial fungicides bixafen and carbendazim (median effective concentration [EC50 ] = 1.21 and 0.89 mg L-1 , respectively). Notably, in vivo bioassay results suggested that compound 3h also showed prominent protective and curative effects (95.6% and 94.2%) at 200 mg L-1 against G. zeae. The scanning electron microscopy study indicated that compound 3h could destroy the morphological integrity of G. zeae hyphae. The in vitro enzyme inhibitory bioassay revealed that compound 3h exhibited potent inhibitory activity against laccase with median inhibitory concentration (IC50 ) values of 4.93 µm, superior to positive control cysteine (IC50  = 35.50 µm), and its binding modes with laccase were elucidated by molecular docking study. In addition, the fluorescent imaging of the dansylamide-labeled derivatives 8 on wheat leaf epidermal cells and the hyphae of G. zeae revealed that this class of hydrazide derivatives could readily permeate into wheat leaves and reached the laccase target in fungal cells. CONCLUSION: Some nopol-based hydrazide derivatives exhibited excellent anti-G. zeae activity and laccase inhibitory activity, which merits further development as a new fungicide candidate for controlling Fusarium head blight. © 2023 Society of Chemical Industry.

Comparative phosphoproteomic analysis reveals that phosphorylation of sucrose synthase GhSUS2 by Ca2+-dependent protein kinases GhCPK84/93 affects cotton fiber development.

Cotton fiber elongation is a critical growth phase that affects final fiber length. Morphological analysis indicated an asynchronous fiber elongation pattern between two cotton varieties, J7-1 and J14-1. Through phosphoproteomic analysis, a total of 89 differentially-phosphorylated proteins (DPPs) were identified in elongating fibers between J7-1 and J14-1. Gene ontology (GO) analysis showed that these DPPs were mainly enriched in sucrose synthase activity, transferase activity, and UDP-glycosyltransferase activity. In J14-1, the phosphorylation level of GhSUS2, a key sucrose synthase in the sucrose metabolism pathway, was significantly higher than that in J7-1. We further revealed that GhSUS2 positively regulates fiber elongation, and GhSUS2-silenced transgenic cotton displayed the phenotype of 'short fibers' compared with the controls. During fiber development, the residue Ser11 in the GhSUS2 protein is phosphorylated by the Ca2+-dependent protein kinases GhCPK84 and GhCPK93. Phosphorylated GhSUS2 is localized in the cytoplasm, whereas unphosphorylated GhSUS2 is localized in the plasma membrane. Moreover, abscisic acid (ABA) could promote the transcription and translation of GhCPK84 and GhCPK93, thereby enhancing the phosphorylation of GhSUS2 to impede fiber elongation. Thus, our data demonstrates that GhSUS2 plays a positive role in fiber development, but its phosphorylation by GhCPK84 and GhCPK93 hinders fiber elongation of cotton.

Mental Health Among University Students, Using the 12-item General Health Questionnaire.

Context: To date, researchers have found that poor mental health was common during the COVID-19 epidemic. Even if they had been relatively resistant to suicidal ideation during the first three waves of the pandemic, university students may experience a delayed impact on their mental health. Objective: The study intended to measure mental health among university students in Wuhu City, China and to identify an effective approach to universities can use to prevent mental-health issues. Design: The research team performed a cross-sectional study. Setting: The study took place at Anhui polytechnic university, Wuhu, China. Participants: Participants were 2371 students at Anhui polytechnic university in Wuhu city, China. Outcome Measures: The research team used the two-item General Health Questionnaire-12 (GHQ-12) to measure participants' mental health. Results: Among the 2371 participants, 1727 had poor mental health (72.84%), including 843 males (48.81%) and 884 females (51.19%). Poor mental health was significantly associated with an urban residential location (P > .01), the female gender (p>0.01), the second school year (P > .01), and the parents' education level of junior high school or below (both P > .01). Conclusions: The current study suggests that poor mental health among university students is common. Being female, from an urban area, and in the second year of school and having parents with an education of junior high school or below had poorer mental health than those who were male, from the countryside, and in the first year of school and who had parents with a higher level of education.

SARS-CoV-2 infection activates CREB/CBP in cellular cyclic AMP-dependent pathways.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global coronavirus disease 2019 (COVID-19) pandemic that has affected the lives of billions of individuals. However, the host-virus interactions still need further investigation to reveal the underling mechanism of SARS-CoV-2 pathogenesis. Here, transcriptomics analysis of SARS-CoV-2 infection highlighted possible correlation between host-associated signaling pathway and virus. In detail, cAMP-protein kinase (PKA) pathway has an essential role in SARS-CoV-2 infection, followed by the interaction between cyclic AMP response element binding protein (CREB) and CREB-binding protein (CBP) could be induced and leading to the enhancement of CREB/CBP transcriptional activity. The replication of Delta and Omicron BA.5 were inhibited by about 49.4% and 44.7% after knockdown of CREB and CBP with small interfering RNAs, respectively. Furthermore, a small organic molecule naphthol AS-E (nAS-E), which targets on the interaction between CREB and CBP, potently inhibited SARS-CoV-2 wild-type (WT) infection with comparable the half-maximal effective concentration (EC50 ) 1.04 µM to Remdesivir 0.57 µM. Compared with WT virus, EC50 in Calu-3 cells against Delta, Omicron BA.2, and Omicron BA.5 were, on average, 1.5-fold, 1.1-fold, and 1.5-fold higher, respectively, nAS-E had a satisfied antiviral effect against Omicron variants. Taken together, our study demonstrated the importance of CREB/CBP induced by cAMP-PKA pathway during SARS-CoV-2 infection, and further provided a novel CREB/CBP interaction therapeutic drug targets for COVID-19.

A real-world study of effectiveness and safety of generic and original clopidogrel in the treatment of acute coronary syndrome / 中国药房

OBJECTIVE To evaluate the clinical effectiveness and safety of domestic generic and imported original clopidogrel for antiplatelet therapy in patients with acute coronary syndrome （ACS）. METHODS The clinical data of ACS patients in Nanjing Drum Tower Hospital of China Pharmaceutical University from January 2020 to June 2021 were retrospectively collected by using electronic medical record system， and the patients were divided into original drug group （321 cases） and generic drug group （328 cases） according to the drug use. Both groups were given dual antiplatelet therapy with clopidogrel and aspirin. The effectiveness and safety outcomes of the two groups were followed up for 12 months and compared， the related influential factors were analyzed. RESULTS Major adverse cardiovascular events （MACE） occurred in 16 and 22 patients in original drug group and generic drug group respectively， including nonfatal myocardial infarction （4 and 5 cases）， stroke （2 and 4 cases）， revascularization （8 and 3 cases）， cardiovascular related death （2 and 4 cases）， and all-cause death （4 and 6 cases）. There were 12 and 7 patients with major bleeding events， 38 and 29 patients with minor bleeding events， and 33 and 21 patients with non-bleeding adverse events. There was no statistically significant difference in the cumulative incidence of related events （P values of Log-Rank tests were all greater than 0.05）. Cox regression analysis showed that the use of generic clopidogrel did not increase the risk of MACE and major bleeding events in ACS patients [hazard ratio of 1.305 and 0.416， 95% confidence interval of （0.678， 2.512） and （0.155， 1.117）， respectively， P＞0.05]， and the combination of proton pump inhibitors （PPI） could reduce the risk of major bleeding events [hazard ratio of 0.196， 95% confidence interval of （0.063， 0.611）， P＜0.05]. CONCLUSIONS Compared with imported original drug， domestic generic clopidogrel has similar clinical effectiveness and good safety. Combined use of PPI may be a beneficial factor to reduce the occurrence of major bleeding events in patients.

[Influence of coexisting components in Coptidis Rhizoma on excretion of magnoflorine in rat bile, urine, and feces].

Magnoflorine is an important aporphine alkaloid in Coptidis Rhizoma. As reported previously, coexisting components in Coptidis Rhizoma can change the pharmacokinetic characteristics of magnoflorine. To illustrate the interactional links of magnoflorine with its coexisting components in Coptidis Rhizoma, the present study investigated the influence of coexisting components in Coptidis Rhizoma on the excretion of magnoflorine in rat bile, urine, and feces. The rats were dosed with magnoflorine(30 mg·kg~(-1)) and water decoction of Coptidis Rhizoma(equivalent to 30 mg·kg~(-1) magnoflorine) via intragastric administration, and magnoflorine(10 mg·kg~(-1)) by intravenous administration, respectively, and the excretion of magnoflorine in rat bile, urine, and feces in 24 h was observed. The excretion rates of magnoflorine in bile and urine in 24 h were 0.90% and 37.11% respectively after intravenous administration of magnoflorine, which suggested that urination was the main excretive way of magnoflorine. The excretion rates of magnoflorine in feces were 8.77% and 6.18% respectively after intragastric administration of magnoflorine and water decoction of Coptidis Rhizoma, which indicated that defecation was the main excretion route of magnoflorine. The cumulative excretion rates of magnoflorine in the bile, urine, and feces in the Coptidis Rhizoma water decoction group were 77.78%, 79.44%, and 70.47% of those in the magnoflorine group. The results showed that the cumulative excretion rates of magnoflorine in rat bile, urine, and feces were not high, suggesting that magnoflorine was metabolized significantly in rats. The coexisting components of Coptidis Rhizoma could inhibit the excretion of magnoflorine in rat bile, urine, and feces, which was consistent with the decrease in the elimination rate of magnoflorine in the pharmacokinetics of Coptidis Rhizoma water decoction. It indicated interactions between drugs. This study is expected to provide references for the development of magnoflorine-containing new drugs and rational clinical medication of Coptidis Rhizoma.