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Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models.

ABSTRACT: Blood activation and stasis removal from circulation is a central principle for treatment of syndromes related to cerebral and cardiovascular diseases in Chinese herbal medicine. However, blood-activating and stasis-removing patent Chinese herbal medicine (BASR-pCHM) widely used with or without prescription in China and elsewhere are highly variable in composition and manufacture standard, making their safety assessment a challenging task. We proposed that an integrated evaluation of multiple toxicity parameters of BASR-pCHM would provide critical reference and guidelines for their safe clinical application. Examination of standardized extracts from 58 compound BASR-pCHM in vivo in VEGFR2-luc mice and in vitro in cardiac, renal, and hepatic cells identified Naoluotong capsule (NLTC) as a potent organ/cell damage inducer. Composition analysis revealed that NLTC was the one that contained nonherbal ingredients among the BASR-pCHM collection. In vivo and in vitro experiments confirmed that NLTC, as well as its chemical supplement tolperisone hydrochloride, caused organ and cell damage by reducing cell viability, mitochondrial mass/activity, while the NLTC herbal components did not. Taken together, our study showed that safety evaluation of patent herbal medicines already on market is still necessary and urgently needed. In addition, chemical/herbal interactions should be considered as an important contributor of potential toxicity when evaluating the safety of herbal medicine.

SUBMITTER: Liu X

PROVIDER: S-EPMC6757273 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models.

Liu Xinyan X Shao Rui R Yang Xinyue X Xiao Guangxu G He Shuang S Feng Yuxin Y Zhu Yan Y

Frontiers in pharmacology 20190912

Blood activation and stasis removal from circulation is a central principle for treatment of syndromes related to cerebral and cardiovascular diseases in Chinese herbal medicine. However, blood-activating and stasis-removing patent Chinese herbal medicine (BASR-pCHM) widely used with or without prescription in China and elsewhere are highly variable in composition and manufacture standard, making their safety assessment a challenging task. We proposed that an integrated evaluation of multiple to ...[more]

PMID: 31607901

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Project description:BackgroundHypercholesterolemia is an important key contributory factor for ischemic heart disease and is associated with age, high blood pressure, a family history of hypercholesterolemia, and diabetes. Chinese herbal medicines have been used for a long time as lipid-lowering agents.ObjectivesTo assess the effects of Chinese herbal medicines on hypercholesterolemia.Search strategyWe searched the following databases: The Cochrane Library (issue 8, 2010), MEDLINE (until July 2010), EMBASE (until July 2010 ), Chinese BioMedical Database (until July 2010), Traditional Chinese Medical Literature Analysis and Retrieval System (until July 2010), China National Knowledge Infrastructure (until July 2010), Chinese VIP Information (until July 2010), Chinese Academic Conference Papers Database and Chinese Dissertation Database (until July 2010), and Allied and Complementary Medicine Database (until July 2010).Selection criteriaWe considered randomized controlled clinical trials in hypercholesterolemic participants comparing Chinese herbal medicines with placebo, no treatment, and pharmacological or non-pharmacological interventions.Data collection and analysisTwo review authors independently extracted data and assessed the risk of bias. We resolved any disagreements with this assessment through discussion and a decision was achieved based by consensus. We assessed trials for the risk of bias against key criteria: random sequence generation, allocation concealment, blinding of participants, incomplete outcome data, selective outcome reporting and other sources of bias.Main resultsWe included 22 randomized trials (2130 participants). The mean treatment duration was 2.3 ± 1.3 months (ranging from one to six months). Twenty trials were conducted in China and 18 trials were published in Chinese. Overall, the risk of bias of included trials was high or unclear. Five different herbal medicines were evaluated in the included trials, which compared herbs with conventional medicine in six comparisons (20 trials), or placebo (two trials). There were no outcome data in any of the trials on cardiovascular events and death from any cause. One trial each reported well-being (no significant differences) and economic costs. No serious adverse events were observed. Xuezhikang was the most commonly used herbal formula investigated. A significant effect on total cholesterol (two trial, 254 participants) was shown in favor of Xuezhikang when compared with inositol nicotinate (mean difference (MD) -0.90 mmol/L, 95% confidence interval (CI) -1.13 to -0.68) .Authors' conclusionsSome herbal medicines may have cholesterol-lowering effects. Our findings have to be interpreted with caution due to high or unclear risk of bias of the included trials.

Project description:In recent years, liver injury induced by Traditional Chinese Medicines (TCMs) has gained increasing attention worldwide. Assessing the hepatotoxicity of compounds in TCMs is essential and inevitable for both doctors and regulatory agencies. However, there has been no effective method to screen the hepatotoxic ingredients in TCMs available until now. In the present study, we initially built a large scale dataset of drug-induced liver injuries (DILIs). Then, 13 types of molecular fingerprints/descriptors and eight machine learning algorithms were utilized to develop single classifiers for DILI, which resulted in 5416 single classifiers. Next, the NaiveBayes algorithm was adopted to integrate the best single classifier of each machine learning algorithm, by which we attempted to build a combined classifier. The accuracy, sensitivity, specificity, and area under the curve of the combined classifier were 72.798, 0.732, 0.724, and 0.793, respectively. Compared to several prior studies, the combined classifier provided better performance both in cross validation and external validation. In our prior study, we developed a herb-hepatotoxic ingredient network and a herb-induced liver injury (HILI) dataset based on pre-clinical evidence published in the scientific literature. Herein, by combining that and the combined classifier developed in this work, we proposed the first instance of a computational toxicology to screen the hepatotoxic ingredients in TCMs. Then Polygonum multiflorum Thunb (PmT) was used as a case to investigate the reliability of the approach proposed. Consequently, a total of 25 ingredients in PmT were identified as hepatotoxicants. The results were highly consistent with records in the literature, indicating that our computational toxicology approach is reliable and effective for the screening of hepatotoxic ingredients in Pmt. The combined classifier developed in this work can be used to assess the hepatotoxic risk of both natural compounds and synthetic drugs. The computational toxicology approach presented in this work will assist with screening the hepatotoxic ingredients in TCMs, which will further lay the foundation for exploring the hepatotoxic mechanisms of TCMs. In addition, the method proposed in this work can be applied to research focused on other adverse effects of TCMs/synthetic drugs.

Dataset Information

Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models.

Publications

Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models.

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