Jiang Huajuan
Huang Xulong1,2†
Zhou Yongfeng
Ren Chaoxiang
Pei Jin- 1State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu, China
- 2Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
Cardio-cerebrovascular diseases are the leading cause of death worldwide and there is currently no optimal treatment plan. Chinese herbal medicine injection (CHI) is obtained by combining traditional Chinese medicine (TCM) theory and modern production technology. It retains some characteristics of TCM while adding injection characteristics. CHI has played an important role in the treatment of critical diseases, especially cardio-cerebrovascular diseases, and has shown unique therapeutic advantages. TCMs that promote blood circulation and remove blood stasis, such as Salvia miltiorrhiza, Carthami flos, Panax notoginseng, and Chuanxiong rhizoma, account for a large proportion of CHIs of cardio-cerebrovascular disease. CHI is used to treat cardio-cerebrovascular diseases and has potential pharmacological activities such as anti-platelet aggregation, anti-inflammatory, anti-fibrosis, and anti-apoptosis. However, CHIs have changed the traditional method of administering TCMs, and the drugs directly enter the bloodstream, which may produce new pharmacological effects or adverse reactions. This article summarizes the clinical application, pharmacological effects, and mechanism of action of different varieties of CHIs commonly used in the treatment of cardio-cerebrovascular diseases, analyzes the causes of adverse reactions, and proposes suggestions for rational drug use and pharmaceutical care methods to provide a reference for the rational application of CHIs for cardio-cerebrovascular diseases.
Introduction
Cardio-cerebrovascular disease is one of the most serious diseases that threaten human health today; its morbidity and mortality rates have surpassed those of tumor diseases and now rank first (Liberale et al., 2021; Xu et al., 2022). The heart and brain are the most closely related organs physiologically, and brain tissue relies on blood circulation driven by the heart to maintain normal physiological functions. At the same time, cardiovascular and cerebrovascular diseases are pathologically based on vascular occlusion caused by atherosclerotic rupture related to blood lipid levels. When abnormal blood rheology occurs, atherosclerosis may involve multiple organs, particularly the heart and brain (Novo et al., 2014; Novo et al., 2019; Keeter et al., 2022). Furthermore, cardio-cerebrovascular diseases have the same pathological basis. Research data show that about 10%–45% of patients with heart disease may have a stroke, about 78.1%–90.2% of patients with cerebrovascular disease have an abnormal electrocardiogram, and 12.7% can be complicated by cerebral infarction (Xu et al., 2021; Lu et al., 2022).
Although conventional Western medical treatments such as nitrates, statins, receptor blockers, clopidogrel, and aspirin have good effects on cardio-cerebrovascular diseases, there are still great risks, such as embolism and bleeding caused by excessive antithrombotics (Wang Y. et al., 2022; Sikora et al., 2022). Chinese herbal injections (CHIs) play an irreplaceable role in the treatment of cardio-cerebrovascular diseases and have economic and social benefits (Feng et al., 2021; Li et al., 2022b). An increasing number of doctors tend to use certain CHIs combined with conventional Western medicine to improve their therapeutic effect (Li et al., 2015a; Liu et al., 2016). As a new dosage form of traditional Chinese medicine (TCM) preparation, CHI not only has the characteristics of injection, but also retains the characteristics of TCM to a certain extent. Its active ingredients and modern pharmacological effects are clear, and it avoids degradation of the gastrointestinal tract and the first-pass effect of the liver following oral drug administration. The clinical application of CHI is more convenient, its effect is faster, and it plays an important role in the treatment of acute and severe diseases. The research and development of CHI varieties mainly focus on the treatment of cardio-cerebrovascular diseases, respiratory systems, and tumors; in particular, the therapeutic effect of cardio-cerebrovascular diseases has been recognized by doctors and patients. A total of 134 types of CHI have been listed, encompassing 158 types of raw materials for prescription decoction pieces, and the majority (56.7%) of medicinal materials are single-agent. The types and sales of CHI for the treatment of cardio-cerebrovascular diseases are the most numerous (Hao et al., 2020).
In terms of medicine composition, TCM to promote blood circulation and remove blood stasis accounts for a large proportion of CHI for cardio-cerebrovascular diseases, such as Salvia miltiorrhiza, Carthami flos, Panax notoginseng, and Chuanxiong rhizoma (Li et al., 2015a; Sun et al., 2022). Cardio-cerebrovascular diseases such as cerebral thrombosis and coronary heart disease are related to enhanced platelet function, blood thickening, and changes in hemodynamic characteristics (Gresele et al., 2021; Li et al., 2022c). In TCM, drugs that promote blood circulation and remove blood stasis dredge blood vessels and eliminate blood stasis, which can change the platelet function and hemodynamics of patients (Li D. et al., 2022). Patients with cardio-cerebrovascular diseases can use drugs to promote blood circulation and remove blood stasis to clear blocked blood vessels and improve blood supply. TCM for promoting blood circulation and removing blood stasis has unique advantages for the treatment of cardio-cerebrovascular diseases (Li et al., 2015a; Guo R. et al., 2020).
CHI for cardio-cerebrovascular diseases
The CHI clinically used for the treatment of cardio-cerebrovascular diseases includes extracts obtained from TCM or the effective parts and single components obtained by further purification. TCM prescription injections are obtained by extracting and purifying TCM prescriptions based on the compatibility of TCM. Among these, S. miltiorrhiza, C. flos, P. notoginseng, and C. rhizoma are important drugs developed for the treatment of cardio-cerebrovascular diseases. The details of each CHI were obtained from the Chinese Medicine Information Query Platform (https://www.dayi.org.cn/), as shown in Table 1.
TABLE 1. CHIs for the treatment of cardio-cerebrovascular diseases.
Single TCM extract injection
CHI is prepared from a single component extracted and purified from Chinese herbal medicines such as PI. Puerarin is an isoflavone derivative with a crown expanding effect isolated from Pueraria lobata radix. Puerarin can be used to treat coronary heart disease, angina pectoris, and hypertension (Ma et al., 2022; Shao et al., 2022). Puerarin treatment causes an expansion of coronary blood vessels and cerebral blood vessels, improves local blood flow, improves microcirculation, inhibits platelet aggregation, reduces muscle oxygen consumption, and increases oxygen supply (Zeng et al., 2021; Chen D. et al., 2022; Lv et al., 2022).
CHI can be prepared from a single TCM extraction mixture, such as DSI, HHI, HQI, or DZXXI, as shown in Figure 1. DSI and SLI were prepared by extraction and purification of S. miltiorrhiza. Salvia miltiorrhiza promotes blood circulation, regulates menstruation, removes blood stasis, relieves pain, cools the blood, eliminates carbuncle, eliminates trouble, and soothes the nerves (Li H. et al., 2021; Wang SM. et al., 2022). Its main chemical components are danshensu, salvianolic acid, and tanshinone IIA, which can inhibit the activity of various coagulation factors and stimulate the plasmin system, thereby reducing thrombus formation and improving microcirculation. At the same time, S. miltiorrhiza has a good preventive effect on blood lipid metabolism by reducing the content of denatured lipoprotein, thereby preventing the development of atherosclerosis and reducing the incidence of cerebrovascular disease (Wang ZY. et al., 2022). Salvia miltiorrhiza can also reduce the content of oxygen free radicals produced by cardiovascular and cerebrovascular diseases, thereby protecting myocardial cells and brain tissue. In particular, Tanshinone IIA can increase the residence time of drugs in brain tissue (Zhong et al., 2021).
FIGURE 1. Single TCM extract injection; (A) Puerarin Injection; (B) Danshen injection; (C) Honghua injection; (D) Xuesaitong injection; (E) Shuxuening injection; (F) Xinmailong injection; (G) Dazhu Hongjingtian injection; (H) Huangqi injection.
HHI and SYI were extracted and purified from the safflower. Safflower promotes blood circulation, removes stasis, relieves pain, and detoxifies blood. Salvia miltiorrhiza and safflower are essential medicines for promoting blood circulation and removing blood stasis (Orgah et al., 2020; Zhao et al., 2022). The main components of safflower are flavonoids, which are classified as quinoid chalcones, represented by hydroxysafflor yellow A, and common flavonoids, represented by kaempferol. The SYI was prepared by extracting the effective parts of the safflower. Safflower yellow can block platelet-activating factors, inhibit the release of serotonin, reduce peripheral resistance of blood vessels, expand cardiovascular and cerebrovascular vessels, inhibit platelet aggregation, significantly reduce blood viscosity and plasma viscosity, and improve the erythrocyte aggregation index; thus, blood platelet aggregation in the stasis model was reduced, and microcirculation disturbance was significantly improved. Prothrombin time following treatment with safflower yellow was delayed (Wang L. et al., 2021).
XSTI were prepared from the total saponins of Panax notoginseng. Panax notoginseng promotes blood circulation, removes blood stasis, reduces swelling and calms pain, promotes hemostasis, and is nourishing. It is the main drug used to treat traumatic injuries (Wang et al., 2016; Yang et al., 2018). Panax notoginseng saponins have a wide range of effects, such as dilation of the coronary arteries, improvement of left ventricular diastolic function, and reduction the concentration of Ca2+ in cardiomyocytes. It can also inhibit platelet aggregation and promote fibrinolysis (Duan et al., 2018; Xu CC. et al., 2019).
SXNI was prepared from Ginkgo leaf extract and GDI was prepared by mixing Ginkgo biloba L. leaf extract and dipyridamole. Ginkgo biloba L. leaves contain active ingredients such as flavonoid glycosides and terpenoid lactones, including quercetin, kaempferol, bilobalide, and ginkgolide, which have functions such as promoting blood circulation and remove blood stasis, dredge collaterals, relieve pain, astringe the lungs, relieve asthma, reduce turbidity, and lower lipids (Tian et al., 2017; Liu et al., 2021). Ginkgo biloba L. leaves can be used for blood stasis blocking collaterals, chest pain and heart pain, stroke hemiplegia, lung deficiency, cough and asthma, and hyperlipidemia (Wang et al., 2021a; Li et al., 2021d; Liang et al., 2022). Ginkgo biloba L. leaves can effectively inhibit platelet-activating factors, abnormal platelet aggregation, and thrombosis and reduce blood lipids and viscosity (Sarkar et al., 2020; Li R. et al., 2021).
XMLI was prepared from the extract of the animal TCM Periplaneta americana. Periplaneta americana is a natural animal medicine that can eliminate inflammation and edema, promote wound healing, and improve immune function (Lin et al., 2019; Zeng et al., 2019; Liao et al., 2022; Pang et al., 2022). HJTI is prepared from an extract of the traditional Chinese medicine Rhodiolae Crenulatae Radix et Rhizoma. Dazhu Rhodiolae has pharmacological effects including protection of the heart and nerves, anti-fatigue, anti-aging, anti-radiation, and immune regulation (Fan et al., 2020; Li et al., 2021c; Chen Y. et al., 2022).
TCM prescription injection
The compatibility of TCM prescriptions to reduce toxicity and increase efficacy is a characteristic of the clinical application of TCM. Based on the compatibility and combination characteristics of TCM prescriptions, a batch of TCM prescription injections was innovatively developed, as shown in Figure 2. Danhong injection (DHI) is obtained by water extraction and alcohol precipitation of two medicinal materials, S. miltiorrhiza and safflower. Salvia miltiorrhiza and safflower are currently widely used as clinical medicines to promote blood circulation and remove blood stasis (Li M. et al., 2018). SMI was derived from Shendongyin in “Zhengyin Maizhi,” written by Qin Jingming during the Ming Dynasty. It is a TCM preparation composed of red ginseng and Ophiopogonis radix. It nourishes qi, removes qi, nourishes yin, promotes body fluids, and nourishes blood vessels (Yu JH. et al., 2019; Xu HM. et al., 2019). MLNI is a TCM prescription developed based on the classic medical prescription “Si Miao Yong An San” in “Yanfang Xinbian,” guided by integrated traditional Chinese and Western medicine. It comprises Lonicerae japonicae flos, Scrophulariae radix, Dendrobii caulis, and Achyranthis bidentatae radix. Its functions include clearing heat, nourishing yin, promoting blood circulation, and removing blood stasis (Wang and Tian, 2014; Yang et al., 2015). XNJI was extracted from the Angong Niuhuang Pill, a classic first-aid prescription for stroke. It mainly consists of several TCM such as Moschus, Borneolum syntheticum, and Gardeniae Fructus. It is the only CHI approved in China for the treatment of acute cerebral hemorrhage and acute ischemic stroke in ambulances (Wang L. et al., 2022; Liu et al., 2022).
FIGURE 2. TCM Prescription Injection; (A) Danhong injection; (B) Mailuoning Injection; (C) Shengmai Injection; (D) Xiangdan injection; (E) Xingnaojing injection; (F) Shenmai injection; (G) Danshen Ligustrazine Injection; (H) Shenxiong Glucose Injection.
The DLI is one of the most commonly used injections in clinical practice. Unlike the traditional compatibility method, this injection combines the extract of S. miltiorrhiza with the active ingredients of Ligusticum chuanxiong (Xie et al., 2021; Ye et al., 2021). CHI is composed of the main active ingredients of these two medicinal materials. For example, SXI is composed of ligustrazine hydrochloride, the active ingredient of Chuanxiong, and Danshensu, the active ingredient of S. miltiorrhiza (Lu et al., 2020; Lu et al., 2021). Based on the classic drug pair theory of TCM, CHIs with effective active ingredients have been gradually developed. The injection obtained by combining the active ingredients has the advantages of a defined chemical composition, an evident pharmacological mechanism, and clinical indications.
Pharmacological effects of Chinese herbal injection in the cardio-cerebrovascular diseases
In recent years, based on the clinical application of CHIs, researchers have revealed their efficacy and mechanism of action through in vitro and in vivo pharmacological studies. Numerous studies have shown that CHIs for the treatment of cardio-cerebrovascular diseases have potential pharmacological activities, such as anti-platelet aggregation, anti-inflammatory, anti-fibrosis, and anti-apoptosis activities (Table 2; Figure 3).
TABLE 2. Pharmacological effects of CHIs in the cardio-cerebrovascular diseases.
FIGURE 3. Data visualization of some Chinese herbal medicines, compounds, pharmacological effects, and mechanisms for the treatment of cardio-cerebrovascular diseases.
Anti-platelet aggregation
DHI can inhibit inflammation and platelet aggregation, reduce immune response and peroxidation, and protect vascular endothelium and organ function, thus preventing and treating cardiovascular diseases (Zou et al., 2018; Bi et al., 2019). DHI can inhibit blood lipid levels and platelet aggregation rate in rats with hyperlipidemia. Meanwhile, thrombin time (TT), activated partial thrombin time (APTT), prothrombin time (PT), 6-K-PGF1a, PGI2, and PGE2 mRNA expression were significantly increased after DHI treatment, while the expression of TXA2 was significantly decreased (Fan et al., 2018). Based on path analysis and CMAP query of microarray data, researchers have found that anti-inflammatory response and anti-platelet coagulation are the main mechanisms of XSTI against stroke (Wang et al., 2015).
Lipid profile and atherosclerosis
SXNI can effectively protect the brain and heart from I/R injury through the TNFRSF12a-mediated common pathway of atherosclerotic signaling and inflammatory responses (Lyu et al., 2018). DHI attenuates high-fat diet-induced atherosclerosis and macrophage lipid accumulation by modulating the PI3K/AKT pathway (Zhou et al., 2019). The effect of DHI on DC maturation and immune function induced by oxidized low-density lipoprotein is mainly through the activation of peroxisome proliferator-activated receptor γ (PPARγ) agonist signaling pathways (Liu et al., 2012).
Anti-inflammatory
SLI attenuates inflammatory responses in BMMs and HUVECs. GHI can significantly improve brain I/R injury in rats, which may be achieved by inhibiting inflammation. GHI significantly reduces serum nitric oxide (NO), inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), interleukin-1b (IL-1b), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) levels (Ai et al., 2017). Salvianolate treats myocardial infarction by inhibiting the TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways (Qiu et al., 2018). XSTI, when combined with aspirin and clopidogrel, can protect rats from focal cerebral I/R injury by inhibiting oxidative stress and inflammation and regulating the NOX2/IL-6/STAT3 pathway. SXNI can prevent myocardial I/R injury by reducing oxidative stress, inflammation, and thrombosis (Zhu et al., 2021). SXNI can reduce the levels of inflammatory cytokines in serum, the levels of procoagulant molecules in plasma, and the expression of TLR4/NF-κB in rats (Wang R. et al., 2019). SXNI effectively protects the brain and heart from I/R injury through a common tnfrsf12a-mediated pathway involved in atherosclerotic signaling and inflammatory responses (Lyu et al., 2018). XNJI ameliorates cerebral I/R injury by inhibiting SIRT1-mediated inflammatory response (Zhang YM. et al., 2020).
Anti-fibrotic and anti-apoptotic activities
Salvianolate reduces atrial fibrillation by inhibiting the TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in rats after myocardial infarction, thereby inhibiting atrial fibrosis (Qiu et al., 2018). DHI protects the heart of rats with myocardial infarction by resisting cardiomyocyte apoptosis and angiogenesis, and reducing myocardial fibrosis (Chen JR. et al., 2016). Pretreatment with SFI enhanced the expression of adenosine receptor A in a dose-dependent manner compared to that in the MI/R-post group (Wang et al., 2021b).
Myocardial ischemia and cardiac hypertrophy
SXNI preconditioning has a cardioprotective effect on myocardial I/R injury, manifested as a reduced infarct size, improved cardiac function, and improved mitochondrial function (Li T. et al., 2019). SMI reduces apoptosis and enhances angiogenesis after myocardial I/R injury in rats. SMI-driven reduction in apoptosis is associated with changes in the ratio of Bcl-2 to Bax expression, whereas treatment-induced angiogenesis is associated with enhanced vascular endothelial growth factor A (VEGFA) expression (Liu X. et al., 2018). XSTI attenuates myocardial I/R injury by enhancing pyruvate dehydrogenase-mediated aerobic metabolism (Zhao et al., 2017). DHI attenuates isoproterenol-induced cardiac hypertrophy by modulating p38 and NF-κB pathways (Zhou et al., 2019).
Cerebral ischemia
XSTI, when combined with freeze-dried sulfate injection, protects rats from focal cerebral I/R injury by inhibiting oxidative stress and the Nrf-2/Keap1 pathway (Wang FJ. et al., 2018). XNJI protects rats from cerebral I/R injury and alleviates blood-brain barrier damage by inhibiting the underlying mechanism of the NLRP3 inflammasome (Qu et al., 2019). DHI may reduce inflammation by maintaining the integrity of the brain-blood barrier and regulating TLR4-related signaling pathways, thereby effectively improving the prognosis of cerebral I/R injury (Qian et al., 2018).
Regulating blood pressure and circulation
DHI reduces vascular remodeling and upregulates the kallikrein-kinin system in spontaneously hypertensive rats (Yang XH. et al., 2017). DHI prevents hypertension-induced renal injury by downregulating the expression of renal injury molecules and myoglobin in spontaneously hypertensive rats (Orgah et al., 2018). HHI can affect connective tissue growth factor; transforming growth factor-β and integrin expression can regulate pulmonary artery remodeling, thus affecting the wall thickness of the pulmonary and myocardial arterioles, which is conducive to the control of pulmonary hypertension (Chen et al., 2021).
Clinical application of Chinese herbal injection in the cardio-cerebrovascular diseases
Most clinical trials of CHI for the treatment of cardio-cerebrovascular diseases have been conducted in China. In recent years, some scholars have collected relevant published randomized controlled trials for Bayesian network meta-analysis. We collected and summarized literature on the clinical application of CHIs to cardio-cerebrovascular diseases in recent years to provide a reference for the clinical use of CHIs in the treatment of cardio-cerebrovascular diseases, as shown in Figure 4.
FIGURE 4. Clinical application of CHIs in cardio-cerebrovascular diseases, take Danhong injection as an example.
Stroke
The present study conducted a network meta-analysis of randomized controlled trials on the efficacy of CHI in the treatment of acute cerebral infarction, including 64 studies with 6,225 participants involving 15 TCM injections. In terms of apparent efficiency, DHI is most likely the best treatment option. In terms of improving nerve damage, SXNI has the highest probability of being the best treatment option (Huang et al., 2022).
In a randomized controlled trial of SYI in the treatment of acute cerebral infarction, the National Institute of Health Stroke Scale score in the SYI group decreased, and the hemorheological indices of red blood cell deformation and aggregation were significantly improved. The prothrombin time was increased, fibrinogen, TNF-α, and IL-1β levels were increased, and IL-6 levels were decreased (Li et al., 2015b). In a Bayesian network meta-analysis of randomized controlled trials of Danshen class injection in the treatment of acute cerebral infarction, including 157 randomized controlled trials with a total of 15,570 patients, the results showed that tanshinone IIA sodium sulfonate injection plus Western medicine is clinically effective; it is superior to other drugs in terms of neurological impairment and activities of daily living. DSI and SLI performed excellently in improving blood rheology (Liu S. et al., 2019).
A study conducted A meta-analysis of randomized controlled trials on the efficacy and safety of PI in the treatment of acute ischemic stroke. The meta-analysis identified 35 randomized controlled trials with a total of 3,224 participants. The results showed that PI was superior to the control drug in terms of clinical effectiveness, and the neurological deficit was significantly improved (Zheng et al., 2017).
A systematic review and meta-analysis of XNJI in the treatment of acute ischemic stroke showed that XNJ plus conventional treatment alleviated neurological deficits in acute ischemic stroke. Compared to DHI combined with conventional treatment, XNJ combined with conventional therapy reduces mortality (Tian et al., 2021; Wang L. et al., 2022). The researchers meta-analyzed 29 studies with a total of 2,638 patients. Compared with conventional treatment, XNJI is more effective, significantly reduces hs-CRP levels, enhances activities of daily living, and alleviates hematoma and edema (Ma et al., 2020). In a meta-analysis of the clinical efficacy of XNJI in the treatment of cerebral infarction, 53 randomized controlled trials involving a total of 4,915 participants, the results showed that compared to traditional treatment alone, XNJI can significantly improve the total effective rate, daily life enhanced ability, reduced infarct size, reduced neurological damage. XNJ can improve hemorheology and reduce whole-blood viscosity, plasma viscosity, and hematocrit. XNJ can also reduce cholesterol and triglyceride levels (Ma et al., 2017).
An efficacy and safety study of GDI in the treatment of ischemic stroke, with data from 39 trials including 3,182 ischemic stroke patients, showed that the general response of the neurological function in the conventional treatment and the GDI groups was significantly improved. The patients’ hemorheology and blood lipid indexes were also significantly improved after combined treatment (Wang YS. et al., 2017; Xue et al., 2019).
Myocardial infarction and cardiomyopathy
Through a systematic review and meta-analysis of randomized controlled trials, some studies have compared the efficacy of DHI at different time points in the perioperative period of acute myocardial infarction. The analysis included 23 studies, all of which showed that the efficacy of the DHI was better (He et al., 2021). Some researchers have meta-analyzed GDI in the adjuvant treatment of angina pectoris, including 41 randomized controlled trials involving 4,462 patients. The combined application of GDI and Western medicine in the treatment of angina pectoris has a higher total effective rate and reduces plasma viscosity levels, fibrinogen, whole blood low shear viscosity, and whole blood high shear viscosity (Tan et al., 2018).
Some researchers have conducted a meta-analysis of 26 randomized controlled trials involving 3,447 participants to evaluate the therapeutic effect of XMLI on chronic heart failure. The results showed that XMLI plus conventional treatment improved the total efficacy rate. Compared with conventional treatment alone, XMLI combined with conventional treatment can increase left ventricular ejection fraction and 6-min walk distance, and reduce left ventricular end-diastolic diameter, serum brain natriuretic peptide, and N-terminal pro-brain natriuretic peptide (Lu et al., 2018). A randomized, double-blind, controlled study analyzed the effects of SMI on energy metabolism in patients with heart failure. The results showed that SMI improved patients’ energy metabolism compared to the trimetazidine and control groups, as evidenced by changes in serum-free fatty acid, lactic acid, pyruvate, and branched-chain amino acid levels (Wang SM. et al., 2020). This was a randomized, double-blind, multicenter, placebo-controlled clinical study on the efficacy and safety of SMI in the treatment of patients with chronic heart failure. The improvement in the form 36 hearth survey score and TCM syndrome score was better than that in the control group, the use of SMI treatment was well tolerated, and there were no obvious safety issues (Xian et al., 2016). In a cost-effectiveness analysis of SYI for the treatment of stable angina pectoris in China, SYI combined with conventional therapy was a cost-effective treatment option compared with conventional therapy for unstable angina pectoris (Xuan et al., 2018). A network meta-analysis of CHIs in the treatment of pulmonary heart disease, which compared the efficacy of seven CHIs with Western medicine in the treatment of pulmonary heart disease, included 118 randomized controlled trials with 10,085 patients. The results showed that Shenfu injection, SMI, and Shenqi Fuzheng injection combined with Western medicine may be the best treatment for pulmonary heart disease (Wang KH. et al., 2020).
Atherosclerosis and coronary artery disease
A total of 53 qualified randomized controlled trials involving 6,401 patients were included in the treatment of acute coronary syndrome with DSI. The results showed that compared with Western medicine treatment alone, DSI combined with Western medicine treatment could significantly improve the curative effect (Guo SY. et al., 2020). A systematic review and meta-analysis of the efficacy of DHI combined with coronary revascularization in the treatment of acute coronary syndrome, included 14 studies involving 1,533 patients. DHI combined with surgical treatment of acute coronary syndrome can significantly improve acute coronary syndrome and reduce the incidence of complications after coronary intervention (Zou et al., 2018). SMI can effectively increase cardiac output, stroke volume, and ejection fraction in patients undergoing off-pump coronary artery bypass surgery, and improve the safety of anesthesia management (Liu QX. et al., 2018).
Hypertension and hypertrophy
Some researchers have conducted a meta-analysis of tanshinone IIA sulfonate sodium injection in the treatment of hypertensive nephropathy, including 16 trials involving 1,696 patients. Tanshinone IIA sodium sulfonate injection combined with angiotensin receptor blocker (ARB) therapy is more effective than ARB monotherapy in regulating hypertensive nephropathy, manifested as improvement of glomerular filtration rate and reduction of urinary protein, cystatin, urinary immunoglobulin G, and urinary transferrin. In addition, combination therapy allows for better control of systolic and diastolic blood pressure (Xu JY. et al., 2019).
Some researchers have investigated the efficacy of DHI combined with antihypertensive drugs for the treatment of hypertensive nephropathy. The meta-analysis included 15 studies and the results showed that DHI combined with antihypertensive drugs was more effective in reducing microalbuminuria than antihypertensive drugs alone. The drug has the advantage of lowering systolic blood pressure, diastolic blood pressure, and serum creatinine (Li YZ. et al., 2020).
Safety concerns, toxicity, and synergistic effects of CHIs
Although CHIs have been used clinically for many years and play an indispensable role in the treatment of cardio-cerebrovascular diseases, their adverse reactions have always been a focus of clinical attention. As the injection is a special dosage form, it is more likely to cause adverse reactions. CHIs are mostly complex systems containing many biologically active ingredients; therefore, the possibility of complex unforeseen effects will increase. Modern researchers have conducted extensive research on the safety of CHIs, including their quality control through chemical and biological methods. Through a pharmacokinetic study of CHIs, drug absorption, distribution, metabolism, and excretion in vivo were analyzed to evaluate their safety.
Adverse reactions to CHIs have always been the focus of attention. Scientific and reasonable quality control methods are crucial to ensure the stability and safety of their clinical application. Chemical and biological evaluation is the main of quality control methods for CHI. Because chemical components are critical to the efficacy of CHIs, component detection is the primary method for the quality control of CHI. For example, in the production process of SMI, its quality control index components were selected through the analysis of the component transfer process, and the quality control method of SMI injection was established (Zhao CX. et al., 2019). Quantitative analysis of SLI by 1H-qNMR and its quality control. qNMR can be used as a routine method for quality control of SLI and may be used for the quantification of diastereomers in other TCM preparations (Chen XL. et al., 2016). Rapid identification of the chemical constituents of DHI using liquid chromatography-mass spectrometry and precursor ion scanning enhanced liquid chromatography-tandem mass spectrometry (Li C. et al., 2019; Xu LL. et al., 2019). Rapid identification of chemical constituents in HJTI by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) can also be used to identify the chemical constituents of other Rhodiola Rosea-containing Chinese medicine formulations Element (Liu YN. et al., 2019). The phytochemical components of SXNI were identified using ultra-high-performance liquid chromatography-Q-precise mixed quadrupole orbital high-resolution mass spectrometry (UHPLC-Q-orbitrap HRMS) and nuclear magnetic resonance (NMR) techniques (Yu ST. et al., 2019). The detection of haptens in SXNI is based on human serum albumin fluorescence. A method for determining curcuminone, curcuminenol, curcuminenone, and gemmanone in XNJI was established based on a high-performance liquid chromatography-diode array (Pan et al., 2015).
Affected by the concept of “the higher the content of the index components, the better the quality,” there are still many drawbacks to a single chemical evaluation. It is easy to cause the post-marketing TCM products to be “qualified” according to the current quality standards, but cases of excessive biological activity affecting the clinical treatment effect occur occasionally. Therefore, biological evaluation is indispensable for the quality control of CHIs. For example, HHI detects mass fluctuations by chemical fingerprinting (ultra-performance liquid chromatography-tandem mass spectrometry) and bioassays (including cell-based bio-atlas assays and enzymatic assays) to screen out abnormal samples of HHI, and 33 compounds have been identified in HHI (Feng et al., 2018). In addition, in vitro anticoagulant activity evaluations of seven HHI samples from different companies through in vitro anticoagulant activity tests (Wang KH. et al., 2018). The efficacy and consistency of different batches of XSTI were evaluated based on bioactive chemical markers. First, the chemical structure of the XSTI was systematically characterized. Second, through in vivo validation based on the adjusted efficacy score, Panax notoginsenoside R1, ginsenoside Rg1, Re, Rb1, and Rd were identified as bioactive chemical markers for XSTI treatment of cardio-cerebrovascular diseases to assess the consistency between the batches (Yang ZZ. et al., 2017).
Owing to the particularity of the administration of CHIs, their safety has always been a concern for everyone. Therefore, pharmacokinetic research and analysis of the absorption, distribution, metabolism, and excretion of CHIs in vivo are important. Some researchers have developed the pharmacokinetics of ligustrazine after single and multiple intravenous injections of Shenxiong glucose in rats. After single and multiple intravenous injections of SXG, the pharmacokinetics of ligustrazine in rats showed a linear relationship with a half-life of approximately 35 min. Ligustrazine is easily distributed in organs with high perfusion and almost disappears from the organs 90 min after injection (Wang Q. et al., 2019). Pharmacokinetic study of salvianolic acid and ligustrazine in rat plasma after intravenous administration of DLI. The results showed that the elimination half-life (t1/2), AUC0-t, and Co in the tanshinol group were 30%–40% higher than those in the tanshinol ligustrazine injection group (Jiao et al., 2020). Some researchers have investigated the distribution kinetics of puerarin in the hippocampus of rats treated with puerarin injection after acute focal cerebral ischemia. The AUC of puerarin in the embolic hippocampus (AUC0–120min) was higher than that in the normal hippocampus. The average dwell time was higher than that of a normal hippocampus (Kong et al., 2019).
The content and pharmacokinetic analysis of borneol and muskone after the intravenous administration of XNJI in rats were determined by GC-MS/MS. At 8 and 1.5 h after intravenous injection of XNJ, the concentrations of borneol and muskone were 10 and 2.5 ng/mL (Song et al., 2017). Some researchers have also identified biologically active anti-angiogenic components targeting tumor endothelial cells in SMI through multi-dimensional pharmacokinetics, and protopanaxadiol (PPD) ginsenoside (Rb1, Rb2, Rb3, Rc, and Rd) concentrations were higher than those of protopanaxadiol (Rg1 and Re) and oleanane types (Rb1, Rb2, Rb3, Rc, and Rd). Among the PPD-type ginsenosides, Rd showed the highest concentration in tumors and TECs after repeated injections. In vivo bioactivity results showed that Rd inhibited neovascularization in tumors, normalized tumor vascular architecture, and enhanced the antitumor effect of 5-fluorouracil in xenografted mice. Furthermore, Rd inhibited endothelial cell migration and tube formation in vitro. In conclusion, Rd may be an important active form that exerts antiangiogenic effects on tumors after SMI treatment (Zhong et al., 2020).
Re-evaluation of the post-marketing safety of CHIs is also important to ensure the safety of clinical medication. Some researchers have evaluated the factors influencing suspected allergic reactions and systemic adverse reactions after SXNI. A randomized controlled study and cohort study were conducted on adverse drug reactions to SXNI using a computer database. When SXNI was used in combination with the chemical drugs, the adverse reaction rate was 4.36%. The incidence of allergic reactions to SXNI is also affected by the drug, treatment time, single dose, indications, and off-label use (Wang C. et al., 2018).
Perspectives and challenges
The theory of TCM is summed up with long-term human experience, and its basis is oral or external administration. CHI has changed the traditional administration of TCM, which may produce new pharmacological effects or adverse reactions. In most cases, traditional medicine has limited guidance on the compatibility and proportion of CHIs. In addition, CHIs have the characteristics of a single component and multiple components, and exist as a single herb or prescription. Most CHI herbal studies are unclear, and pharmacology, pharmacokinetics, adverse reactions, and mechanisms of action research are not sufficiently thorough. In recent years, based on the multi-component and multi-target characteristics of CHIS, researchers have revealed the material basis of the efficacy of CHIS and its mechanism of action in treating diseases through network pharmacology, metabolomics, transcriptomics, and other technologies (Wang Z. et al., 2021). In addition, a large sample multicenter clinical trial of CHIS is conducive to ensuring the safety and effectiveness of its clinical application (Jiang et al., 2019; Cao et al., 2022; Yan et al., 2022).
Research on pharmaceutical preparations for CHIs is scarce. The technical requirements set standardized requirements for the pharmaceutical research content of CHIs, such as raw materials, excipients, preparation technology, and quality standards. Compared with oral TCM preparations, the quality of raw materials for CHIs should be higher, and the medicinal parts, origin (including origin processing), harvest season, storage conditions, and production of raw materials should be fixed. In terms of the preparation process, developers should fully explain the rationality of the process and comprehensively consider the impact of the process on the safety, effectiveness, and quality controllability of CHIs.
CHIs should have higher quality standards to ensure the safety and effectiveness of clinical use; therefore, quality research is very important in the research and development process of CHIs. Quality research includes literature research, chemical composition research, qualitative and quantitative analysis methods, and biological quality control methods. The quality control items of CHIs should consider the injection characteristics and sensitively reflect changes in drug quality (Wang N. et al., 2018; Tu et al., 2021). It is important to establish the pharmacodynamic material basis of CHIs and to rapidly detect harmful components to ensure safety and effectiveness (Bu et al., 2018; Zang et al., 2018).
Conclusion
Compared with TCM preparations, CHIs avoid degradation of the gastrointestinal tract and the first-pass effect of the liver during traditional administration. The clinical application of CHI is more convenient, and its onset is faster. CHIs have been used clinically for many years and have played an important role in the treatment of acute and severe cardio-cerebrovascular diseases. However, some adverse reactions occur as a result of its complexity and deficiencies in development and production. These issues can be addressed by expanding the scope of our research. Through research, the main components of the injection can be determined and quality control oversight can be carried out so that the quality standard can be controlled. At the same time, further research on the mechanism of action and pharmacokinetics can reveal the scientific connotation of CHIs. In addition to standardizing clinical use and strengthening supervision, CHIs have broad application prospects.
Author contributions
JH performed the research and drafted the manuscript. RC, HX, ZY, XB, and WY proposed amendments to the manuscript. PJ helped to coordinate support and funding. All authors read and approved the final manuscript.
Funding
The research work was financially supported by the National Natural Science Foundation of China (U19A2010), the Sichuan Province Science and Technology Planning Project (2021YFYZ0012-5) and the national multidisciplinary innovation team project of traditional Chinese medicine (ZYYCXTD-D-202209).
Acknowledgments
We would like to thank PJ and Chaomei Fu for their guidance on the selection of this paper. We would like to thank Editage (www.editage.cn) for English language editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Ai, J., Wan, H., Shu, M., Zhou, H., Zhao, T., Fu, W., et al. (2017). Guhong injection protects against focal cerebral ischemia-reperfusion injury via anti-inflammatory effects in rats. Arch. Pharm. Res. 40 (5), 610–622. doi:10.1007/s12272-016-0835-4
Bi, C., Li, P. L., Liao, Y., Rao, H. Y., Li, P. B., Yi, J., et al. (2019). Pharmacodynamic effects of Dan-hong injection in rats with blood stasis syndrome. Biomed. Pharmacother. 118, 109187. doi:10.1016/j.biopha.2019.109187
Bu, Y., Hu, Q., Xu, K., Xie, X., and Wang, S. (2018). Improved cell membrane bioaffinity sample pretreatment technique with enhanced stability for screening of potential allergenic components from traditional Chinese medicine injections. J. Mater Chem. B 6 (4), 624–633. doi:10.1039/c7tb02768k
Cao, X., Liu, H., Zhou, M., Chen, X., and Long, D. (2022). Comparative efficacy of five Chinese medicine injections for treating dilated cardiomyopathy with heart failure: A bayesian network meta-analysis. J. Ethnopharmacol. 282, 114604. doi:10.1016/j.jep.2021.114604
Chen, A. F., Ding, S. B., Kong, L. L., Xu, J. P., He, F., Ru, C. H., et al. (2021). Safflower injection inhibits pulmonary arterial remodeling in a monocrotaline-induced pulmonary arterial hypertension rat model. Zeitschrift Fur Naturforschung Sect. C-a J. Biosci. 76 (1-2), 27–34. doi:10.1515/znc-2020-0004
Chen, D., Zhang, H. F., Yuan, T. Y., Sun, S. C., Wang, R. R., Wang, S. B., et al. (2022a). Puerarin-V prevents the progression of hypoxia- and monocrotaline-induced pulmonary hypertension in rodent models. Acta Pharmacol. Sin. Physiol. 43(9), 2325–2339. doi:10.1038/s41401-022-00865-y
Chen, J. R., Cao, W. J., Asare, P. F., Lv, M., Zhu, Y., Li, L., et al. (2016a). Amelioration of cardiac dysfunction and ventricular remodeling after myocardial infarction by danhong injection are critically contributed by anti-TGF-beta-mediated fibrosis and angiogenesis mechanisms. J. Ethnopharmacol. 194, 559–570. doi:10.1016/j.jep.2016.10.025
Chen, J., Wei, J., Huang, Y., Ma, Y., Ni, J., and Li, M. (2018). Danhong injection enhances the therapeutic efficacy of mesenchymal stem cells in myocardial infarction by promoting angiogenesis. Ther. Efficacy Mesenchymal Stem Cells Myocard. Infarct. by Promot. Angiogenesis. Front Physiol, 9, 991. doi:10.3389/fphys.2018.00991
Chen, X. L., Guo, Y. J., Hu, Y. J., Yu, B. Y., and Qi, J. (2016b). Quantitative analysis of highly similar salvianolic acids with 1 H qNMR for quality control of traditional Chinese medicinal preparation Salvianolate Lyophilized Injection. J. Pharm. Biomed. Analysis 124, 281–287. doi:10.1016/j.jpba.2016.02.016
Chen, Y., Tang, M., Yuan, S., Fu, S., Li, Y., Li, Y., et al. (2022b). Rhodiola rosea: A therapeutic candidate on cardiovascular diseases. Oxidative Med. Cell. Longev. 2022, 1348795. doi:10.1155/2022/1348795
Cui, Q., Zhang, Y. L., Ma, Y. H., Yu, H. Y., Zhao, X. Z., Zhang, L. H., et al. (2020). A network pharmacology approach to investigate the mechanism of Shuxuening injection in the treatment of ischemic stroke. J. Ethnopharmacol. 257, 112891. doi:10.1016/j.jep.2020.112891
Duan, L., Xiong, X. J., Hu, J. Y., Liu, Y. M., and Wang, J. (2018). Efficacy and safety of oral Panax notoginseng saponins for unstable angina patients: A meta-analysis and systematic review. Phytomedicine 47, 23–33. doi:10.1016/j.phymed.2018.04.044
Fan, F., Yang, L., Li, R., Zou, X., Li, N., Meng, X., et al. (2020). Salidroside as a potential neuroprotective agent for ischemic stroke: A review of sources, pharmacokinetics, mechanism and safety. Biomed. Pharmacother. 129, 110458. doi:10.1016/j.biopha.2020.110458
Fan, H., Li, M., Yu, L., Jin, W., Yang, J., Zhang, Y., et al. (2018). Effects of Danhong Injection on platelet aggregation in hyperlipidemia rats. J. Ethnopharmacol. 212, 67–73. doi:10.1016/j.jep.2017.10.017
Fan, Z., Guo, C., Zhang, Y., Yao, J., Liao, L., and Dong, J. (2019). Hongjingtian injection inhibits proliferation and migration and promotes apoptosis in high glucose-induced vascular smooth muscle cells. Drug Des. Devel Ther. 13, 4115–4126. doi:10.2147/DDDT.S220719
Feng, C., Wan, H., Zhang, Y., Yu, L., Shao, C., He, Y., et al. (2020). Neuroprotective effect of danhong injection on cerebral ischemia-reperfusion injury in rats by activation of the PI3K-akt pathway. Front. Pharmacol. 11, 298. doi:10.3389/fphar.2020.00298
Feng, L., Wu, X. J., Cao, T., and Wu, B. (2021). The efficacy and safety of Xuesaitong injection combined with Western medicines in the treatment of ischemic stroke: An updated systematic review and meta-analysis. Ann. Palliat. Med. 10 (9), 9523–9534. doi:10.21037/apm-21-1828
Feng, W. W., Zhang, Y., Tang, J. F., Zhang, C. E., Dong, Q., Li, R. Y., et al. (2018). Combination of chemical fingerprinting with bioassay, a preferable approach for quality control of Safflower Injection. Anal. Chim. Acta 1003, 56–63. doi:10.1016/j.aca.2017.11.069
Gresele, P., Guglielmini, G., Del Pinto, M., Calabro, P., Pignatelli, P., Patti, G., et al. (2021). Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: From the START antiplatelet registry. Int. J. Cardiol. 327, 176–182. doi:10.1016/j.ijcard.2020.10.079
Guo, R., Li, L., Su, J., Li, S., Duncan, S. E., Liu, Z. H., et al. (2020a). Pharmacological activity and mechanism of tanshinone IIA in related diseases. Drug Des. Dev. Ther. 14, 4735–4748. doi:10.2147/DDDT.S266911
Guo, S. Y., Wu, J. R., Ni, M. W., Jia, S. S., Zhang, J. Y., Zhou, W., et al. (2020b). Comparative efficacy of danshen class injections for treating acute coronary syndrome: A multidimensional bayesian network meta-analysis of randomized controlled trials. Front. Pharmacol. 11, 1260. doi:10.3389/fphar.2020.01260
Hao, L. J., L, A. H., and S, J. Y. (2020). Statistical analysis of raw materials of traditional Chinese medicine injections and their prescriptions. Mod. Chin. Tradit. Med. 3 (22), 322–331.
He, Q. Y., Yu, X. Y., Xiao, Z., Sun, X., Zhu, W. F., Yi, X. Q., et al. (2021). Comparison of the efficacy of danhong injections at different time-points during the perioperative period of acute myocardial infarction: A systematic review and meta-analysis of randomized controlled trials. Front. Pharmacol. 12, 643446. doi:10.3389/fphar.2021.643446
Huang, P. Y., Chen, Y., Zhang, H. B., Chen, B. J., Zhao, S., Feng, Y. C., et al. (2022). Comparative efficacy of Chinese herbal injections for septic shock: A bayesian network meta-analysis of randomized controlled trials. Front. Pharmacol. 13, 850221. doi:10.3389/fphar.2022.850221
Huang, W., Yang, Y., Zeng, Z., Su, M., Gao, Q., and Zhu, B. (2016). Effect of Salvia miltiorrhiza and ligustrazine injection on myocardial ischemia/reperfusion and hypoxia/reoxygenation injury. Mol. Med. Rep. 14 (5), 4537–4544. doi:10.3892/mmr.2016.5822
Jiang, C., Shen, J., Shou, D., Wang, N., Jing, J., Zhang, G., et al. (2019). Identification of high-risk patients for ADR induced by traditional Chinese medicine injection: A nested case-control study. Sci. Rep. 9 (1), 16721. doi:10.1038/s41598-019-53267-2
Jiao, W. J., Lei, Z., Zhao, X., Wang, K., Ma, A. L., Du, L., et al. (2020). Pharmacokinetic study of tanshinol and ligustrazine in rat plasma after intravenous administration of tanshinol and Danshen Chuanxiongqin Injection. Biomed. Chromatogr. 34 (9), e4869. doi:10.1002/bmc.4869
Keeter, W. C., Ma, S., Stahr, N., Moriarty, A. K., and Galkina, E. V. (2022). Atherosclerosis and multi-organ-associated pathologies. Seminars Immunopathol. 44 (3), 363–374. doi:10.1007/s00281-022-00914-y
Kong, H., Zhang, G. L., Cheng, J. J., Shi, R. F., Zhang, M. L., Cao, P., et al. (2019). Distribution kinetics of puerarin in rat hippocampus after acute local cerebral ischemia. J. Pharm. Biomed. Analysis 164, 196–201. doi:10.1016/j.jpba.2018.10.038
Li, C., Yang, J. H., Tong, X., Zhao, C., He, Y., and Wan, H. T. (2019a). Precursor ion scan enhanced rapid identification of the chemical constituents of Danhong injection by liquid chromatography-tandem mass spectrometry: An integrated strategy. J. Chromatogr. A 1602, 378–385. doi:10.1016/j.chroma.2019.04.023
Li, D., Li, Y., Yang, S., Yu, Z., Xing, Y., and Wu, M. (2022a). Mechanism and potential target of blood-activating Chinese botanical drugs combined with anti-platelet drugs: Prevention and treatment of atherosclerotic cardiovascular diseases. Front. Pharmacol. 13, 811422. doi:10.3389/fphar.2022.811422
Li, H., Gao, C., Liu, C., Liu, L., Zhuang, J., Yang, J., et al. (2021a). A review of the biological activity and pharmacology of cryptotanshinone, an important active constituent in Danshen. Biomed. Pharmacother. 137, 111332. doi:10.1016/j.biopha.2021.111332
Li, H., Mao, Y., Zhang, Q., Han, Q., Man, Z., Zhang, J., et al. (2016). Xinmailong mitigated epirubicin-induced cardiotoxicity via inhibiting autophagy. J. Ethnopharmacol. 192, 459–470. doi:10.1016/j.jep.2016.08.031
Li, H. Q., Wei, J. J., Xia, W., Li, J. H., Liu, A. J., Yin, S. B., et al. (2015a). Promoting blood circulation for removing blood stasis therapy for acute intracerebral hemorrhage: A systematic review and meta-analysis. Acta Pharmacol. Sin. 36 (6), 659–675. doi:10.1038/aps.2014.139
Li, L. J., Li, Y. M., Qiao, B. Y., Jiang, S., Li, X., Du, H. M., et al. (2015b2015). The value of safflower yellow injection for the treatment of acute cerebral infarction: A randomized controlled trial. Evidence-Based Complementary Altern. Med. 2015, 1–6. doi:10.1155/2015/478793
Li, L., Li, J., Wang, Q., Zhao, X., Yang, D., Niu, L., et al. (2020a). Shenmai injection protects against doxorubicin-induced cardiotoxicity via maintaining mitochondrial homeostasis. Front. Pharmacol. 11, 815. doi:10.3389/fphar.2020.00815
Li, L., Sha, Z., Wang, Y., Yang, D., Li, J., Duan, Z., et al. (2019b). Pre-treatment with a combination of Shenmai and Danshen injection protects cardiomyocytes against hypoxia/reoxygenation- and H2O2-induced injury by inhibiting mitochondrial permeability transition pore opening. Exp. Ther. Med. 17 (6), 4643–4652. doi:10.3892/etm.2019.7462
Li, M., Zhou, J., Jin, W. F., Li, X. H., and Zhang, Y. Y. (2018a). Danhong injection combined with t-PA improves thrombolytic therapy in focal embolic stroke. Front. Pharmacol. 9. doi:10.3389/fphar.2018.00308
Li, R., Xia, Z., Li, B., Tian, Y., Zhang, G., Li, M., et al. (2021b). Advances in supercritical carbon dioxide extraction of bioactive substances from different parts of Ginkgo biloba L. Molecules 26 (13), 4011. doi:10.3390/molecules26134011
Li, T., Zhang, Y., Tian, J., Yang, L., and Wang, J. (2019c). Ginkgo biloba pretreatment attenuates myocardial ischemia-reperfusion injury via mitoBKCa. Am. J. Chin. Med. 47 (5), 1057–1073. doi:10.1142/S0192415X1950054X
Li, X., Guo, K., Zhang, R., Wang, W., Sun, H., Yague, E., et al. (2022b). Exploration of the mechanism of salvianolic acid for injection against ischemic stroke: A research based on computational prediction and experimental validation. Front. Pharmacol. 13, 894427. doi:10.3389/fphar.2022.894427
Li, X., Guo, T., Feng, Q., Bai, T., Wu, L., Liu, Y., et al. (2022c). Progress of thrombus formation and research on the structure-activity relationship for antithrombotic drugs. Eur. J. Med. Chem. 228, 114035. doi:10.1016/j.ejmech.2021.114035
Li, X., Yuan, T., Chen, D., Chen, Y., Sun, S., Wang, D., et al. (2018b). Cardioprotective effects of puerarin-V on isoproterenol-induced myocardial infarction mice is associated with regulation of PPAR-Υ/NF-κB pathway. Molecules 23 (12), 3322. doi:10.3390/molecules23123322
Li, Y., Cai, M., Mao, G. X., Shu, Q. F., Liu, X. B., and Liu, X. L. (2021c). Preclinical evidence and possible mechanisms of Rhodiola rosea L. and its components for ischemic stroke: A systematic review and meta-analysis. Front. Pharmacol. 12, 736198. doi:10.3389/fphar.2021.736198
Li, Y., Xu, C., Wang, H., Liu, X., Jiang, L., Liang, S., et al. (2021d). Systems pharmacology reveals the multi-level synergetic mechanism of action of Ginkgo biloba L. leaves for cardiomyopathy treatment. J. Ethnopharmacol. 264, 113279. doi:10.1016/j.jep.2020.113279
Li, Y. Z., Yan, S. H., Qian, L. C., Wu, L. H., Zheng, Y. W., and Fang, Z. Y. (2020b). Danhong injection for the treatment of hypertensive nephropathy: A systematic review and meta-analysis. Front. Pharmacol. 11, 909. doi:10.3389/fphar.2020.00909
Li, Z., Wang, H., Xiao, G., Du, H., He, S., Feng, Y., et al. (2021e). Recovery of post-stroke cognitive and motor deficiencies by Shuxuening injection via regulating hippocampal BDNF-mediated Neurotrophin/Trk Signaling. Biomed. Pharmacother. 141, 111828. doi:10.1016/j.biopha.2021.111828
Li, Z., Xiao, G., Lyu, M., Wang, Y., He, S., Du, H., et al. (2020c). Shuxuening injection facilitates neurofunctional recovery via down-regulation of G-CSF-mediated granulocyte adhesion and diapedesis pathway in a subacute stroke mouse model. Biomed. Pharmacother. 127, 110213. doi:10.1016/j.biopha.2020.110213
Liang, H., Yuan, X., Sun, C., Sun, Y., Yang, M., Feng, S., et al. (2022). Preparation of a new component group of Ginkgo biloba leaves and investigation of the antihypertensive effects in spontaneously hypertensive rats. Biomed. Pharmacother. 149, 112805. doi:10.1016/j.biopha.2022.112805
Liao, Q., Pang, L., Li, J. J., Zhang, C., Li, J. X., Zhang, X., et al. (2022). Characterization and diabetic wound healing benefits of protein-polysaccharide complexes isolated from an animal ethno-medicine Periplaneta americana L. Int. J. Biol. Macromol. 195, 466–474. doi:10.1016/j.ijbiomac.2021.12.018
Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., and Montecucco, F. (2021). Cytokines as therapeutic targets for cardio- and cerebrovascular diseases. Basic Res. Cardiol. 116 (1), 23. doi:10.1007/s00395-021-00863-x
Lin, S. S., Liu, C. X., Wang, X. L., and Mao, J. Y. (2019). Intervention mechanisms of Xinmailong injection, a Periplaneta americana extract, on cardiovascular disease: A systematic review of basic researches. Evid. Based Complement. Altern. Med. 2019, 8512405. doi:10.1155/2019/8512405
Liu, G., Lin, J., Zhang, L., Gao, Q., Wang, Z., Chang, Z., et al. (2022). Uncovering the mechanism of the xingnaojing injection against ischemic stroke using a combined network pharmacology approach and gut microbiota analysis. Evid. Based Complement. Altern. Med. 2022, 5886698. doi:10.1155/2022/5886698
Liu, H. Y., Wang, S. J., Sun, A. J., Huang, D., Wang, W., Zhang, C. Y., et al. (2012). Danhong inhibits oxidized low-density Lipoprotein&ndash;Induced immune maturation of dentritic cells via a peroxisome proliferator activated receptor <I>γ</I>–Mediated pathway. J. Pharmacol. Sci. 119 (1), 1–9. doi:10.1254/jphs.11226fp
Liu, L., Wang, Y., Zhang, J., and Wang, S. (2021). Advances in the chemical constituents and chemical analysis of Ginkgo biloba leaf, extract, and phytopharmaceuticals. J. Pharm. Biomed. Anal. 193, 113704. doi:10.1016/j.jpba.2020.113704
Liu, Q. X., Wu, H. Y., Wang, J. J., and Li, X. M. (2018a). Effects of Shenmai injection on the values of CO, SV, and ef in patients undergoing off-pump coronary artery bypass graft: A randomized, clinical trial. Medicine 97 (10), e0085. doi:10.1097/MD.0000000000010085
Liu, S., Wang, K. H., Duan, X. J., Wu, J. R., Zhang, D., Liu, X. K., et al. (2019a). Efficacy of danshen class injection in the treatment of acute cerebral infarction: A bayesian network meta-analysis of randomized controlled trials. Evidence-Based Complementary Altern. Med. 2019, 1–12. doi:10.1155/2019/5814749
Liu, X. T., Ren, P. W., Peng, L., Kang, D. Y., Zhang, T. L., Wen, S., et al. (2016). Effectiveness and safety of ShenXiong glucose injection for acute ischemic stroke: A systematic review and GRADE approach. BMC Complement. Altern. Med. 16, 68. doi:10.1186/s12906-016-1038-8
Liu, X., Tan, W., Yang, F., Wang, Y., Yue, S., Wang, T., et al. (2018b). Shengmai injection reduces apoptosis and enhances angiogenesis after myocardial ischaemia and reperfusion injury in rats. Biomed. Pharmacother. 104, 629–636. doi:10.1016/j.biopha.2018.04.180
Liu, Y. N., Chen, C. H., Qiu, J. W., Fang, Z. B., Wu, H. B., Zhang, X. X., et al. (2019b). Characterization of the chemical constituents in Hongjingtian injection by liquid chromatography quadrupole time-of-flight mass spectrometry. Biomed. Chromatogr. 33 (3), e4446. doi:10.1002/bmc.4446
Lu, D. Y., Sun, J., Zheng, J., Zheng, L., Xue, W. N., Li, C., et al. (2021). Shenxiong glucose injection inhibits H2O2-induced H9c2 cell apoptosis by activating the ERK signaling pathway. Biomed. Pharmacother. 143, 112114. doi:10.1016/j.biopha.2021.112114
Lu, D., Zhang, Y., Xue, W., Sun, J., Yang, C., Lin, C., et al. (2020). Shenxiong glucose injection protects H9c2 cells from CoCl2-induced oxidative damage via antioxidant and antiapoptotic pathways. Nat. Product. Commun. 15 (4), 1934578X2092005. doi:10.1177/1934578x20920054
Lu, X. F., Liu, Z. Y., Cui, Q. M., Liu, F. C., Li, J. X., Niu, X. G., et al. (2022). A polygenic risk score improves risk stratification of coronary artery disease: A large-scale prospective Chinese cohort study. Eur. Heart J. 43 (18), 1702–1711. doi:10.1093/eurheartj/ehac093
Lu, X. H., Zhang, L., Wang, J. B., Liu, H. H., Li, H. T., Zhou, H. Q., et al. (2018). Clinical efficacy and safety of Xinmailong injection for the treatment of chronic heart failure: A meta-analysis. Front. Pharmacol. 9, 810. doi:10.3389/fphar.2018.00810
Lv, J. Y., Shi, S. Q., Zhang, B. X., Xu, X., Zheng, H. R., Li, Y. M., et al. (2022). Role of puerarin in pathological cardiac remodeling: A review. Pharmacol. Res. 178, 106152. doi:10.1016/j.phrs.2022.106152
Lyu, M., Cui, Y., Zhao, T., Ning, Z., Ren, J., Jin, X., et al. (2018). Tnfrsf12a-Mediated atherosclerosis signaling and inflammatory response as a common protection mechanism of shuxuening injection against both myocardial and cerebral ischemia-reperfusion injuries. Front. Pharmacol. 9, 312. doi:10.3389/fphar.2018.00312
Ma, R. S., Zhao, L. C. Y., Zhao, Y. M., and Li, Y. (2022). Puerarin action on stem cell proliferation, differentiation and apoptosis: Therapeutic implications for geriatric diseases. Phytomedicine 96, 153915. doi:10.1016/j.phymed.2021.153915
Ma, X., Wang, T., Wen, J. X., Wang, J., Zeng, N., Zou, W. J., et al. (2020). Role of Xingnaojing Injection in treating acute cerebral hemorrhage A systematic review and meta-analysis. Medicine 99 (15), e19648. doi:10.1097/MD.0000000000019648
Ma, X., Yang, Y. X., Chen, N. A., Xie, Q., Wang, T., He, X., et al. (2017). Meta-analysis for clinical evaluation of xingnaojing injection for the treatment of cerebral infarction. Front. Pharmacol. 8, 485. doi:10.3389/fphar.2017.00485
Novo, G., Sansone, A., Rizzo, M., Guarneri, F. P., Pernice, C., and Novo, S. (2014). High plasma levels of endothelin-1 enhance the predictive value of preclinical atherosclerosis for future cerebrovascular and cardiovascular events: A 20-year prospective study. J. Cardiovasc. Med. 15 (9), 696–701. doi:10.2459/JCM.0000000000000121
Novo, S., Carita, P., Lo Voi, A., Muratori, I., Tantillo, R., Corrado, E., et al. (2019). Impact of preclinical carotid atherosclerosis on global cardiovascular risk stratification and events in a 10-year follow-up: Comparison between the algorithms of the framingham heart study, the European SCORE and the Italian 'progetto cuore. J. Cardiovasc. Med. 20 (2), 91–96. doi:10.2459/JCM.0000000000000740
Orgah, J. O., He, S., Wang, Y., Jiang, M., Wang, Y., Orgah, E. A., et al. (2020). Pharmacological potential of the combination of Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua) for diabetes mellitus and its cardiovascular complications. Pharmacol. Res. 153, 104654. doi:10.1016/j.phrs.2020.104654
Orgah, J. O., Wang, M., Yang, X. H., Wang, Z. L., Wang, D. D., Zhang, Q., et al. (2018). Danhong injection protects against hypertension-induced renal injury via down-regulation of myoglobin expression in spontaneously hypertensive rats. Kidney & Blood Press. Res. 43 (1), 12–24. doi:10.1159/000486735
Pan, W. D., Yang, L. X., Feng, W. H., Lin, L. M., Li, C., Liu, W. W., et al. (2015). Determination of five sesquiterpenoids in Xingnaojing injection by quantitative analysis of multiple components with a single marker. J. Sep. Sci. 38 (19), 3313–3323. doi:10.1002/jssc.201500494
Pang, L., Liao, Q., Zou, L., Zhang, C., Nie, X., Yi, Z. W., et al. (2022). Two glycoproteins from medicinal insect Periplaneta americana (L.) promote diabetic wound healing via macrophage polarization modulation. Int. J. Biol. Macromol. 209, 2130–2141. doi:10.1016/j.ijbiomac.2022.04.193
Qi, J., Yu, J., Tan, Y., Chen, R., Xu, W., Chen, Y., et al. (2017). Mechanisms of Chinese Medicine Xinmailong's protection against heart failure in pressure-overloaded mice and cultured cardiomyocytes. Sci. Rep. 7, 42843. doi:10.1038/srep42843
Qian, J., Zhao, X. P., Wang, W. T., Zhang, S. J., Hong, Z. P., Chen, X. L., et al. (2018). Transcriptomic study reveals recovery of impaired astrocytes contribute to neuroprotective effects of danhong injection against cerebral ischemia/reperfusion-induced injury. Front. Pharmacol. 9, 250. doi:10.3389/fphar.2018.00250
Qiu, H., Liu, W., Lan, T., Pan, W., Chen, X., Wu, H., et al. (2018). Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats. Phytomedicine 51, 255–265. doi:10.1016/j.phymed.2018.09.238
Qu, X-Y., Zhang, Y-M., Tao, L-N., Gao, H., Zhai, J-H., Sun, J-M., et al. (2019). XingNaoJing injections protect against cerebral ischemia/reperfusion injury and alleviate blood-brain barrier disruption in rats, through an underlying mechanism of NLRP3 inflammasomes suppression. Chin. J. Nat. Med. 17 (7), 498–505. doi:10.1016/S1875-5364(19)30071-8
Sarkar, C., Quispe, C., Jamaddar, S., Hossain, R., Ray, P., Mondal, M., et al. (2020). Therapeutic promises of ginkgolide A: A literature-based review. Biomed. Pharmacother. 132, 110908. doi:10.1016/j.biopha.2020.110908
Shao, H., Huang, Y., Xu, D., Huang, S., and Tong, R. (2022). A systematic review and meta-analysis on the efficacy of puerarin injection as adjunctive therapy for unstable angina pectoris. Front. Cardiovasc. Med. 9, 763567. doi:10.3389/fcvm.2022.763567
Sikora, J., Karczmarska-Wodzka, A., Bugieda, J., and Sobczak, P. (2022). The importance of platelets response during antiplatelet treatment after ischemic stroke-between benefit and risk: A systematic review. Int. J. Mol. Sci. 23 (3), 1043. doi:10.3390/ijms23031043
Song, Y. F., Chu, Y., Ma, X. H., Zheng, H. R., Bai, X. L., Zhou, S. P., et al. (2017). GC-MS/MS method for the determination and pharmacokinetic analysis of borneol and muscone in rat after the intravenous administration of Xingnaojing injection. J. Sep. Sci. 40 (21), 4264–4271. doi:10.1002/jssc.201700341
Sun, W., Zhang, L. S., Fang, Z. R., Han, L. F., Wang, Q. Y., Leng, Y. Z., et al. (2022). Shuxuetong injection and its peptides enhance angiogenesis after hindlimb ischemia by activating the MYPT1/LIMK1/Cofilin pathway. J. Ethnopharmacol. 292, 115166. doi:10.1016/j.jep.2022.115166
Tan, D., Wu, J. R., Cui, Y. Y., Zhao, Y., Zhang, D., Liu, S., et al. (2018). Ginkgo leaf extract and dipyridamole injection as adjuvant treatment for angina pectoris: A meta-analysis of 41 randomized controlled trials. Chin. J. Integr. Med. 24 (12), 930–937. doi:10.1007/s11655-018-2557-6
Tian, F., Xu, L. H., Wang, B., Tian, L. J., and Ji, X. L. (2015). The neuroprotective mechanism of puerarin in the treatment of acute spinal ischemia-reperfusion injury is linked to cyclin-dependent kinase 5. Neurosci. Lett. 584, 50–55. doi:10.1016/j.neulet.2014.09.049
Tian, J. F., Liu, Y., and Chen, K. J. (2017). Ginkgo biloba extract in vascular protection: Molecular mechanisms and clinical applications. Curr. Vasc. Pharmacol. 15 (6), 532–548. doi:10.2174/1570161115666170713095545
Tian, Z. Y., Feng, L. D., Xie, Y., Xu, D. H., Zhang, C. Y., Kong, L. B., et al. (2021). Chinese herbal medicine xingnaojing injection for acute ischemic stroke: An overview of systematic reviews and meta-analyses. Front. Pharmacol. 12, 659408. doi:10.3389/fphar.2021.659408
Tu, Y., Li, L., Wang, Z., and Yang, L. (2021). Advances in analytical techniques and quality control of traditional Chinese medicine injections. J. Pharm. Biomed. Anal. 206, 114353. doi:10.1016/j.jpba.2021.114353
Wang, C., Shi, Q. P., Ding, F., Jiang, X. D., Tang, W., Yu, M. L., et al. (2018a). Reevaluation of the post-marketing safety of Shuxuening injection based on real-world and evidence-based evaluations. Drug Des. Dev. Ther. 12, 757–767. doi:10.2147/DDDT.S156000
Wang, D. J., and Tian, H. (2014). Effect of Mailuoning injection on 8-iso-prostaglandin F2 alpha and superoxide dismutase in rabbits with extremity ischemia-reperfusion injury. J. Surg. Res. 192 (2), 464–470. doi:10.1016/j.jss.2014.06.008
Wang, F., He, Q., Wang, J., Yuan, Q., Guo, H., Chai, L., et al. (2017a). Neuroprotective effect of salvianolate lyophilized injection against cerebral ischemia in type 1 diabetic rats. BMC Complement. Altern. Med. 17 (1), 258. doi:10.1186/s12906-017-1738-8
Wang, F. J., Wang, S. X., Chai, L. J., Zhang, Y., Guo, H., and Hu, L. M. (2018b). Xueshuantong injection (lyophilized) combined with salvianolate lyophilized injection protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress. Acta Pharmacol. Sin. 39 (6), 998–1011. doi:10.1038/aps.2017.128
Wang, J., Chen, X. L., Bai, W. R., Wang, Z. Z., Xiao, W., and Zhu, J. B. (2021a). Study on mechanism of Ginkgo biloba L. Leaves for the treatment of neurodegenerative diseases based on network pharmacology. Neurochem. Res. 46 (7), 1881–1894. doi:10.1007/s11064-021-03315-z
Wang, J., Wang, X. H., Wan, W. P., Guo, Y. Y., Cui, Y. F., Liu, W. B., et al. (2021b). Effects of Shenfu injection on myocardial adenosine receptors in rats with myocardial ischemia-reperfusion postconditioning. Hum. Exp. Toxicol. 40 (12), S300–S309. doi:10.1177/09603271211041668
Wang, K. H., Li, S. F., Zhao, Y., Li, H. X., and Zhang, L. W. (2018c). In vitro anticoagulant activity and active components of safflower injection. Molecules 23 (1), 170. doi:10.3390/molecules23010170
Wang, K. H., Wu, J. R., Wang, H. J., Duan, X. J., Zhang, D., Wang, Y. Z., et al. (2020a). Comparative efficacy of Chinese herbal injections for pulmonary heart disease: A bayesian network meta-analysis of randomized controlled trials. Front. Pharmacol. 11, 634. doi:10.3389/fphar.2020.00634
Wang, L., Botchway, B. O. A., and Liu, X. (2021c). The repression of the HMGB1-TLR4-NF-κb signaling pathway by safflower yellow may improve spinal cord injury. Front. Neurosci. 15, 803885. doi:10.3389/fnins.2021.803885
Wang, L., Fan, X., Chen, Y., Liang, X., Shen, W., and Zhang, Y. (2022a). Efficacy and safety of xingnaojing injection for emergency treatment of acute ischemic stroke: A systematic review and meta-analysis. Front. Pharmacol. 13, 839305. doi:10.3389/fphar.2022.839305
Wang, L. L., Yu, Y. R., Yang, J. H., Zhao, X. P., and Li, Z. (2015). Dissecting Xuesaitong's mechanisms on preventing stroke based on the microarray and connectivity map. Mol. Biosyst. 11 (11), 3033–3039. doi:10.1039/c5mb00379b
Wang, N., Li, Z. Y., Zheng, X. L., Li, Q., Yang, X., and Xu, H. (2018d). Quality assessment of kumu injection, a traditional Chinese medicine preparation, using HPLC combined with chemometric methods and qualitative and quantitative analysis of multiple alkaloids by single marker. Molecules 23 (4), 856. doi:10.3390/molecules23040856
Wang, Q., Sun, H. P., Yu, L., Ma, X. P., Jiang, B. P., Bi, H. Q., et al. (2019a). Pharmacokinetic behaviors of ligustrazine after single- and multiple-dose intravenous Shenxiong glucose injection in rats by high-performance liquid chromatography. Naunyn-Schmiedebergs Archives Pharmacol. 392 (5), 565–572. doi:10.1007/s00210-018-01608-9
Wang, R., Wang, M., Zhou, J., Ye, T., Xie, X., Ni, D., et al. (2019b). Shuxuening injection protects against myocardial ischemia-reperfusion injury through reducing oxidative stress, inflammation and thrombosis. Ann. Transl. Med. 7 (20), 562. doi:10.21037/atm.2019.09.40
Wang, S. M., Ye, L. F., and Wang, L. H. (2020b). Shenmai injection improves energy metabolism in patients with heart failure: A randomized controlled trial. Front. Pharmacol. 11, 459. doi:10.3389/fphar.2020.00459
Wang, S. M., Ye, L. F., and Wang, L. H. (2022b). Traditional Chinese medicine enhances myocardial metabolism during heart failure. Biomed. Pharmacother. 146, 112538. doi:10.1016/j.biopha.2021.112538
Wang, T., Guo, R. X., Zhou, G. H., Zhou, X. D., Kou, Z. Z., Sui, F., et al. (2016). Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (burk.) FH chen: A review. J. Ethnopharmacol. 188, 234–258. doi:10.1016/j.jep.2016.05.005
Wang, Y., Chen, W., Zhou, J., Wang, Y., Wang, H., and Wang, Y. (2022c). Nitrate metabolism and ischemic cerebrovascular disease: A narrative review. Front. Neurology 13, 735181. doi:10.3389/fneur.2022.735181
Wang, Y. S., Mu, H., Jiang, Y., Gao, Y. L., Liu, Z. H., Zhu, C. T., et al. (2017b). A systematic review and meta-analysis of randomized controlled clinical trials of Ginkgo leaf extract and dipyridamole injection combined with aspirin for the treatment of cerebral infarction. Int. J. Clin. Exp. Med. 10 (8), 11304–11313.
Wang, Z., Wan, H., Tong, X., He, Y., Yang, J., Zhang, L., et al. (2021d). An integrative strategy for discovery of functional compound combination from Traditional Chinese Medicine: Danhong Injection as a model. Biomed. Pharmacother. 138, 111451. doi:10.1016/j.biopha.2021.111451
Wang, Z. Y., Sun, Y. Z., Bian, L. H., Zhang, Y. L., Zhang, Y., Wang, C. G., et al. (2022d). The crosstalk signals of Sodium Tanshinone IIA Sulfonate in rats with cerebral ischemic stroke: Insights from proteomics. Biomed. Pharmacother., 151.
Xian, S. X., Yang, Z. Q., Lee, J., Jiang, Z. P., Ye, X. H., Luo, L. Y., et al. (2016). A randomized, double-blind, multicenter, placebo-controlled clinical study on the efficacy and safety of Shenmai injection in patients with chronic heart failure. J. Ethnopharmacol. 186, 136–142. doi:10.1016/j.jep.2016.03.066
Xiao, G., Lyu, M., Wang, Y., He, S., Liu, X., Ni, J., et al. (2019). Ginkgo flavonol glycosides or ginkgolides tend to differentially protect myocardial or cerebral ischemia-reperfusion injury via regulation of TWEAK-fn14 signaling in heart and brain. Front. Pharmacol. 10, 735. doi:10.3389/fphar.2019.00735
Xie, F., Zhang, B., Dai, S., Jin, B., Zhang, T., and Dong, F. (2021). Efficacy and safety of Salvia miltiorrhiza (Salvia miltiorrhiza bunge) and ligustrazine injection in the adjuvant treatment of early-stage diabetic kidney disease: A systematic review and meta-analysis. J. Ethnopharmacol. 281, 114346. doi:10.1016/j.jep.2021.114346
Xu, C. C., Wang, W. W., Wang, B., Zhang, T., Cui, X. M., Pu, Y. Q., et al. (2019a). Analytical methods and biological activities of Panax notoginseng saponins: Recent trends. J. Ethnopharmacol. 236, 443–465. doi:10.1016/j.jep.2019.02.035
Xu, H. M., Liu, Y., Wang, D. S., and Zhang, Z. Q. (2019b). Shenmai injection maintains blood-brain barrier integrity following focal cerebral ischemia via modulating the expression and trafficking of occludin in lipid rafts. J. Ethnopharmacol. 237, 55–63. doi:10.1016/j.jep.2019.03.034
Xu, J. Y., Zhang, C. H., Shi, X. Q., Li, J., Liu, M., Jiang, W. M., et al. (2019c). Efficacy and safety of sodium tanshinone IIA sulfonate injection on hypertensive nephropathy: A systematic review and meta-analysis. Front. Pharmacol. 10, 1542. doi:10.3389/fphar.2019.01542
Xu, J., Zhang, X., Jin, A., Pan, Y., Li, Z., Meng, X., et al. (2022). Trends and risk factors associated with stroke recurrence in China, 2007-2018. Jama Netw. Open 5 (6), e2216341. doi:10.1001/jamanetworkopen.2022.16341
Xu, L. L., Shang, Z. P., Bo, T., Sun, L., Guo, Q. L., Qiao, X., et al. (2019d). Rapid quantitation and identification of the chemical constituents in Danhong Injection by liquid chromatography coupled with orbitrap mass spectrometry. J. Chromatogr. A 1606, 460378. doi:10.1016/j.chroma.2019.460378
Xu, Z., Lu, D., Yuan, J., Ren, M., Ma, R., Xie, Q., et al. (2021). Storax, A promising botanical medicine for treating cardio-cerebrovascular diseases: A review. Front. Pharmacol. 12, 785598. doi:10.3389/fphar.2021.785598
Xuan, J. W., Huang, M., Lu, Y. J., and Tao, L. B. (2018). Economic evaluation of safflower yellow injection for the treatment of patients with stable angina pectoris in China: A cost-effectiveness analysis. J. Altern. Complementary Med. 24 (6), 564–569. doi:10.1089/acm.2017.0284
Xue, P., Ma, Z. Y., and Liu, S. G. (2019). Efficacy and safety of Ginkgo leaf extract and dipyridamole injection for ischemic stroke: A systematic review and meta analysis. Front. Pharmacol. 10, 1403. doi:10.3389/fphar.2019.01403
Yan, Z., Feng, Z., Jiao, Z., Wang, G., Chen, C., and Feng, D. (2022). Safety of using traditional Chinese medicine injections in primary medical institutions: Based on the spontaneous reporting system 2016–2020 in henan Province, China. Front. Pharmacol. 13, 761097. doi:10.3389/fphar.2022.761097
Yang, B. R., Yuen, S. C., Fan, G. Y., Cong, W. H., Leung, S. W., and Lee, S. M. Y. (2018). Identification of certain Panax species to be potential substitutes for Panax notoginseng in hemostatic treatments. Pharmacol. Res. 134, 1–15. doi:10.1016/j.phrs.2018.05.005
Yang, W., Shi, Z., Yang, H. Q., Teng, J., Zhao, J., and Xiang, G. (2015). Mailuoning for acute ischaemic stroke. Cochrane Database Syst. Rev. 1, CD007028. doi:10.1002/14651858.CD007028.pub3
Yang, X. H., Orgah, J., Wang, D. D., Fan, G. W., Hu, J. Y., Han, J. H., et al. (2017a). Danhong injection reduces vascular remodeling and up-regulates the Kallikrein-kinin system in spontaneously hypertensive rats. Sci. Rep. 7, 4308. doi:10.1038/s41598-017-04661-1
Yang, Z. Z., Shao, Q., Ge, Z. W., Ai, N., Zhao, X. P., and Fan, X. H. (2017b). A bioactive chemical markers based strategy for quality assessment of botanical drugs: Xuesaitong injection as a case study. Sci. Rep. 7, 2410. doi:10.1038/s41598-017-02305-y
Ye, L. F., Zheng, Y. R., and Wang, L. H. (2015). Effects of Shenmai injection and its bioactive components following ischemia/reperfusion in cardiomyocytes. Exp. Ther. Med. 10 (4), 1348–1354. doi:10.3892/etm.2015.2662
Ye, T., Li, Y., Xiong, D., Gong, S., Zhang, L., Li, B., et al. (2021). Combination of Danshen and ligustrazine has dual anti-inflammatory effect on macrophages and endothelial cells. J. Ethnopharmacol. 266, 113425. doi:10.1016/j.jep.2020.113425
Yu, J. H., Li, Y. H., Liu, X. Y., Ma, Z., Michael, S., Orgah, J. O., et al. (2019a). Mitochondrial dynamics modulation as a critical contribution for Shenmai injection in attenuating hypoxia/reoxygenation injury. J. Ethnopharmacol. 237, 9–19. doi:10.1016/j.jep.2019.03.033
Yu, S. T., Li, J., Guo, L., Di, C. X., Qin, X. M., and Li, Z. Y. (2019b). Integrated liquid chromatography-mass spectrometry and nuclear magnetic resonance spectra for the comprehensive characterization of various components in the Shuxuening injection. J. Chromatogr. A 1599, 125–135. doi:10.1016/j.chroma.2019.04.008
Yuan, Q., Wang, J. X., Li, R. L., Jia, Z. Z., Wang, S. X., Guo, H., et al. (2021). Effects of salvianolate lyophilized injection combined with Xueshuantong injection in regulation of BBB function in a co-culture model of endothelial cells and pericytes. Brain Res. 1751, 147185. doi:10.1016/j.brainres.2020.147185
Zang, Q., Gao, Y., Huang, L., He, J., Lin, S., Jin, H., et al. (2018). Rapid and sensitive liquid chromatography-tandem mass spectrometric method for the quantitative determination of potentially harmful substance 5,5'-oxydimethylenebis (2-furfural) in traditional Chinese medicine injections. Acta Pharm. Sin. B 8 (2), 235–241. doi:10.1016/j.apsb.2017.11.002
Zeng, C., Liao, Q., Hu, Y., Shen, Y., Geng, F., and Chen, L. (2019). The role of Periplaneta americana (blattodea: Blattidae) in modern versus traditional Chinese medicine. J. Med. Entomology 56 (6), 1522–1526. doi:10.1093/jme/tjz081
Zeng, J., Zheng, S. Z., Chen, Y. Z., Qu, Y. M., Xie, J. Y., Hong, E. H., et al. (2021). Puerarin attenuates intracerebral hemorrhage-induced early brain injury possibly by PI3K/Akt signal activation-mediated suppression of NF-kappa B pathway. J. Cell. Mol. Med. 25 (16), 7809–7824. doi:10.1111/jcmm.16679
Zhang, L., Wang, Y., Li, C., Shao, C., Zhou, H., Yang, J., et al. (2020a). Dan hong injection protects against cardiomyocytes apoptosis by maintaining mitochondrial integrity through keap1/nuclear factor erythroid 2-related factor 2/JNK pathway. Front. Pharmacol. 11, 591197. doi:10.3389/fphar.2020.591197
Zhang, S., Zhang, L., Zhang, H., Fan, G., Qiu, J., Fang, Z., et al. (2017). Hongjingtian injection attenuates myocardial oxidative damage via promoting autophagy and inhibiting apoptosis. Oxidative Med. Cell. Longev. 2017, 6965739. doi:10.1155/2017/6965739
Zhang, Y. M., Qu, X. Y., Tao, L. N., Zhai, J. H., Gao, H., Song, Y. Q., et al. (2020b). XingNaoJing injection ameliorates cerebral ischaemia/reperfusion injury via SIRT1-mediated inflammatory response inhibition. Pharm. Biol. 58 (1), 16–24. doi:10.1080/13880209.2019.1698619
Zhang, Y. M., Qu, X. Y., Zhai, J. H., Tao, L. N., Gao, H., Song, Y. Q., et al. (2018). Xingnaojing injection protects against cerebral ischemia reperfusion injury via PI3K/Akt-Mediated eNOS phosphorylation. Evid. Based Complement. Altern. Med. 2018, 2361046. doi:10.1155/2018/2361046
Zhao, C., Li, X., Li, X., Xu, Y., Ma, M., Wang, S., et al. (2019a). Salvianolate lyophilized injection (SLI) strengthens blood-brain barrier function related to ERK1/2 and Akt signaling pathways. Brain Res. 1720, 146295. doi:10.1016/j.brainres.2019.06.014
Zhao, C. X., Liu, H., Miao, P. Q., Wang, H. E., Yu, H. S., Wang, C. H., et al. (2019b). A strategy for selecting "Q-Markers" of Chinese medical preparation via components transfer process analysis with application to the quality control of Shengmai injection. Molecules 24 (9), 1811. doi:10.3390/molecules24091811
Zhao, X., He, Y., Zhang, Y., Wan, H., Wan, H., and Yang, J. (2022). Inhibition of oxidative stress: An important molecular mechanism of Chinese herbal medicine (Astragalus membranaceus, Carthamus tinctorius L., radix Salvia miltiorrhizae, etc.) in the treatment of ischemic stroke by regulating the antioxidant system. Oxidative Med. Cell. Longev. 2022, 1425369. doi:10.1155/2022/1425369
Zhao, X., Zhang, F., and Wang, Y. (2017). Proteomic analysis reveals Xuesaitong injection attenuates myocardial ischemia/reperfusion injury by elevating pyruvate dehydrogenase-mediated aerobic metabolism. Mol. Biosyst. 13 (8), 1504–1511. doi:10.1039/c7mb00140a
Zheng, Q. H., Li, X. L., Mei, Z. G., Xiong, L., Mei, Q. X., Wang, J. F., et al. (2017). Efficacy and safety of puerarin injection in curing acute ischemic stroke A meta-analysis of randomized controlled trials. Medicine 96 (1), e5803. doi:10.1097/MD.0000000000005803
Zhong, C. J., Jiang, C., Ni, S. Y., Wang, Q. Z., Cheng, L. G., Wang, H., et al. (2020). Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics. Acta Pharm. Sin. B 10 (9), 1694–1708. doi:10.1016/j.apsb.2019.12.011
Zhong, C., Lin, Z., Ke, L., Shi, P., Li, S., Huang, L., et al. (2021). Recent research progress (2015-2021) and perspectives on the pharmacological effects and mechanisms of tanshinone IIA. Front. Pharmacol. 12, 778847. doi:10.3389/fphar.2021.778847
Zhou, J., Zhang, L., Zheng, B., Zhang, L., Qin, Y., Zhang, X., et al. (2020). Salvia miltiorrhiza bunge exerts anti-oxidative effects through inhibiting KLF10 expression in vascular smooth muscle cells exposed to high glucose. J. Ethnopharmacol. 262, 113208. doi:10.1016/j.jep.2020.113208
Zhou, M. X., Ren, P., Li, S. A., Kang, Q. F., Zhang, Y., Liu, W. H., et al. (2019). Danhong injection attenuates high-fat-induced atherosclerosis and macrophage lipid accumulation by regulating the PI3K/AKT insulin pathway. J. Cardiovasc. Pharmacol. 74 (2), 152–161. doi:10.1097/FJC.0000000000000691
Zhu, J., Ye, Q., Xu, S., Chang, Y. X., Liu, X., Ma, Y., et al. (2019). Shengmai injection alleviates H2O2induced oxidative stress through activation of AKT and inhibition of ERK pathways in neonatal rat cardiomyocytes. J. Ethnopharmacol. 239, 111677. doi:10.1016/j.jep.2019.01.001
Zhu, T., Meng, X. B., Dong, D. X., Zhao, L. Y., Qu, M. W., Sun, G. B., et al. (2021). Xuesaitong injection (lyophilized) combined with aspirin and clopidogrel protect against focal cerebral ischemic/reperfusion injury in rats by suppressing oxidative stress and inflammation and regulating the NOX2/IL-6/STAT3 pathway. Ann. Palliat. Med. 10 (2), 1650–1667. doi:10.21037/apm-20-1681
Zou, J. B., Zhang, X. F., Wang, J., Wang, F., Cheng, J. X., Yang, F. Y., et al. (2018). The therapeutic efficacy of danhong injection combined with percutaneous coronary intervention in acute coronary syndrome: A systematic review and meta-analysis. Front. Pharmacol. 9, 550. doi:10.3389/fphar.2018.00550
Keywords: Chinese herbal injection, cardio-cerebrovascular diseases, clinical application, pharmacological effects, traditional Chinese medicine
Citation: Huajuan J, Xulong H, Bin X, Yue W, Yongfeng Z, Chaoxiang R and Jin P (2023) Chinese herbal injection for cardio-cerebrovascular disease: Overview and challenges. Front. Pharmacol. 14:1038906. doi: 10.3389/fphar.2023.1038906
Received: 07 September 2022; Accepted: 13 February 2023;
Published: 24 February 2023.
Edited by:
Hai-Dong Guo, Shanghai University of Traditional Chinese Medicine, ChinaReviewed by:
Hui Cui, Guangzhou University of Chinese Medicine, ChinaPeter Akah, University of Nigeria, Nsukka, Nigeria
Copyright © 2023 Huajuan, Xulong, Bin, Yue, Yongfeng, Chaoxiang and Jin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ren Chaoxiang, NzY0NzkzOTUwQHFxLmNvbQ==; Pei Jin, cGVpeGppbkAxNjMuY29t
†These authors have contributed equally to this work