Research Progress in Toxicity and Toxicity-reducing and Efficacy-enhancing Compatibility of Radix Aconiti Lateralis Praeparata

Si LIN Huizhen QIN Lingyu DENG Hua ZHU

Abstract Radix Aconiti Lateralis Praeparata contains alkaloids, flavonoids, polysaccharides, organic acids and organic alkalis, among which diester alkaloids are important effective ingredients, which can be used for treating heart failure, rheumatic heart disease, coronary heart disease, hypotension, shock and other diseases. However, it also contains the main ingredients that produce toxic effects and are highly toxic to the cardiovascular system, nervous system, digestive system, reproductive system, embryos, and livers and kidneys. In this study, we analyzed the toxicity-reducing and efficacy-enhancing effects of the compatibility of Radix Aconiti Lateralis Praeparata with with single herbs Glycyrrhiza uralensis Fisch., Panax ginseng C. A. Meyer, Zingiber ojjicinale Rosc. and Rheum palmatum L., aiming to provide references for further exploring the appropriate compatibility conditions of traditional Chinese medicine in the future and improving the safety of the clinical application of Radix Aconiti Lateralis Praeparata.

Key words Radix Aconiti Lateralis Praeparata; Toxicity; Toxicity reducing and efficacy enhancing; Compatibility

Received: January 25, 2021  Accepted: March 23, 2021

Supported by Guangxi Key Laboratory of Zhuang and Yao Medicines (GKJZ ［2014］ 32); Guangxi "2011 Collaborative Innovation Center"-Collaborative Innovation Center for Zhuang and Yao Medicines (GJKY ［2013］ 20); Guangxi First-class Discipline: Chinese Pharmacy (0501802815); National Natural Science Foundation of China (82060695); National Medicine Resources and Application Engineering Research Center of Guangxi Zhuang Autonomous Region (GFGGJH ［2020］ 2605).

Si LIN (1998-), male, P. R. China, master, devoted to research about identification and analysis of traditional Chinese medicine.

*Corresponding author. E-mail: zhuhuagx@163.com.

Radix Aconiti Lateralis Praeparata was first published in Shen Nongs Herbal Classic, and refers to the processed product of the daughter roots of Aconitum carmichaclii. It has the effects of rescuing from collapse by restoring yang, replenishing fire and helping yang, and dispelling cold to relieve pain［1］. Radix Aconiti Lateralis Praeparata is widely used in clinical practice, and has significant efficacy on heart failure, rheumatic heart disease, coronary heart disease, hypotension, shock and other diseases［2］. Due to the high toxicity of Radix Aconiti Lateralis Praeparata, improper clinical application can cause poisoning or even death, so it has been considered by ancient and modern physicians as "the drug most useful and most difficult to use［3］". How to maximize the efficacy of Radix Aconiti Lateralis Praeparata in clinical practice while reducing its toxic and side effects has always been a hot spot and difficult problem for clinical doctors and scholars to continuously research and explore［4］. In this study, the toxicological reports related to Radix Aconiti Lateralis Praeparata and literatures related to its toxicity reduction and efficacy enhancement were summarized.

Effective and Toxic Ingredients of Radix Aconiti Lateralis Praeparata

Radix Aconiti Lateralis Praeparata contains a variety of ingredients such as alkaloids, flavonoids, proteins, organic acids, polysaccharides, and organic bases［5］. Aconitum alkaloids are the main active components of Radix Aconiti Lateralis Praeparata. They are not only the toxic components of Radix Aconiti Lateralis Praeparata, but also the main medicinal components. Among them, the diester alkaloids are the most toxic, and the monoester alkaloids have lower toxicity, only 1/100-1/200 of that of diester alkaloids［6-8］. Alcoholamine alkaloids have weaker activity, and low toxicity, only 1/2 000 of that of diester alkaloids［9］. Diester alkaloids include aconitine, hypoaconitine, mesaconitine, neoaconitine, talatisamine, etc.［10］. People can experience symptoms of poisoning after oral administration of 0.2 mg of aconitine, and death can be caused by intramuscular injection of 0.2 to 0.3 mg and oral administration of 3 to 4 mg［11］. The toxic dose of Radix Aconiti Lateralis Praeparata decoction pieces taken by humans is 15-30 g［12］. Its toxicity is huge and the dosage is narrow, which limits the use by clinicians. Therefore, it is more beneficial to summarize the toxicological studies of Radix Aconiti Lateralis Praeparata for its clinical application.

Radix Aconiti Lateralis Praeparata Toxicity Study

Radix Aconiti Lateralis Praeparata can strengthen the heart, treat heart failure, but also can cause cardiotoxicity. It can relieve pain, but also cause neurotoxicity. It is also toxic to the digestive system, reproductive system, and embryonic development［13］. The toxicity and effect of Radix Aconiti Lateralis Praeparata can be transformed, and the dosage of the medicine is one of the key points of the transformation of its toxicity and effect［3］.

Cardiovascular system toxicity

Some research results indicate that the heart and cardiomyocytes are important toxicity-efficacy target organ and target cells of Radix Aconiti Lateralis Praeparata［14］. Diester alkaloids are the main material basis for cardiotoxicity caused by Radix Aconiti Lateralis Praeparata, while other components play the role of strengthening the heart and protecting the myocardium. Radix Aconiti Lateralis Praeparatas remarkable heart-strengthening and anti-arrhythmic effects have been confirmed in many animal models such as rats, rabbits, toads, cats and dogs［15］. Aconitine, hypoaconitine and other diester alkaloids in Radix Aconiti Lateralis Praeparata can induce arrhythmia, while benzyl isoquinoline alkaloids such as higenamine have antiarrhythmic effects［16-17］. The toxic effect of diester C19 diterpene alkaloids on the heart is produced by overexciting the vagus nerve and directly damaging cardiomyocytes［18］. Aconitine directly causes arrhythmia and produces an indirect centripetal effect of mediating activation of cardiotoxicity［19］. Other scholars have found that long-term low-dose aconitine can increase the expression and activity of related transporters and prevent further acute toxicity［20］. Studies have shown that after long-term oral administration of higher doses of Radix Aconiti Lateralis Praeparata extract to rats, serum biomarkers showed cardiac dysfunction, which was mainly manifested as myocardial necrosis and vasodilation［21］. Studies［22-23］ have found that hypoaconitine could increase the beating frequency of myocardial cells, and caused Ca2+ overload in myocardial cells, which further caused myocardial cell death and arrhythmia. Shi et al.［24］ found that neoaconitine could shorten the action potential duration of the in-vitro papillary muscles of guinea pigs, leading to arrhythmia. Some studies have found that aconitine relatively prolongs the action potential time course (APD90-30) by regulating the activity of Ca2+ channels［25］, and increases the time course from the beginning of the QRS wave group to the end of the T wave, thereby inducing torsade de pointes ventricular arrhythmia［21］. Another study established a type 2-ryanodine receptor (RyR2) gene knockout model of cardiomyocytes and found that aconitine induced an up-regulation of the expression of RyR2 mRNA protein in cardiomyocytes, which might lead to defects in Ca2+ channel function and intracellular calcium signal abnormalities and then cause tachycardia or arrhythmia［26］.

Nervous system toxicity

The neurotoxicity of Radix Aconiti Lateralis Praeparata includes the two aspects of the central nervous system and the peripheral nervous system［27］. Radix Aconiti Lateralis Praeparata has the effects of first excitement and then paralysis on the central nervous system and sensory nerves, resulting in severe neurological dysfunction; and the damage to the peripheral nervous system shows various neurological symptoms: facial and limb nerve endings numbness, loss of tactile sensation, muscle stiffness, restricted limb movement, etc. Due to the blood-brain barrier and other physiological barriers, Radix Aconiti Lateralis Praeparata may be more toxic to the peripheral nervous system than the central nervous system［13］. Related studies have found that different concentrations (0.1, 0.5, 1.5, 10, 50, 100 μmol/L) of aconitine had a significant inhibitory effect on the growth of midbrain dopamine neuron cells for 48 h［28］, and it also had a significant inhibitory effect on the vitality of rat hippocampal neurons［29］, showing a direct neurocytotoxic effect. Rao et al.［30］ found that 0.5% aconitine significantly inhibited the proliferation of retinal nerve cells, and its neurotoxicity might be related to the regulation of Bcl-2 and ras gene expression. The study of Peng［31］ showed that aconitine had neurotoxic effects on cerebral cortical neurons, which could affect the structure and function of neurons. Aconitum can quickly trigger the release of dopamine in the body in vitro, while excessive dopamine causes excessive oxidative stress and neuronal dysfunction, and induces neuronal apoptosis. In a pathological state, excessive dopamine will cause the production of reactive oxygen species to be unable to be effectively eliminated, and ultimately lead to neuronal death［32］.

Liver and kidney toxicity

Although there are no reports on deaths of patients caused by liver and kidney damage due to aconitine poisoning［33］, nausea, vomiting, burning in the stomach, salivation and abdominal pain, diarrhea and renal failure, proteinuria and other adverse effects have been found［34］. Metabolomics research methods show that aconitine, hypoaconitine and neoaconitine can interfere with renal tubular function within 24 h of acting on rats［35］. Some scholars［36］ found that diester C19 diterpene alkaloids could acutely accelerate liver and kidney cell apoptosis in a short period of time. The cause of toxicity may be due to the effect of the blood-brain barrier, which leads to extremely high levels of these compounds in the liver and kidney (2.5 to 22, 1.8 to 11.7 times that in the blood, respectively), and high levels in the heart (1 to 3 times that in the blood)［37-38］, which further cause apoptosis due to its cytotoxicity. Studies have shown that oral administration of Radix Aconiti Lateralis Praeparata extract can increase the level of alanine aminotransferase in serum and cause damage and necrosis of liver tissue, or increase the level of serum creatinine and blood urea nitrogen and cause histological changes and atrophy of renal tissue cells［39］.

Digestive system toxicity

Studies have found that Radix Aconiti Lateralis Praeparata had a cytotoxic effect on the interstitial cells of Cajal which are closely related to gastrointestinal motility. When 0.1% aconitine acted on Cajal cells in the mouse colon, it reduced the contents of Na+, K+, Ca2+ and glycogen, and the content of MDA increased significantly, showing obvious cytotoxicity［13］.

Embryo toxicity

Xiao［40］ found that when aconitine was higher than a certain concentration, it had a certain inhibitory effect on the morphological differentiation and growth of rat embryos. In addition, aconitine could affect nerves, heart and other tissues, and finally interfere with the development of normal rat embryonic tissues［41］.

Reproductive toxicity

Zhang et al.［42］ used a high concentration of Aconitum alkaloids in animal experiments and found that the proliferation of rat testicular cells was significantly inhibited, indicating that Aconitum alkaloids had strong reproductive toxicity. Studies have found that the reproductive toxicity of Radix Aconiti Lateralis Praeparata extract may be closely related to the decrease of progesterone (P), follicle stimulating hormone (FSH), estradiol (E2), luteinizing hormone (LH) and other components［43］.

Study on the Compatibility for Increasing Efficacy and Reducing Toxicity

The routine use of Radix Aconiti Lateralis Praeparata is similar to the amount of poisoning. Reducing toxicity and enhancing efficacy is the key to ensuring the safety of clinical medication.

Compatibility of Radix Aconiti Lateralis Praeparata with Zingiber ojjicinale Rosc.

Effect of reducing toxicity

Gingerol, the main component of Z. ojjicinale, has the effect of restricting and reconciling the toxicity of aconitine. Compared with Radix Aconiti Lateralis Praeparata decoction alone, the co-decoction of Radix Aconiti Lateralis Praeparata and Z. ojjicinale can not only reduce the content of toxic components such as aconitine, but also play a role in antagonizing the cardiotoxicity caused by aconitine［44］.

Effect of increasing efficacy

After the combined use with Z. ojjicinale, it can significantly increase coronary blood-flow volume, significantly increase the activity of myocardial superoxide dismutase (SOD), reduce the content of malondialdehyde (MDA)［45］, reduce myocardial energy requirements, and promote the release of adrenaline to achieve the purpose of rescuing from collapse by restoring yang. Z. ojjicinale can enhance the energy metabolism level of the model microbes, regulate the changes in the intracellular Ca2+ concentration of mitochondria in animal model cells of yang deficiency and heart failure, enhance the mitochondrial energy metabolism function, and enhance the "hot" nature of Radix Aconiti Lateralis Praeparata［46］.

Compatibility of Radix Aconiti Lateralis Praeparata with Glycyrrhiza uralensis Fisch.

Effect of reducing toxicity

Glycyrrhiza flavonoids and glycyrrhizin in G. uralensis can reduce the contents of ester alkaloids and diester alkaloids in Radix Aconiti Lateralis Praeparata［47］. The glycyrrhizic acid and glycyrrhetinic acid in G. uralensis can neutralize Aconitum alkaloids, can delay or reduce the absorption of toxic alkaloids such as aconitine and reduce the contents of toxic Aconitum alkaloids, and thus have obvious antagonism to the arrhythmia caused by aconitine［48］.

Effect of increasing efficacy

Li et al.［49］ studied the compatibility of A. carmichaclii with G. uralensis in different proportions on the dissolution rates of the main effective components of aconitine and liquiritin in Radix Aconiti Lateralis Praeparata and G. uralensis, and explored the analgesic and anti-inflammatory effects after the compatibility of Radix Aconiti Lateralis Praeparata with G. uralensis. It was found that G. uralensis∶Radix Aconiti Lateralis Praeparata=1∶3 had the best analgesic and anti-inflammatory effects, which were stronger than those of the blank group and single decoction group. Wang et al.［50］ found that the combination of Aconitum alkaloids with G. uralensis triterpene saponins and flavonoids could significantly enhance the cardiotonic effect on frog hearts in vitro, which was more pronounced than using Aconitum alkaloids alone.

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Compatibility of Radix Aconiti Lateralis Praeparata with Panax ginseng C. A. Meyer

Effect of reducing toxicity

Sun et al.［51］ explored the acute toxicity effects of the compatibility of A. carmichaclii with P. ginseng and roasted G. uralensis on mice, and found that P. ginseng and roasted G. uralensis had certain toxicity-reducing effect on A. carmichaclii. The toxicity-reducing ability ranked as: compatibility of P. ginseng with A. carmichaclii>compatibility of P. ginseng, roasted G. uralensis with A. carmichaclii>compatibility of roasted G. uralensis with A. carmichaclii. Li et al.［52］ investigated the effects of the compatibility of P. ginseng, G. uralensis with Radix Aconiti Lateralis Praeparata on the cytochrome P450 (cytochrome P450, CYP450) mRNA transcription level and protein translation level of normal rat liver. The compatibility of P. ginseng, G. uralensis with Radix Aconiti Lateralis Praeparata could increase the expression of CYP450 enzymes, reduce the accumulation time of aconitine in the body, and play a role in reducing toxicity. When the ratio of Radix Aconiti Lateralis Praeparata to P. ginseng was 1∶0.5, it had an inhibitory effect on the toxicity of Radix Aconiti Lateralis Praeparata to cardiomyocytes, and compared with the control group, the spontaneous beating frequency and the content of malondialdehyde (MDA) in the cardiomyocytes were significantly reduced (P<0.05), and superoxide dismutase (SOD) activity, Bcl-2 protein expression and Bcl-2 m RNA expression significantly increased (P<0.05)［53］.

Effect of increasing efficacy

The compatibility of P. ginseng with Radix Aconiti Lateralis Praeparata can effectively increase the expression level of IL-10 in the blood, and inhibit the expression of inflammatory factors, thereby improving the survival rate of rats with heart failure; and it can also effectively inhibit the expression levels of IL-18 and TNF-α, improve the heart function of rats with heart failure, and has a better effect than using P. ginseng or Radix Aconiti Lateralis Praeparata alone［54］. After the compatibility of Radix Aconiti Lateralis Praeparata with P. ginseng decoction at a ratio of 1∶2, its heart strengthening effect is significantly better than that of the Radix Aconiti Lateralis Praeparata decoction alone. The combination of the two can improve the relevant hemodynamic indexes of rats［55］; and it can feedback and adjust the content of NT-ProBNP, angiotensin II (Ang II) and atrial natriuretic peptide (ANP) in the plasma of rats with acute heart failure by improving the myocardial systolic and diastolic function, thereby better achieving the effects of rescuing from collapse by restoring yang and alleviating heart failure［56］.

Compatibility of Radix Aconiti Lateralis Praeparata with Rheum palmatum L.

Effect of reducing toxicity

Gao et al.［57］ used mice to observe the effects of Radix Aconiti Lateralis Praeparata compatible  with different proportions of R. palmatum L. on the toxicity and efficacy of Radix Aconiti Lateralis Praeparata and found that with the increase of the ratio of R. palmatum, the acute toxicity LD50 of Radix Aconiti Lateralis Praeparata showed an increasing trend, and the inhibitory rate of R. palmatum on the cardiac arrhythmia of Radix Aconiti Lateralis Praeparata gradually increased. The content of the main Aconitum alkaloids decreased after the compatibility with R. palmatum, and R. palmatum had a dose-dependent antagonistic effect on the toxicity of A. carmichaclii. Furthermore, the compatibility of R. palmatum with Radix Aconiti Lateralis Praeparata could reduce the toxicity of Radix Aconiti Lateralis Praeparata without affecting the efficacy of Radix Aconiti Lateralis Praeparata. After the compatibility of Radix Aconiti Lateralis Praeparata with R. palmatum in different proportions, the contents of Radix Aconiti Lateralis Praeparata total alkaloids, ester alkaloids and diester alkaloids all decreased significantly, with the highest drop rates of 47%, 64%, and 92%, respectively, and the magnitude of the decrease was directly proportional to the amount of R. palmatum［58］.

Effect of increasing efficacy

The study of "Dahuang Fuzi Decoction" found that the compatibility of the two drugs could significantly shorten the defecation time of mice with cold constipation, increase the amount of feces, and enhance their bowel motility［59］.

Conclusions and Prospect

The toxic effects of Radix Aconiti Lateralis Praeparata pervasive throughout the body are closely related to the content of the three main toxic components of aconitine, hypaconitine and neoaconitine, the absorption, distribution, metabolism and excretion of which will determine the direct or indirect damaging effects of Radix Aconiti Lateralis Praeparata on cells. In future research, the plasma concentration monitoring of the main toxic components of diester alkaloids can be further carried out. Research on the correlation between the toxicity and toxicokinetics of diester alkaloids will help to understand their toxicity mechanisms and clinical safety assessment and is an effective means to prevent potential cardiotoxicity and neurotoxicity. The material basis of Chinese medicine for reducing the toxicity of Radix Aconiti Lateralis Praeparata after its combined use with other medicines not only relies on a single component. The toxicity-reducing and toxicity-antagonizing mechanism of Radix Aconiti Lateralis Praeparata is very complicated. After compatibility, various changes will not only occur in the interaction link, but also in the absorption, distribution, metabolism and excretion of toxic ingredients. After the compatibility of Radix Aconiti Lateralis Praeparata with G. uralensis, P. ginseng, Z. ojjicinale and other traditional Chinese medicines, it can achieve the effects of detoxifying and strengthening the heart and rescuing from collapse by restoring yang by regulating heart function, ion channels, hemodynamics and other pathways. The toxicity and effect of Chinese medicine exist objectively, which is contradictory but unified. Especially in the high-toxicity Chinese medicines with significant curative effects, under the appropriate compatibility conditions, they may exert completely different component transformation and biological effects, thereby realizing the transformation from toxicity to efficacy. Only by establishing more comprehensive, objective, efficient and practical Radix Aconiti Lateralis Praeparata compatibility drug control system can the most useful and most difficult-to-use Radix Aconiti Lateralis Praeparata better serve the clinic.

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