Expert Consensus on the Clinical Application of Tianma Xingnao Capsule in the Treatment of Vascular Cognitive Impairment and Neuropathic Headache

Yaming LIN, Wei CHEN, Linyuan HU, Zhifang DUAN

Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming 650021, China

Abstract The prescription of Tianma Xingnao Capsule is composed of Gastrodiae Rhizoma, Pheretima, Acori Tatarinowii Rhizoma, Polygalae Radix, Rehmanniae Radix Praeparata, and Cistanches Herba.It has effects of nourishing liver and kidney, dredging collaterals and relieving pain.More than 20 years of clinical application and evidence-based medical research have shown that Tianma Xingnao Capsule has a significant therapeutic effect on vascular cognitive impairment and neuropathic headache.In order to further guide the proper clinical use of this prescription, the consensus expert group conducted a comprehensive analysis of the prescription of Tianma Xingnao Capsule.Combining the existing evidence-based medicine evidence and the experience of clinical experts, this consensus report standardized the usage, dosage, duration and safety of Tianma Xingnao Capsule in the treatment of vascular cognitive impairment and neuropathic headache.It is expected to provide a theoretical basis for clinically reasonable and safe use of Tianma Xingnao Capsule.

Key words Tianma Xingnao Capsule, Vascular cognitive impairment(VCI), Neuropathic headache, Expert consensus

1 Introduction

With the escalation of the aging population worldwide, cognitive impairment and dementia has become a major public health concern.Vascular cognitive impairment(VCI)is recognized as the most common type of dementia after Alzheimer’s disease(AD).The number of VCI patients accounts for about 15%-20% of the total number of dementia patients.Domestic epidemiological studies have shown that the prevalence of VCI among 65-year-olds in China is about 8.7%.It is a serious threat to human health, and it is also a great consumption of economic investment in health resources.Neuropathic headache is mainly induced by nervousness and emotional agitation.After the onset of neuropathic headache, it is mostly manifested as persistent pain in the head and a sense of pressure, which can be unilateral or bilateral, and it is more common in both sides.Neuropathic headache is characterized by recurrence and difficult radical treatment.It brings serious disturbance to patients’ study, work and daily life.

Tianma Xingnao Capsule is derived from classic prescriptions and refined with modern pharmaceutical technology.Clinically, it is used for treating headache, dizziness, memory loss, insomnia, unresponsiveness, tinnitus, backache caused by liver and kidney deficiency.A number of studies have shown that Tianma Xingnao Capsule has a significant preventive effect on diseases such as vascular cognitive impairment and neuropathic headache.In order to guide clinical application more scientifically and rationally, it is necessary to prepare this Expert Consensus on the Clinical Application of Tianma Xingnao Capsule in the Treatment of Vascular Cognitive Impairment and Neuropathic Headache for reference.

2 Scope

This consensus specifies the key issues of Tianma Xingnao Capsule in the treatment of VCI and neuropathic headache, such as the dosage, duration of treatment, precautions, safety, and recommendations for use.It is suitable for medical staff in clinical hospitals at all levels to provide guidance and reference for their rational use of Tianma Xingnao Capsule.

3 Basic information of the drug

3.1 Drug prescription and efficacyThe prescription of Tianma Xingnao Capsule is composed of Gastrodiae Rhizoma, Pheretima, Acori Tatarinowii Rhizoma, Polygalae Radix, Rehmanniae Radix Praeparata, and Cistanches Herba.It has effects of nourishing liver and kidney, dredging collaterals and relieving pain[1-2].According to the records ofChinesePharmacopoeia[3], Gastrodiae Rhizoma has functions of extinguishing wind to arrest convulsions, stabilizing the liver-yang, and dispelling wind to free the collateral vessels and can be used for treating convulsions in children, epilepsy and convulsions, tetanus, headache, dizziness, hand and foot failure, numbness of the limbs, rheumatic arthralgia.Pheretima has functions of clearing heat and settling fright, calming panting and relieving strangury and is used for treating high fever, dizziness, convulsions, arthralgia, numbness, hemiplegia, pulmonary heat, cough, edema and oliguria.Acori Tatarinowii Rhizoma(shi chang pu)has functions of opening the orifices to sweep phlegm, resolving dampness and increasing the appetite, and is often used for treating dizziness, epilepsy, forgetfulness, insomnia, tinnitus and deafness, gastric stuffiness and diarrhea.Polygalae Radix has functions of tranquilizing and coordinating the heart and kidney, dispelling phlegm, and alleviating edema, and is often used for treating profuse dreaming due to heart and kidney non-interaction, forgetfulness and palpitations, trance, unsatisfactory expectoration, swollen sores, swelling and painful breasts.Rehmanniae Radix Praeparata has functions of tounifying blood and nourishing yin, nourishing essence and filling marrow and is used for treating blood deficiency and chlorosis, heart palpitations, irregular menstruation, uterine bleeding, liver and kidney yin deficiency, waist and knee weakness, bone steaming and hot flashes, night sweats and nocturnal emission, internal heat to quench thirst, dizziness, tinnitus, early white hair.Cistanches Herba has functions of nourishing kidney yang and benefiting essence and blood, moistening the intestines and relaxing the bowels, and is used for treating kidney yang deficiency, deficiency of essence and blood, impotence and infertility, sore waist and knees, weak muscles and bones, dry intestines and constipation.

3.2 Prescription analysisTianma Xingnao Capsule has the effects of nourishing liver and kidney, freeing the collateral vessels and relieving pain.It is used for headache, dizziness, memory loss, insomnia, slow response, tinnitus, backache caused by liver and kidney deficiency.In the prescription, Gastrodiae Rhizoma is the monarch drug.It is sweet in taste and calm in nature.It enters liver meridian, and can calm the liver, eliminate wind and stop spasm.Pheretima is salty in taste and enters the liver, stomach, lung and bladder meridian, and has effects of clearing heat and calming liver, extinguishing wind and relieving spasm, freeing the collateral vessels, removing numbness and relieving pain.Acori Tatarinowii Rhizoma is pungent and bitter, and slightly warm in nature, enters the heart, liver and spleen meridians, and has functions of opening the orifices to sweep phlegm, reducing dampness and promoting flow of qi, expelling wind and numbness, reducing swelling and relieving pain.Polygalae Radix is bitter and pungent in taste, and mild in nature, enters heart, kidney, and lung meridians, and has functions of tranquilizing, removing phlegm, and reducing swelling.Rehmanniae Radix Praeparata is sweet in taste and slightly warm in nature, enters liver and kidney meridians, and has effects of nourishing blood and benefiting the essence and filling the marrow.Cistanches Herba is sweet and salty in taste and warm in nature, and has effects of nourishing the kidney yang and benefiting the essence and blood[4].Combination of these medicines achieves the functions of nourishing the liver and kidney, calming liver, extinguishing wind, and freeing the collateral vessels and relieving the pain.

4 Pharmaceutical Research

4.1 Overview of the pharmacological research on the components of the prescriptionAccording to findings of modern pharmacological studies, Gastrodiae Rhizoma can regulate blood flow speed, maintain blood vessel tension, improve low endothelin status, inhibit the up-regulation of NO and β-endorphin levels, restore neuropeptides to a steady state, and play a role in treating headaches[5-6].Gastrodin, the active component of Gastrodiae Rhizoma, has the pharmacological effects of antioxidant, inhibiting the neurotoxicity of excitatory amino acids, improving circulation, and increasing cerebral blood flow.Besides, it can significantly inhibit the activity of AchE in the brain, increase the activity of choline acetyltransferase, remove superoxide in the brain tissue, and promote the self-repair of brain cells, thereby playing a brain-protective role in the progression of vascular dementia[7-8].Pheretima has a protective effect on cerebral ischemia-reperfusion injury[9], as well as sedative, hypnotic and anticonvulsant effects[10].Its active component lumbrokinase(LK)can improve blood rheology and coagulation in patients with vascular dementia, reduce fibrinogen, and achieve the effect of treating vascular dementia[11-12].The combination of Acori Tatarinowii Rhizoma and Polygalae Radix can significantly increase the activity of superoxide dismutase in the brain tissue of rats, inhibit the production of malondialdehyde and NO, thereby reducing brain tissue damage caused by free oxygen, and improving and delaying aging[13].Hypertension, arteriosclerosis and obstruction of cerebral circulation are the main factors leading to cerebrovascular dementia.Acori Tatarinowii Rhizoma and Polygalae Radix contain a lot of oleic acid and linoleic acid, and oleic acid can lower blood total cholesterol and low-density lipoprotein cholesterol, and play a significant role in the prevention and treatment of coronary heart disease, hypertension and other cardiovascular diseases.Linoleic acid can reduce cholesterol levels in serum and liver, and inhibit the formation of arterial thrombosis, prevent myocardial infarction, thereby reducing the incidence of vascular dementia[14].The volatile oil components such as α-asarone and β-asarone in Acori Tatarinowii Rhizoma can act on the central nervous system and have anti-depressant, brain-stimulating, anti-hypoxic effects, as well as hypnotic, sedative, and anti-convulsant effects, intelligence benefiting and brain protective functions, so as to effectively treat vascular dementia[15].The ketones in Polygalae Radix have obvious analgesic effects and can inhibit hyperalgesia caused by bradykinin and substance P[16].Rehmanniae Radix Praeparata can prolong the action time of pentobarbital sodium and thiopental sodium at subthreshold hypnotic doses, and it can also antagonize the excitatory and convulsive effect of isoniazid on mice, suggesting that Rehmanniae Radix Praeparata has a certain central inhibitory effect[17].In addition, Rehmanniae Radix Praeparata can enhance the human hematopoietic function, regulate immunity, and enhance memory and anti-aging effects[18].

4.2 Pharmacodynamic research

4.2.1Improving learning and memory function.Tianma Xingnao Capsule can inhibit the up-regulation of MDA level in rat brain tissue, reduce AChE activity, and inhibit the increase of lipofuscin content in brain tissue, suggesting that Tianma Xingnao Capsule can improve the learning and memory function of memory impairment model animals through a variety of ways, and its action mechanism may be related to reducing the activity of AChE in brain tissue and inhibiting lipid peroxidation[19-20].

4.2.2Effects on blood circulation.Tianma Xingnao Capsule can significantly inhibit AA or ADP-induced platelet aggregation in rabbits, indicating that it has strong anti-platelet aggregation effects and can prevent and treat thromboembolic diseases with increased platelet aggregation[21-22].In addition, Tianma Xingnao Capsule can significantly increase cerebral blood flow, prolong the panting time of mice after decapitation, significantly increase the content of Evans in brain tissue, and can promote the dilation of auricular arterioles, venules and auricular capillaries in mice[23-24].

4.2.3Neuroprotective effect.Tianma Xingnao Capsule can significantly promote the recovery of EEG potential amplitude during reperfusion, and reduce the content of water and calcium in the cortex of gerbils after 5 d of reperfusion in a dose-dependent manner[25].

4.2.4Anti-dizziness and analgesic effect.Related pharmacological experiments show that Tianma Xingnao Capsule can significantly prolong the licking time of hot-plate-induced pain model mice, and inhibit the writhing response of acetic acid-induced pain model mice, suggesting that Tianma Xingnao Capsule may exert an anti-hypoxic effect by expanding the cerebral blood vessels, which is conducive to preventing and treating dizziness and headache caused by hypoxia in the brain tissue[26].

4.2.5Sedative and hypnotic effects.Tianma Xingnao Capsule can cooperate with the inhibitory effect of chlorpromazine on autonomous activities in mice, inhibit the excitatory effect of amphetamine-induced autonomous activities, enhance the effect of pentobarbital sodium in inducing mice to fall asleep, and prolong sleep time[26].

4.3 Toxicological research(i)Acute toxicity research: The maximum tolerated dose of Tianma Xingnao Capsule administered to mice was greater than 15.4 g/kg, which has reached 385 times the clinical dose of 40 mg/kg, but no obvious toxicity is seen[27].(ii)Long-term toxicity research: Long-term toxicity experiment of Tianma Xingnao Capsule in rats by intragastric administration for 26 weeks.The doses were 1, 2, 4 g/(kg·d)(25, 50, and 100 times the usual clinical dose), and the results showed no obvious toxic reaction, no abnormal changes in organ function and histology and no delayed toxicity reaction was observed[27].

5 Overview of clinical research evidences

5.1 Vascular cognitive impairment(VCI)A randomized controlled experiment of 180 patients with mild to moderate vascular dementia(deficiency of liver and kidney, upper harassment of liver wind)was carried out.The experimental group was given Tianma Xingnao Capsule, with the Compound Congrong Yizhi Capsule as the control drug.The results indicate that the efficacy of the Alzheimer’s Disease Assessment Scale-Cognitive(ADAS-cog), Vascular Dementia Syndrome Differentiation Scale, and Mini-Mental State Examination(MMSE)in the experimental group were 71.11%, 91.11%, and 80.00%, respectively, all significant higher than 62.22%, 77.78%, and 20.00% of the control group(P<0.05), suggesting that Tianma Xingnao Capsule can improve the cognitive function of patients with mild to moderate vascular dementia, improve concentration, and also significantly improve the symptoms of dizziness and tinnitus in patients, and it is better than Compound Congrong Yizhi Capsule of the control group compound[28].Lai Jianmingetal.[29]selected 121 VCI patients and divided them into experimental group and control group using the random number table method, and both groups were given conventional treatment.The experimental group was given Tianma Xingnao Capsule, 0.8 g/time, 3 times/d, and the control group was given Aniracetan Capsules.The cognitive function of the two groups was observed before and after treatment(MoCA scale, MMSE scale, ADL-R scale), Vascular dementia symptom score(SDSVD)(TCM syndrome scale)and other curative effect indicators.The results show that Tianma Xingnao Capsule can enhance cognitive ability of patients, improve clinical symptoms, effectively treat VCI and have high safety.The combined use of Tianma Xingnao Capsule and Oxiracetam Capsules has a definite clinical effect on improving the cognitive dysfunction of stroke patients.Compared with the control group, the MMES and ADL scores of the combination group were significantly better than those of the control group(P<0.05), and the total effective rate was 85.71%, which was significantly higher than 73.53% of the control group(P<0.05)[30].Furthermore, Tianma Xingnao Capsule can also be used to treat cognitive dysfunction caused by brain trauma.According to the study of Li Puyangetal.[31], Tianma Xingnao Capsule can improve the MMSE and ADL scores of patients with cognitive impairment in traumatic brain injury, and compared with the control group, there is a statistical difference(P<0.01), with a total effective rate of 84.6%, significantly better than 61.8% of the control group(P<0.05).

5.2 Neuropathic headacheA clinical experiment of vascular neuropathic headache showed that after 4 weeks of treatment, the total effective rate of Tianma Xingnao capsule group was significantly better than that of the control group(ibuprofen + flunarizine capsule)(P<0.05)[32].Many other studies have shown that Tianma Xingnao Capsule combined with flunarizine capsule has significant clinical effects in the treatment of vascular neuropathic headaches and can significantly improve headache symptoms of patients[33-36].Dai Nan and Du Jumei[37]used a randomized, double-blind, parallel-controlled, multi-center clinical research method, taking 140 patients with chronic tension-type headache(deficiency of liver and kidney, upper harassment of liver wind)as the research objects, and the experimental group was taken orally Tianma Xingnao Capsule, the control group was given Compound Gouteng Tablet.They found that compared with the control group, the experimental group can significantly reduce headache symptoms, improve TCM syndromes, and improve the life quality of patients, and the total effective rate is significantly higher than that of the control group(P<0.05).

6 Recommendations for clinical application

6.1 VCI

6.1.1VCI is a common complication of cerebrovascular disease, ranging from mild cognitive impairment to dementia.The cause of VCI is complex, and symptomatic treatment is required once clinically confirmed.At present, Western medicine does not have any specific drugs, but it only improves memory and cognitive functions, delays the progression of the disease, improves the life quality of patients, and prolongs life.

6.1.2Commonly used therapeutic drugs are as follows.(i)Activator that improves and promotes blood circulation in the brain and brain cell metabolism, dilates blood vessels and increase cerebral blood flow, thereby increasing the utilization of cerebral blood oxygen and glucose, and improving memory.(ii)Neuroprotective agents, such as nimodipine.(iii)Cholinesterase inhibitors, such as donepezil, rivastigmine,etc.(iv)Estrogen replacement can enhance the activity of neurotransmitters such as acetylcholine, activate nerve growth factors, promote and maintain the growth of nerve function, and protect brain cells.At present, the application of integrated traditional Chinese and western medicine to treat the VCI is the most commonly used clinical method.Studies have shown that traditional Chinese medicine has a clear clinical effect in improving the cognitive function and improving the recovery of patients with mild to moderate vascular dementia.Tianma Xingnao Capsule has the effects of nourishing liver and kidney, freeing the collateral vessels and relieving pain.In addition, pharmacological studies have shown that Tianma Xingnao Capsule can improve cerebral blood circulation, increase the utilization of cerebral blood oxygen and glucose, inhibit cholinesterase activity, and has a definite effect on headache, dizziness and memory loss caused by liver and kidney deficiency.

6.1.3Treatment methods.For mild to moderate VCI patients, Tianma Xingnao Capsule can be used alone or in combination with conventional western medicine, and Tianma Xingnao Capsule can be used orally, 2 capsules/time, 3 times/d.The recommended course of treatment is 6 months to prevent mild of cognitive impairment into the course of dementia.For the treatment of severe cognitive impairment patients, it is recommended to combine western medicines with Tianma Xingnao Capsule.

6.2 Neuropathic headache(i)Neuropathic headaches mainly refer to tension headaches, functional headaches and vascular neuropathic headaches, which are mostly caused by mental tension or anger.The symptoms mainly include persistent head pain, pressure, and heaviness.Some patients complain that they have a "tightening feeling" on the head.Most patients have bilateral headaches, mostly on both sides, posterior occiput and top of the head or the entire head.The neuropathic headache is characterized by a long course, unclear etiology, difficult to treat and prone to recurring attacks, which affect the life quality of patients.(ii)There are no clinically effective drugs and methods for the treatment of this disease.At present, the clinical treatment is mostly combined with traditional Chinese and western medicine, and the effect is better than that simply using western medicine.Western medicines for the treatment of neuropathic headache mainly symptomatic treatment, and commonly used drugs include vasoconstrictors, magnesium preparations, calcium antagonists, analgesics, anti-anxiety and sedatives.(iii)Treatment method: Tianma Xingnao Capsule can be taken orally combined with western medicine treatment, 2 capsules/time, 3 times/d, and the recommended course of treatment is 3 months.

7 Safety

The previous clinical research and adverse reaction monitoring results show that the incidence of adverse reactions of Tianma Xingnao Capsule is low, mainly due to gastrointestinal discomfort, which can be relieved by itself.

8 Precautions and instructions

(i)Avoid smoking, alcohol and spicy and pungent food.(ii)For hypertensive headaches and unexplained headaches, please go to hospital to seek medical advice.Supplementary instructions: VCI and neuropathic headache are often accompanied by hypertension, so it is necessary to analyze the content of this article in depth.Tianma Xingnao Capsule has been put on the market for a long time, the blood pressure control measures were insufficient at that time.In addition, due to insufficient research on the Cistanches Herba in the prescription at the time of the market, it is believed that the drug is a tonic drug with a warm nature and sweet taste, which may lead to a rise in blood pressure and increase the risk of cerebrovascular accidents.However, with the development of science and the in-depth research on the prescription Chinese medicinal materials of Tianma Xingnao Capsule, it is now generally believed that Cistanches Herba will not raise blood pressure, and with the continuous improvement of blood pressure control drugs, blood pressure has been basically controlled.Therefore, Tianma Xingnao Capsule can be used for long-term treatment when the blood pressure is basically stable.Moreover, extensive animal and clinical application cases have proved that the drug has the effects of nourishing liver and kidney, freeing collateral vessels and relieving pain, and has significant effects on improving blood pressure and headaches that are accompanied by patients with hypertension.(iii)Patients with chronic diseases such as heart disease, diabetes, liver disease, and kidney disease should take it under the guidance of a physician.(iv)This drug should not be taken for a long time.If the symptoms are not relieved after taking for 3 d, please go to the hospital for treatment.Supplementary instructions: It means that the patient cannot take this drug for a long time by himself.The symptoms are not relieved after taking the medicine for 3.The patient should go to the hospital for treatment.The headache is considered to be complicated.If the patient takes the drug for a long time without a diagnosis, it may cause delays in the condition.Therefore, if the physician judges the application of the drug based on the patient’s condition, the patient may take Tianma Xingnao Capsule for a long time and there will be no adverse reactions.(v)Strictly follow the usage and dosage.The elderly and infirm should take it under the guidance of a physician.(vi)People who are allergic to this drug are forbidden to use it with caution.(vii)It is forbidden to take this drug when its properties have been changed.(viii)If other medicines are taken at the same time, please consult your physician or pharmacist before using this drug.

9 Prospects

In recent years, both domestic and foreign studies on traditional Chinese medicine(TCM)have continued to deepen, and traditional Chinese medicine has also played an important role in many medical fields.The unique syndrome differentiation and medication system of TCM is based on the broad medical cognitive system of syndromes.It is based on the treatment of disease and pathogenesis.It is also the theoretical basis of TCM for treating different diseases with the same methods.Tianma Xingnao Capsule can not only treat the VCI and neuropathic headache, but also improve neurotic tinnitus and vertigo symptoms.It has created a new application field in the treatment of cerebral infarction and vertebrobasilar arterial insufficiency.

Chief Clinical Expert:Lin Yaming(Yunnan Provincial Hospital of Traditional Chinese Medicine).

Consensus Expert Group:Ding Yanbing(Hubei Provincial Hospital of Traditional Chinese Medicine); Wang Jian(Affiliated Hospital of Changchun University of Chinese Medicine); Lu Yun(Affiliated Hospital of Chengdu University of Traditional Chinese Medicine); Qiao Lijun(Guangdong Provincial Hospital of TCM); Li Lejun(Wuxi Traditional Chinese Medicine Hospital); Liu Xiangzhe(The First Affiliated Hospital of Henan University of TCM); An Hongwei(Liuzhou Traditional Chinese Medicine Hospital); Shi Jing(Dongzhimen Hospital of Beijing University of Chinese Medicine); Zou Wei(The First Affiliated Hospital of Heilongjiang University of Chinese Medicine); Wang Han(The First Affiliated Hospital of Anhui University of Chinese Medicine); Lin Yaming(Yunnan Provincial Hospital of Traditional Chinese Medicine); Zhao Yuanqi(Guangdong Provincial Hospital of TCM); Zhou Zhen(The Second Affiliated Hospital of Tianjin University of TCM); Zhou Ziyi(Guangdong Provincial Hospital of TCM); Yu Xiaofei(Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine); Zhao Min(The First Affiliated Hospital of Henan University of TCM); Guo Jianwen(Guangdong Provincial Hospital of TCM); Guo Zengyuan(Inner Mongolia Autonomous Region Hospital of Traditional Chinese Medicine); Zhao Yang(The Third Affiliated Hospital of Nanjing University of Chinese Medicine); Gao Ying(Shenyang Second Hospital of Chinese Medicine); Chang Jingling(Dongzhimen Hospital of Beijing University of Chinese Medicine); Huang Hongmin(Hainan Provincial Hospital of Traditional Chinese Medicine); Han Zucheng(Shanxi Hospital of Traditional Chinese Medicine); Jiao Liming(Shanxi Provincial Hospital of Traditional Chinese Medicine); Lei Li(Beibei Traditional Chinese Medical Hospital in Chongqing); Cai Yefeng(Guangdong Provincial Hospital of TCM).

Consensus Secretary Group:Chen Wei(Yunnan Provincial Hospital of Traditional Chinese Medicine); Hu Linyuan(Yunnan Provincial Hospital of Traditional Chinese Medicine).

Conflicts of interest

There are no conflicts of interes.