Thinking and practice on clinical safety evaluation of combination of traditional Chinese medicine and western medicine

Rui Zheng, Zhao Chen, Chen Zhao, Xiao-Yu Zhang, Ming-Yue Ma, Yang Sun, Hong-Cai Shang＊

1Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China.

2Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences. No. 16, Nanxiaojie, Dongzhimennei, Dongcheng District, Beijing 100700, China.

3Department of Pharmacy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China.

Abstract

China is gradually establishing a multidisciplinary diagnosis and treatment system of traditional Chinese medicine (TCM) and western medicine. TCM-drug combination is prone to adverse reactions.Clinical feature is the appearance of adverse reactions, and target is the internal mechanism. The establishment of feature and target correlation model will contribute to the development of this field.This paper introduces the four steps of feature-target correlation method that risk identification, feature extraction, sign target correlation and experimental research. Xiyanping-Ribavirin combination is as an example to illustrate this method. It is expected that the method will be popularized and applied to protect clinical safety.

Keywords Safety; TCM-drug combination; Clinical feature; Target; Feature-target correlation method

Highlights

The combination of traditional Chinese medicine (TCM) and western medicine is prone to adverse reactions. This article explains the safety evaluation of the TCM-drug combination from the perspective of the connection between clinical features and target mechanism. This paper introduces feature-target correlation method and takes Xiyangping-Ribavirin combination as an example to present applications.

In 2021, the General Office of the State Council issued several policies and measures on accelerating the development of Traditional Chinese Medicine (TCM)with characteristics, emphasizing the promotion of complementary and coordinated development of TCM and Western medicine, and gradually establishing a multidisciplinary diagnosis and treatment system of TCM and Western medicine [1]. TCM and Western medicine are complementary to each other and improve the clinical efficacy. However, they are derived from different theories, and TCM-drug combination is also prone to adverse reactions (ADRs).It is necessary to provide targeted clinical safety evaluation methods for TCM-drug combination to protect the efficacy. This article introduces the analysis of TCM-drug combination, the main steps of the "feature-target correlation method"and application examples, to promote the development of related fields.

Thinking about TCM-drug combination

At present, a variety of software have been developed to evaluate the safety of drug-drug combination. Micromedex ? Drug Reax is widely recognized for its ability to provide information on the potential mechanism, occurrence (fast or delayed) and severity of combination’s ADRs. A study has compared the database information with the clinicians' assessment, and found that the consistency was poor [2]. It may be due to the scattered sources of clinical characteristics and mechanism evidence.

Clinical feature is the appearance of ADRs

Clinical features are extrinsic appearance. When the balance of body is broken, it is easiest to observe the changes on clinical characteristics. The Naranjo scoring method, Karch and Lasagna evaluation method and other comprehensive analysis method mainly evaluate the characteristics of ADRs and the drug use, providing a preliminary judgment for the causal relationship [3]. LIU et al. adds known clinical features, which improves the stability of the prediction model [4], suggesting that features play a key role in evaluation of ADRs. How to make good use of the existing ways to collect clinical safety information and extract comprehensive clinical features of TCM-drug combinations’ ADRs is a key step in the clinical safety evaluation.

The external manifestations of ADRs can be expressed in different systems, but the internal mechanisms are same. For example, anaphylactoid reaction can be manifested in the skin, digestive or respiratory system. Its common internal mechanism is the change of vascular permeability [5]. The permeability of blood vessels in the skin is increased. The plasma albumin is exuded and the inflammatory reaction breaks out, causing skin rash, itching and other symptoms.Increasing vascular permeability in intestinal tissue can lead to mucosal edema,abdominal pain, diarrhea, et al.

Target is the internal mechanism of ADRs

The internal mechanism causes appearance. Aconitine is absorbed quickly and produce abnormal rhythm disorder and/or trigger malignant arrhythmia within a few minutes [6]. Dose accumulation and internal mechanism regulation make external symptoms appear. For example, the mechanism of genetic material damage caused by accumulating aristolochic acid leads to nephrotoxicity [7].

Different from the clinical safety evaluation of chemical drugs and biological agents, the difficulties in the safety of TCM mainly come from the complexity and the unpredictability [8]. The guidelines of the European Drug Administration describe the target markers related to the risk induced toxicity, suggesting that ADRs are related to the target of induced toxicity [9]. This characteristic also appears in the TCM-drug combination, and the situation is more complex.

The "Effective theory" holds that the superposition of multiple components on each single target [10] constitute the pharmacological action mechanism of TCM,and the toxic effect is the same. TCM involves the action of multiple compounds on multiple targets and pathways. Drug, as a new factor, forms a more complex target network. Herb and drugs may successively enter the vacancy, and the target position is occupied to a certain extent (quantity/proportion). Superposition effect appears to regulate the activation of drug metabolizing enzymes and initiate ADRs.Identifying the activated targets and pathways in ADRs is helpful to correlate clinical features and target mechanisms.

External manifestations related to internal mechanisms

Many internal and external factors lead to ADRs. Mechanism is the internal aspect of ADRs, which needs to be indirectly recognized through researches. The clinical feature is the extrinsic appearance of ADRs. The internal mechanism and appearance of ADRs occur in the human body, which is a unified whole. It is a deepening study to associate the internal mechanism from the appearance.

The clinical safety evaluation methods, such as comprehensive analysis and reasoning, pay more attention to the drug-feature relationship. If the drug intrinsic mechanism research is limited and the clinical characteristics are ignored, a lot of resources may be consumed in the screening process, and the data from laboratory cannot guide clinical practice.

The external manifestation not closely related to the internal mechanism cannot reflect the real situation. This may be the reason for the difference between Uppsala Monitoring Center's standard and Naranjo's algorithm in determining the causality of ADRs [11]. Therefore, how to extract and summarize clinical features from the real world? Which pathways are affected by the TCM-drug combination？The thought details are shown in Figure 1.

Figure 1 Analysis of clinical safety evaluation about TCM-drug combination

Some professors pointed out that how to relate the macro "state" with micro"target" of TCM is a key issue in the development [12]. The "state-target syndrome differentiation" is proposed to realize the organic combination of "macro syndrome differentiation" to regulate the disease state and "micro targeting" to solve chemical indicators [13], that is, the combination of micro and macro.

Expanding to the field of clinical safety evaluation of TCM-drug combination also requires the correlation between macro and micro. It is holistic to analyze the risk from the macro features to the micro target regulation mechanism of ADRs.Precision is the historical demand for the development of TCM. Components of TCM activating/inhibiting target network is the direction of continuous research and development. The correlation analysis between clinical features and target mechanisms will be more closely studied.

The main steps of "feature-target correlation method "

Under the background, our team proposed the feature-target correlation method in the early stage [14]. It refers to the clinical safety evaluation method used to associate the clinical features with the target mechanism in TCM-drug combination and to indicate the risk. Based the previous articles, this paper further explains the implementation of the feature-target correlation method to facilitate its popularization and application. Specific steps include risk identification,feature extraction, sign target correlation and experimental verification, as shown in Figure 2.

Figure 2 Main steps of the feature-target correlation method

Risk identification

TCM-drug combination has the characteristics of complex clinical application.Efficient application of existing data is an important part of ADRs assessment. The national adverse reaction monitoring spontaneous reporting system contains extensive and detailed case information, including severity, age, sex, nationality,drug interaction, et al. The factors in the system can be used to analyze which combination has a strong impact on the severity as a preliminary risk identification.

Feature extraction

The multiple evidences were used to synthesize all information sources, including centralized hospital monitoring, literature, spontaneous reporting system data, et al. Several parts of the data are complementary and show multi-angle characteristics to avoid unilateral information loss or bias, to analyze the clinical characteristics and relevant information of combined ADRs, including the incidence of ADRs, dosage, frequency, symptom contact strength, et al.

Sign-target correlation

The existing database is set with relevant clinical characteristics as the key words,which is consistent with medication standard. The network target analysis is an important prediction method for studying the relationship between drugs, targets and diseases. It helps to explain the synergistic mechanism between active components of drugs, and provides reference for the study of clinical safety evaluation.

Experimental verification

Establishing animal models corresponding to clinical features are helpful to carrying out relevant experimental validation studies on TCM-drug combination.For the first time, the injection was used in combination with skin rash, pruritus and other symptoms. Lacking immune process, it conformed to the characteristics of clinical anaphylactoid reaction (skin rash). Anaphylactic reaction is characterized by changes in vascular permeability. Evans blue staining can be used to observe the blue staining of mouse auricle, evaluating the changes in vascular permeability.

Case description

Xiyanping injection (XYP) was approved for marketing in 2002. XYP has the effects of clearing heat, detoxification. It is widely used in treating respiratory inflammation, bacterial dysentery, et al. It is often combined with drugs such as antibiotics. It also plays an important role in the treatment of COVID-19 [15].However, in 2017, XYP was called off nationwide due to more than 10 adverse events. The feature-target correlation method was used to analyze and found that age and XYP-Ribavirin were the risk factors of the severity of adverse events [16].Multiple evidences suggested that 57.9% of the adverse events occurred in the first combination, of which 56.4% were skin and accessory reactions [17]. Rash is the main clinical feature and conforms to the characteristics of anaphylactoid reaction.Through network target analysis, the co-regulation of rash targets may enhance the regulation of inflammation and apoptosis related pathways. It is suggested that the XYP-ribavirin combination has certain advantages in clinical efficacy [18], but in the process of combination, attention should be paid to ensuring the time interval or replacement of infusion apparatus.

Summary

The clinical safety problems of TCM-drug combination are exposed in the real world. The collection of multiple sources is a multi-aspect demonstration of clinical practice. By building multiple evidences, we can extract the clinical characteristics and construct the association of biological pathways. The clinical features are closely linked with the target mechanism, which is helpful to remove the confounding factors and prompt the mechanism research. In clinical practice,we should pay attention to possible ADRs, find them in time and protect clinical safety.