Potential cardiotoxicity induced by Euodiae Fructus: In vivo and in vitro experiments and untargeted metabolomics research.

Background: Euodiae Fructus, a well-known herbal medicine, is widely used in Asia and has also gained in popularity in Western countries over the last decades. It has known side effects, which have been observed in clinical settings, but few studies have reported on its cardiotoxicity. Methods: In the present study, experiments using techniques of untargeted metabolomics clarify the hazardous effects of Euodiae Fructus on cardiac function and metabolism in rats in situations of overdosage and unsuitable syndrome differentiation. In vitro assays are conducted to observe the toxic effects of evodiamine and rutaecarpine, two main chemical constituents of Euodiae Fructus, in H9c2 and neonatal rat cardiomyocytes (NRCMs), with their signaling mechanisms analyzed accordingly. Results: The cardiac cytotoxicity of evodiamine and rutaecarpine in in vivo experiments is associated with remarkable alterations in lactate dehydrogenase, creatine kinase, and mitochondrial membrane potential; also with increased intensity of calcium fluorescence, decreased protein expression of the cGMP-PKG pathway in H9c2 cells, and frequency of spontaneous beat in NRCMs. Additionally, the results in rats with Yin deficiency receiving a high-dosage of Euodiae Fructus suggest obvious cardiac physiological dysfunction, abnormal electrocardiogram, pathological injuries, and decreased expression of PKG protein. At the level of endogenous metabolites, the cardiac side effects of overdose and irrational usage of Euodiae Fructus relate to 34 differential metabolites and 10 metabolic pathways involving among others, the purine metabolism, the glycerophospholipid metabolism, the glycerolipid metabolism, and the sphingolipid metabolism. Conclusion: These findings shed new light on the cardiotoxicity induced by Euodiae Fructus, which might be associated with overdose and unsuitable syndrome differentiation, that comes from modulating the cGMP-PKG pathway and disturbing the metabolic pathways of purine, lipid, and amino acid. Continuing research is needed to ensure pharmacovigilance for the safe administration of Chinese herbs in the future.

Network Analysis of the Herb-Drug Interactions of Citrus Herbs Inspired by the "Grapefruit Juice Effect".

This study was performed to investigate the herb-drug interactions (HDIs) of citrus herbs (CHs), which was inspired by the "grapefruit (GF) juice effect". Based on network analysis, a total of 249 components in GF and 159 compounds in CHs exhibited great potential as active ingredients. Moreover, 360 GF-related genes, 422 CH-related genes, and 111 genes associated with drug transport and metabolism were collected, while 25 and 26 overlapping genes were identified. In compound-target networks, the degrees of naringenin, isopimpinellin, apigenin, sinensetin, and isoimperatorin were higher, and the results of protein-protein interaction indicated the hub role of UGT1A1 and CYP3A4. Conventional drugs such as erlotinib, nilotinib, tamoxifen, theophylline, venlafaxine, and verapamil were associated with GF and CHs via multiple drug transporters and drug-metabolizing enzymes. Remarkably, GF and CHs shared 48 potential active compounds, among which naringenin, tangeretin, nobiletin, and apigenin possessed more interactions with targets. Drug metabolism by cytochrome P450 stood out in the mutual mechanism of GF and CHs. Molecular docking was utilized to elevate the protein-ligand binding potential of naringenin, tangeretin, nobiletin, and apigenin with UGT1A1 and CYP3A4. Furthermore, in vitro experiments demonstrated their regulating effect. Overall, this approach provided predictions on the HDIs of CHs, and they were tentatively verified through molecular docking and cell tests. Moreover, there is a demand for clinical and experimental evidence to support the prediction.

[Series of group standards of Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions].

Drug instructions,the statutory and technical documents recording effectiveness and safety information,are an important basis for guiding doctors,pharmacists,and patients to use drugs rationally,and their scientificity,standardization,and accuracy directly affect the medication safety of the public. The sections of adverse drug events,contraindications,precautions,warnings,and application for specific populations in drug instructions directly express safety information and measures for rational use of drugs. In the drug life cycle,marketing authorization holders( MAHs) need to update safety information in the instructions promptly to ensure the safety and effectiveness of clinical drug medication. At present,revising instructions is an important measure to control drug risks. In the drug life cycle,in order to standardize the revision of safety information in the instructions by MAHs and eliminate inexact terms such as " unclear",the Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions,a series of group standards,have been established under the guidance of Standardization Department,China Association of Chinese Medicine. Therefore,on the basis of the existing rules and regulations,the standardized technical procedures for revising instructions came into being to help clinical safe and rational medication of drugs,and implement the strategy of " Healthy China".

[Interpretation of Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions].

Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions,a series of group standards,were proposed by Professor ZHANG Bing from Research Center for Pharmacovigilance and Rational Use of Traditional Chinese Medicine,and underwent centralized management by Chinese Association of Chinese Medicine. They were officially released on July 23 and implemented on July 31,2021. The series of group standards consist of six sections,including general principles,adverse drug events,contraindications,precautions,application for special populations,and warnings. The section of general principles is comprised of holistic and programmatic expressions,which explain the general technical requirements for revising the marketed Chinese patent medicine instructions. The other five sections focus on information collection,screening,transformation,and illustration of specific items,forming a standardized revision technical process. This series of standards is the result of multiple rounds of research and the suggestions of more than 200 experts in different professional fields of " medicine-pharmacy-management-law-enterprise" have been gathered therein to reach a consensus. With the purposes of establishing standardized technical specifications for the revision of safety information in the marketed Chinese patent medicine instructions,guiding marketing authorization holders in revising the instructions,filling the gaps in the research of Chinese patent medicine instructions,promoting the deve-lopment of pharmaceutical care and academic research,and encouraging the rational and safe medication of Chinese patent medicine,the series of group standards is of great significance.

[Technical specification for Instructions for Clinical Application of Chinese Patent Medicines in China Association of Chinese Medicine].

In order to solve the problems of confusion in clinical medication and imperfect instructions in Chinese patent medicines(CPMs), the Standardization Department of the China Association of Chinese Medicine and Center for Pharmacovigilance and Rational use of Chinese Medicine in Beijing University of Chinese Medicine jointly compiled the Instructions for Clinical Application of Chinese Patent Medicines(CPMs). As the interpretation and supplement of drug instruction information, it aims to guide clinical safety and rational use of CPMs. In addition, the technical specification for clinical application description of CPMs has been formulated, which covers the seven processes of "carding instructions, clinical investigation, data retrieval, data screening, evidence classification, path transformation and writing format". It will enable readers of Instructions for Clinical Application of Chinese Patent Medicines to understand the work behind the compilation.

Purification and characterization of bromelain from pineapple (Ananas comosus L.) peel waste.

Bromelain is widely used in food industry and pharmaceutical products due to its strong antioxidant properties. Therefore, the extraction of bromelain from pineapple peel may improve the profitability and sustainability of pineapple industry. The aim of this work is to show the purification, stability, and kinetics of bromelain from pineapple peel. By studying the stability of purified bromelain (PB), we found that the activity of PB was inhibited by Fe3+ , Al3+ , methanol, ethanol, and n-butyl alcohol, while it was increased in the presence of Ca2+ , ethylenediamine tetra acetic acid, glucose, D-xylose, maltose, potassium sodium tartrate, sodium citrate, citric acid, and sodium nitrite. These stability tests will expand the application and space acquisition of bromelain. The kinetics study indicated that the thermal inactivation of PB was conforming to the first-order reaction and the half-life (t1/2 ) of PB under different temperature conditions (45, 55, 65, and 75 °C) was 81.54, 31.12, 10.28, and 5.23 min, respectively. Therefore, the inactivation time of PB can be predicted at different temperatures for food heating processing. PRACTICAL APPLICATION: The potential of utilizing pineapple peel for bromelain extraction might improve the profitability and sustainability of the pineapple industry.

The clinical benefits of Chinese patent medicines against COVID-19 based on current evidence.

The outbreak of emerging infectious pneumonia caused by 2019 Novel Coronavirus (2019-nCoV) has posed an enormous threat to public health, and traditional Chinese medicine (TCM) have made vast contribution to the prevention, treatment and rehabilitation of coronavirus disease 19 (COVID-19) among Chinese population. As an indispensable part of TCM, Chinese patent medicines (CPMs) are highly valued and critically acclaimed in their campaign to contain and tackle the epidemic, they can achieve considerable effects for both suspected cases under medical observation period, and confirmed individuals with serious underlying diseases or critical conditions. Given this, based on the Guideline on Diagnosis and Treatment of Coronavirus Disease 2019 in China, the present review summarized the basic information, clinical evidence and published literatures of recommended CPMs against COVID-19. The details were thoroughly introduced involving compositions, therapeutic effects, clinical indications, medication history of CPMs and the profiles of corresponding research. With regard to infected patients with different stages and syndrome, the preferable potentials and therapeutic mechanism of CPMs were addressed through the comprehensive collection of relevant literatures and on-going clinical trials. This study could provide an insight into clinical application and underlying mechanism of recommended CPMs against COVID-19, with the aim to share the Chinese experience in clinical practice and facilitate scientific development of TCM, especially CPMs in the fierce battle of COVID-19.

[Study on the dynamic variations of Z-ligustilide and n-butylidenephthalide content in essential oil of radix angelicae sinensis from different growth period].

OBJECTIVE: To study the variation of the biomass of the root and active components of Angelica sinensis during different growth periods. METHODS: 27 batches of Angelica sinensis were harvested from different growth periods, and the biomass of underground parts were determined; The Gas Chromatography-Mass Spectrometry (GC-MS) was used for determining the contents of Z-ligustilide and n-Butylidenephthalide in essential oil of Radix Angelicae Sinensis. RESULTS: The average contents of n-Butylidenephthalide and Z-ligustilide were more than 1% and 40% in the total essential oil of Radix Angelicae sinensis respectively. Their contents showed larger difference during different growth period. CONCLUSION: The contents of Z-ligustilide and n-Butylidenephthalide of Radix Angelicae Sinensis is closely related to their growth period.