TBC is an important Tibetan medicine with effects of dispelling cold and relieving pain, it has been used clinically in China for thousands of years. This folk agent comes from the dried tuber root of dried roots of Aconitum pendulum Busch. and Aconitum flavum Hand.-Mazz. (Gansu Medical Products Administration, 2009). TBC is traditionally used for the treatment of RA and joint pain. Many classic Tibetan medicine formulas containing TBC (such as Wuwei Shexiang Wan and Shiwuwei Rupeng Wan) were frequently used by the public to relieve pain and inflammation (China Pharmacopoeia Committee, 1995). Massive evidence from modern researches has demonstrated that TBC exerts multiple pharmacological effects including anti-inflammatory, anti-rheumatism, anesthesia, analgesia, anti-tumor, and anti-bacterial (Hao et al., 2013; Liu et al., 2020; Li et al., 2016). In the recent years, some pharmacologic experiments have been performed to demonstrated the therapeutical potential of TBC for RA. For instance, Fu et al. found that TBC can improve the degree of joint swelling and arthritis index of RA rats by inhibiting the activation of T cells, restoring the normal secretion of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, IL-6 cytokines and improving immune function (Fu et al., 2014). Similar results were aslo reported in another study, it was observed that TBC mitigated RA in rats by inhibiting the secretion of proinflammatory cytokine as well as regulating the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-3 (MMP-3) proteins (Kang, 2013). These results above suggest that TBC has great potential in the treatment of RA.

However, due to the narrow treatment window of TBC, its clinical use is often accompanied with some toxicity reactions, including arrhythmias, hypotension, hypothermia, respiratory depression, muscle paralysis, and central nervous system disorders (Li et al., 2022a). Of note, cardiovascular system damage is the most prominent feature of acute TBC poisoning, and the heart failure induced by malignant arrhythmias is the primary cause of death after TBC poisoning (Zhang et al., 2005). But until now there is no specific antidote for treatment (Wang et al., 2021). Previous phytochemical researches suggested that diterpenoid alkaloids were the major ingredients of TBC that were both the bioactive components and the toxic substances. Aconitine and deoxyaconitine are the representative diterpenoid alkaloids in TBC with high risk of cardiotoxicity (Wang et al., 2019; Zhang et al., 2021). In order to reduce the risk of poisoning reaction, TBC usually undergoes various processing methods mainly including boiling and sand frying before oral using (Liu et al., 2022). The detoxification mechanism is associated with the cleavage of ester bond in toxic diester alkaloids. By long-term boiling or heating, diester alkaloids could translate into low toxicity monoester alkaloids and nonester alkaloid (Qiu et al., 2021). Nevertheless, though the toxicity is greatly reduced, the efficacy is also decreased to some extent. It is worth mentioning that compatibility of medicine is an important method to reduce toxicity and enhance efficacy in Traditional Chinese Medicine system. In order to reduce the risk of poisoning, TBC was freguencely used in combination with other drugs such as HZ.

HZ, the dry ripe fruit of Terminalia chebula Retz. and Terminalia chebula Retz. var. tomentella Kurt. (China Pharmacopoeia Committee, 2020), is one of the most commonly used herbs in Asian area (Pingali et al., 2020). According to the statistics, there are 118 prescriptions containing HZ among the 200 prescriptions included in the Ministry standards of Tibetan medicine, thus HZ is called “king of Tibetan medicine” (Song et al., 2021). HZ is commonly used to treat multiple diseases such as chronic diarrhea, dysentery, hematochezia, rectocele, chronic cough, sore throat and hoarseness (Nigam et al., 2020; Zhao et al., 2020). Besides, HZ also has good effects of detoxification, so HZ often be used combination with Aconitum drugs such as TBC and Caowu to reduce toxic reaction (Wang et al., 2020). In the past few years, there are some studies aimed to demonstrate the attenuation action of HZ on the toxicity of Caowu. It was found that pre-treatment with HZ could obviously mitigate convulsions and reduce mortality caused by Caowu in mice (Li et al., 2021). Some researchers speculated that HZ reduced the toxicity of Caowu because of the tannic acid components from HZ and alkaloids from Caowu in combination with each other, which was eazy to form some insoluble constitutes that was not easy to be absorbed, thus reducing the toxic ingredients into the body (Bao and Na, 2020). Nevertheless, there is still no direct evidence to support this view. Some researchers found Caowu used in combination with HZ or HZ-processed Caowu showed different pharmacokinetic process compared with raw Caowu (Zhi et al., 2020; Zhang, 2019), the findings partly reveal the attenuated principle of HZ on the toxicity of Caowu. Currently, TBC-HZ pair, as a classical combination, appears in many Tibetan medicine formulas which are frequently applied in clinical practice. The compatibility effect and mechanism of TBC co-administered with HZ obtain increasing attention from researchers. But there is still a lack of systematic studies on whether and how HZ impacts the cardiotoxicity and efficacy of TBC.

Therefore, this current study consisted of three aspects: toxicity assessment, efficacy assessment, and pharmacokinetic study. In this work, we analyzed the effect of HZ on the cardiotoxicity and anti-RA effects of TBC. And we compared the change of pharmacokinetic possess of the main active compounds in TBC between TBC group and TBC co-administer with HZ group. These findings will provide evidence for understanding the combination use of TBC and HZ.