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ObjectiveAfter the brain and heart injuries were simulated by myocardial injury caused by acute cerebral ischemia， this study explored the mechanism of Naoxintong capsules in treating brain and heart injuries under cerebral ischemia state with Toll-like receptor （TLR） 2/TLR4 as the breakthrough point. MethodC57BL/6 male mice were randomly assigned into the sham operation， model， Naoxintong， and Ginaton groups. The middle cerebral artery occlusion （MCAO） method was used to establish a mouse model of cerebral ischemia. The neuroethological score， cerebral infarction area， cell apoptosis， ionized calcium-binding adaptor molecule 1 （IBA-1）-positive microglia proportion， and serum levels of N-terminal pro-brain natriuretic peptide （NT-proBNP）， creatine kinase-MB （CK-MB）， and lactic dehydrogenase （LDH） were determined to evaluate the pharmacodynamic effects of Naoxintong capsules on heart and brain injuries after cerebral ischemia in mice. Western blotting was employed to determine the expression of TLR2/TLR4 protein in the brain and heart of mice. ResultCompared with the sham operation group， the model group showed increased cerebral infarction area， neuroethological score， apoptosis rate， IBA-1-positive microglia proportion， and serum levels of NT-proBNP， CK-MB， and LDH （P<0.01）. Naoxintong capsules reduced the cerebral infarction area， neuroethological score， apoptosis rate， IBA-1-positive microglia proportion （P<0.01）， and serum NT-proBNP and CK-MB levels （P<0.05） in mice compared with the model group. Western blotting results showed that Naoxintong Capsules down-regulated the expression levels of TLR2 （P<0.05） in the brain and TLR2 （P<0.01） and TLR4 （P<0.05） in the heart. ConclusionCerebral ischemia can cause myocardial damage， reflecting the pathological process of cardiac injury after cerebral ischemia. Naoxintong capsules can mitigate brain and heart injuries after cerebral ischemia and achieve the simultaneous treatment of the brain and the heart， in which TLR2/TLR4 plays a role.
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ObjectiveTo evaluate the clinical safety of Naoxintong （NXT） capsules after marketing， find out the potential risk factors of the drug as soon as possible， and reveal the incidence， nature， and clinical manifestations of the adverse events （ADE） and adverse reactions （ADR） of NXT capsules， so as to provide a basis for safe use of the drug in clinical practice. MethodA prospective， large-sample， multi-center observational cohort study was conducted to monitor all the 7 345 inpatients and outpatients orally taking NXT in 14 hospitals in China from January to December in 2018， with at least one follow-up. The demographic characteristics， disease type， NXT medication， ADR occurrence， characteristics， and prognosis of the patients were collected. SPSS 23.0 was used for single-factor and multivariate logistic regression to predict the influencing factors of ADR. ResultThe male and female patients accounted for similar proportions. There were 5 081 patients （79.40%） aged ≥60 years and 3 153 patients （49.27%） with body mass index （BMI） exceeding the normal standard. There were 344 （5.38%） patients with a history of allergy to medicines and food， 9 （0.14%） patients with a family history of allergy， and 52 （0.81%） patients with a history of allergic diseases. The ADRs associated with NXT occurred in 22 patients， with the incidence of 0.34%. The clinical manifestations of ADR appeared in 31 cases， involving 10 organs/systems， of which gastrointestinal system damage was the most common （17， 54.84%）. All ADRs were mild or moderate. Most ADRs （19， 86.36%） occurred within 4 weeks after administration. The patients with alleviated NXT-associated ADRs accounted for 81.82%. No indicators related to significant increases in ADR risks were found. ConclusionNXT is well tolerated in the general population. The hospital centralized monitoring for the clinical safety of oral Chinese patent drugs based on HIS data and Web tracking and follow-up system is an essential means for the post-market research on the safety of drugs.
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Through investigating the current research on the effect of Naoxintong Capsules in the treatment of cerebral infarction with Qi deficiency and blood stasis syndrome and coronary heart disease angina pectoris, this study conducted a clinical comprehensive evaluation in "6+1" dimensions [safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine(TCM)], so as to highlight the advantages and clinical value of Naoxintong Capsules. By combining qualitative and quantitative methods, we used the multi-criteria decision analysis(MCDA) model to measure each dimension, and the results thereby were divided into four grades of A, B, C, and D in high-to-low order. Through literature review and evaluation, the adverse effects of Naoxintong Capsules are mainly caused by the gastrointestinal system. Since the safety risk is controllable based on current research, the safety evaluation is grade B. The effectiveness of Naoxintong Capsules combined with conventional western medicine in the treatment of cerebral infarction with Qi deficiency and blood stasis syndrome and coronary heart disease angina pectoris is evaluated as grade A, as compared with conventional therapy alone. The economy of Naoxintong Capsules, compared with Tongxinluo Capsules, is assessed as grade B. According to literature reports, Naoxintong Capsules exhibits outstanding clinical innovation in optimizing the current anti-platelet therapy strategy for patients with coronary heart disease after percutaneous coronary intervention(PCI), and the innovation is class A. Given the capsule formulation is convenient for storage and transportation, and its usage is easy for patients to grasp and accept, the suitability is grade B. The accessibility is grade A considering the price level, availability, and affordability, and the characteristics of TCM are evaluated as grade A from the perspectives of theoretical characteristics and human experience. The results of the comprehensive drug evaluation showed that the clinical value of Naoxintong Capsules is class A for treating cerebral infarction with Qi deficiency and blood stasis syndrome and coronary heart disease angina pectoris. According to the Guidelines for the Management of Comprehensive Clinical Evaluation of Drugs(trial 2021 version) issued by the National Health Commission, relevant policy results for basic clinical drug management can be formulated directly by procedure.
Subject(s)
Humans , Angina Pectoris , Capsules , Cerebral Infarction/drug therapy , Coronary Disease/drug therapy , Drugs, Chinese Herbal , Medicine, Chinese Traditional , Percutaneous Coronary Intervention , QiABSTRACT
Intestinal absorption liquid was prepared by using everted intestinal sac method; meanwhile, its recipes were decomposed or restructured. Platelet aggregation activity was examined by biochemical tests and a microplate reader. One or more kinds of Chinese medicines which displayed inhibiting activity in Naoxintong Capsules were screened through separation and combination of prescription. The results showed that Naoxintong Capsules could inhibit ADP-induced platelet aggregation. Recipe decomposition and restructuring results showed that Salviae Miltiorrhizae Radix et Rhizoma, Paeoniae Radix Rubra, Cinnamomi Ramulus and Hirudo were the main effective medicines in inhibiting platelet aggregation. Furthermore, Cinnamomi Ramulus played a vital role in inhibiting activity among those four kinds of Chinese medicines. Coumarin derived from intestinal absorption liquid of Cinnamomi Ramulus had inhibiting activity in the range of 50-200 μmol·L⁻¹, and other ingredients such as cinnamyl alcohol and cinnamaldehyde also had inhibiting activities. In conclusion, Salviae Miltiorrhizae Radix et Rhizoma, Paeoniae Radix Rubra, Cinnamomi Ramulus and Hirudo are the main components for inhibiting ADP-induced platelet aggregation, and Cinnamomi Ramulus has the most strongest inhibiting activity in Naoxintong Capsules.
Subject(s)
Adenosine Diphosphate , Capsules , Drugs, Chinese Herbal , Intestinal Absorption , Platelet AggregationABSTRACT
OBJECTIVE: To establish a novel ultra-high performance liquid chromatography-quadrupole/orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) method to study the chemical composition of Naoxintong capsules rapidly and accurately. METHODS: The information of accurate mass in full-MS and multistage fragment ions was obtained by the novel UHPLC-Q-Orbitrap technology. Chemical constituents were identified by comparing the relative retention time and the mass data of the reference substances, meanwhile consulting the reference literature or the Mass Bank, Chemical Book network database. RESULTS: Forty-four compounds were finally identified in this study, mainly including flavones, authraquinones, terpenoids and organic acids. CONCLUSION: A method is established in this study to identify various chemical constituents of Naoxintong capsules rapidly, accurately and systematically. What's more, our research will lay a sound theoretical foundation and propose a scientific study idea for the quality control improvement, bioactive components recognition and further clinical application of this herbal formulation.
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Objective: To investigate the protective effects and mechanism of Naoxintong Capsules (NXT) on primary cultured neonate rat brain microvascular endothelial cells (rBMECs) induced by oxygen-glucose deprivation. Methods: The primary cultured rBMECs model was established and the identification of rabbit anti-rat VIII factor was carried out. MTT was used to screen out the concentration range of NXT intestinal absorption solution to pretect rBMEC in vitro, three doses were selected for experiment. The experimental groups were divided into control group, model group, nimodipine group (200 μg/mL, NXT intestinal absorption solution group (62.50 mg/L, 125.00 mg/L, and 250.00 mg/L), and NXT intestinal absorption solution (250.00 mg/L) and LY294002 (20 μmol/L, PI3K/Akt pathway inhibitor) co-administration group. The morphology of rBMECs was observed under inverted microscope. The expression of lactate dehydrogenase (LDH) and matrix metalloproteinase 9 (MMP-9) in the cell supernatant was detected by ELISA kit. The apoptosis was observed by Hoechst33342 staining fluorescence microscope. The early apoptotic rate of rBMECs in each group was detected by FCM, and the expression of PI3K/Akt signaling pathway key proteins was detected by Western blotting. Results: Compared with model group, the administration of NXT could significantly improve the morphology of rBMECs, decrease the intracellular levels of LDH and MMP-9, significantly reduce the number of apoptotic cells and early apoptotic rate of rBMECs, and inhibit the expression of p-Akt, Bcl-2 upregulation, decrease the expression of Bax, and inhibit caspase-3 activity. The addition of LY294002, a specific inhibitor of PI3K/Akt signaling pathway, blocked the signal transduction of this pathway and significantly reduced the protective effect of NXT. Conclusion: NXT have protective effects on rBMECs induced by oxygen-glucose deprivation, and its mechanism is related to the PI3K/Akt signaling pathway.
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OBJECTIVE:To investigate therapeutic efficacy and safety of Naoxintong capsules combined with edaravone in the treatment of acute cerebral infarction. METHODS:80 patients with acute cerebral infarction were analyzed retrospectively and divid-ed into observation group (40 cases) and control group (40 cases) according to drug use. Both groups was given Aspirin enter-ic-coated tablets 10 mg orally,once a day,to control platelet aggregation,20% Mannitol injection 250 mL intravenously,every 12 hours,to control brain edema,Potassium chloride sustained-release tablets 0.5 g orally,3 times a day,to maintain water and elec-trolyte balance and other conventional treatment. Control group was additionally given Edaravone injection 30 mg added into 0.9%Sodium chloride injection 100 mL intravenously within 30 min,once a day;observation group was additionally given Naoxintong capsules 1.6 g,3 times a day on the basis of control group. Treatment course of both groups lasted for 10 d. Clinical efficacies of 2 groups were observed as well as the ET-1 and NO content,IL-8,hs-CRP,FT3,FT4 and TSH level,NIHSS and ADL score,the occurrence of ADR before and after treatment. RESULTS:Total response rate of observation group was significantly higher than that of control group,with statistical significance(P0.05). After treatment,the ET-1 content,IL-8 and hs-CRP level,NIHSS score in 2 groups were significantly lower than before,and the observation group was lower than the control group;the NO content,TSH,ADL score in 2 groups were significantly higher than before,and the ob-servation groups was higher than the control group,with statistical significance(P0.05). No severe ADR was found in 2 groups. CON-CLUSIONS:Based on routine treatment,Naoxintong capsules combined with edaravone in the treatment of acute cerebral infarc-tion can improve therapeutic efficacy and vascular endothelial function,relieve inflammatory reaction and recue TSH levels,more-over,don't increase the occurrence of ADR.