Parkinson’s disease (PD) is a chronic progressive degenerative disease occurring in middle and old age, with the rapid arrival of aging, bringing an increasingly heavy economic and social burden to the world, especially in China, reviewing the current status of Chinese and Western medicine diagnosis and treatment of Parkinson’s disease, because in the current anti-Parkinson’s disease drug therapy can only control the symptoms to a certain extent, but to alleviate The rate of progression of Parkinson’s disease needs to be further studied, and the side effects are quite disturbing to some patients, and it is possible to stop the use of anti-Parkinsonian drugs due to side effects. Existing relevant studies have shown that TCM has some effect on slowing down the progression of PD, and can somehow delay the use of dopamine preparations, delay the rate of increment of dopamine preparations, and to some extent solve the problem of adverse reactions to western drugs and the inability to adhere to the medication due to tolerance of the drugs. The advantages of Chinese medicine in the treatment of this disease are: (1) Chinese medicine is a natural medicine with minimal toxic side effects; (2) it can be taken for a long time; (3) the epistemology and methodology of Chinese medicine is different from Western medicine, and its holistic concept, whole-body adjustment and individualized treatment according to the person’s needs have the potential to treat the disease at its root. However, its disadvantage lies in the slower improvement of symptoms. Parkinson’s disease is a progressive disease, and the application of anti-Parkinsonian drugs is eventually inevitable. Therefore, the use of Western drugs should be used with the use of Chinese medicine at the beginning, can take a combination of drugs, play the role of the respective links and advantages of Chinese and Western drugs, in order to achieve the purpose of increasing the effectiveness of reducing the toxic side effects of Western drugs. Therefore, it is imperative to carry out the identification and treatment of this disease with Chinese medicine. In the combination of Chinese and Western medicine treatment plan, on the basis of using anti-Parkinsonian drugs to ensure a certain degree of symptom control, the use of Chinese medicine treatment, from which to explore the exact efficacy of different prescriptions on Parkinson’s disease, among the many prescriptions to seek a regular use of drugs to guide clinical, to explore how much Chinese medicine can reduce the dose and number of Western drugs, how many times to reduce the degree? How can the safety of treatment be ensured after reducing the number of medications? What is the quality of life? All these questions need to be studied systematically and prospectively.
The current status of domestic and foreign research and development trend.
1.Epidemiological research
Parkinson’s disease, also known as tremor paralysis (paralysis agitans), was first described by British physician James Parkinson (1817), mainly occurs in middle-aged and elderly people over 50 years old, is a common chronic progressive neurodegenerative disease in the elderly. A random sample survey conducted in Beijing, Shanghai and Xi’an from 1997 to 1998 led by Zhang Zhenxin of Peking Union Medical College Hospital showed that the prevalence of Parkinson’s disease among 29,454 residents aged 55 years or older in the population aged 65 years or older was 1.7% (2.74% for those aged 75-84 years and 4.07% for those aged 85 years or older), similar to foreign reports, which estimated that Chinese The prevalence of Parkinson’s disease in China is estimated to be about 1.7 million [1]. Its prevalence increases with age and is estimated to be about 254/100,000 population between the ages of 75 and 84 years, and the number of patients with Parkinson’s disease in China is now more than 2 million [2-3]. While China’s population is aging at a faster rate, the population aged 65 years and above (88.11 million people) accounted for 6.96% of the total population in the fifth national census in 2000, and the population aged 65 years and above increased by 12.34 million (100.45 million people) in the national 1% population sample survey in 2005, accounting for 7.69% of the total population, an increase of 0.73 percentage points [4]. The new “Research Report on the Forecast of China’s Population Aging Development Trend” by the Office of the National Working Committee on Aging analyzes that from 2001 to 2020 is the stage of rapid aging, and from 2021 to 2050 is the stage of accelerated aging, and the burden of old-age security is becoming increasingly heavy and the increasing pressure of medical and health consumption expenditures of the elderly is the direct aging brings to families, society, and the country responsibility and burden to the family, society and the country [5]. Along with the advent of aging society, the incidence and prevalence of Parkinson’s disease has entered an unprecedented “golden period”, how to correctly assess the impact of Parkinson’s disease on the affected individuals and even society and the country, and formulate reasonable countermeasures to control the negative effects to a minimum, is not only a real-time need to dig a well to quench thirst, but also a proactive one. In 1997, the European Parkinson’s Disease Association (EPDA), with the support of the World Health Organization (WHO), designated April 11 as World Parkinson’s Disease Day. Compared with developed countries in Europe and the United States, we are still relatively weak in terms of social awareness and private support for Parkinson’s disease. Therefore, there are calls for the establishment of a Chinese Parkinson’s Disease Day, which is in line with international standards, and the establishment of support organizations for age-related degenerative diseases, such as the Chinese Parkinson’s Disease Federation, to encourage the establishment of special charitable funds to provide scientific guidance and intervention for patients’ life treatment [6].
2. Current status of Western medical treatment
2.1 Pharmacological treatment of Parkinson’s disease
The pathogenesis of PD is not yet clear, and studies have shown that it is related to genetics, environmental factors, infections, aging, oxidative stress, excessive free radical formation and nerve growth factor deficiency, and is the result of the synergistic effect of multiple mechanisms. Once the clinical symptoms of Parkinson’s disease appear, the dopamine neurons in the nigrostriatal system have been reduced by 60-80%, and neuronal degeneration continues to worsen after the onset of the disease, which is the underlying cause of the progressive clinical course of Parkinson’s disease [7].PD, however, still has no effective therapeutic measures. At the 58th Annual Meeting of the American Academy of Neurology (AAN) held in San Diego, USA, in 2006, ANN issued new guidelines for the diagnosis and treatment of PD. It is worth pointing out that the guidelines list many possible treatments for PD patients, including exercise, physical therapy, and speech therapy, in addition to medications and surgical treatments. Modern medical treatment for Parkinson’s is divided into eight classes of drugs: anticholinergics, levodopa analogs, peripheral decarboxylase inhibitors, dopamine receptor agonists, dopamine receptor enhancers, drugs that block and degrade dopamine catabolism, neuron protective drugs and other drugs. However, levodopa is still the most effective drug for PD treatment and is regarded as the “gold standard” of PD drug therapy. The common side effects of compound levodopa are broadly divided into two categories: (1) peripheral side effects: they appear early and are mostly manifested in gastrointestinal discomfort, such as nausea, vomiting and poor appetite; they are manifested in cardiovascular system symptoms, such as hypertension, arrhythmia and postural hypotension. (2) Central side effects: appear later, mostly after high-dose levodopa treatment, such as end-of-dose phenomenon, switch phenomenon, sleep disorders and anxiety, depression and other psychiatric symptoms. Amantadine has anticholinergic effect and can improve the efficacy of levodopa. However, adverse reactions in the gastrointestinal tract and hematopoietic system can occur. Dopamine agonists nausea incidence 18-36% , symptomatic upright hypotension 5-48% , with the highest incidence of pramipexole and cabergoline, as well as confusion, vertigo 11-37% , hallucinations 10-19% , drowsiness incidence can be above 10, with apomorphine up to 35% [8]. Sometimes these side effects have an even more serious impact on the patient’s quality of life than the original disease. Therefore, it is very important to reduce all kinds of side effects. In addition, it cannot be disregarded that dopamine receptor agonists, which are currently widely used in foreign clinics, are expensive, and most patients in China are unlikely to take them for a long time, which is an important reason why levodopa-based preparations are still used as the drug of choice for Parkinson’s disease in China.
At the same time, studies on drug combination taken due to heavy disease, or/and reduction of adverse drug reactions are not very satisfactory, the exploration of the mechanism of interaction between anti-Parkinsonian drugs is not perfect, and the study of the responsiveness of the body to anti-Parkinsonian drugs in different periods of Parkinson’s disease is not thorough [9-11]. Several domestic multicenter randomized (controlled) trials in recent years have also basically responded to some of the above characteristics of the clinical application of anti-Parkinsonian drugs [12-17].
2.2 Surgical treatment of Parkinson’s disease
The surgical treatment of Parkinson’s disease is broadly divided into ablation surgery and restorative surgery represented by cell transplantation. The former is the removal of specific nuclei and neural pathways that cause abnormal activity through brain localization surgery, and has been using high-frequency thermocoagulation to destroy neural tissue morphologically. Currently, surgical stereotactic thalamic lateral nucleus destruction and pallidum destruction are less used due to many problems such as poor long-term efficacy and many side effects. In recent years, deep brain stimulation (deep brain stimulation, DBS) has become an important method for the surgical treatment of Parkinson’s disease. Deep brain stimulation involves implanting electrodes of a brain stimulation device into the nucleus accumbens, generating electrical pulses through a pulse generator placed subcutaneously in the abdomen or chest to chronically stimulate the nucleus accumbens. The most important advantage of DBS is that it is non-destructive and the parameters can be adjusted to achieve optimal control of symptoms. Moreover, DBS is characterized by fewer side effects and complications than other treatments. Therefore, high-frequency stimulation of the ventral intermediate nucleus of the thalamus (Vim), the medial part of the pallidum (Gpi) and the thalamic floor nucleus (STN) has become an increasingly common alternative to destructive surgery in the last decade. Deep brain stimulation therapy, which began in the early 1990s abroad and has been introduced in China since 2003, has significantly improved the clinical remission rate of the disease, but strict indications also exist for DBS [18], and stimulation cessation can cause rebound of all Parkinson’s disease symptoms [19], and the long-term efficacy is still difficult to determine. In addition, surgical complications should not be ignored, such as electrode displacement from the target site, electrode breakage, skin ulceration at the attachment site, subcutaneous hematoma due to oversized subcutaneous balloon, and other complications due to device implantation. Others, such as bleeding and infection due to excessive intraoperative puncture channels, are complications. Coupled with the fact that DBS is a lifelong treatment that requires lifelong maintenance and follow-up of the patient, and that the stimulator is expensive, it is still difficult to be widely performed in developing countries like China.
Cell transplantation, which aims to reconstruct the function of the damaged neural circuits, is a promising treatment for the future. The first treatment to be implemented clinically was autologous adrenal medulla transplantation, which has been gradually abandoned due to excessive surgical trauma, high surgical mortality, and inaccurate long-term efficacy. fetal brain nigrostriatal transplantation, which was started clinically in the 1980s, has shown some recent efficacy. However, 5-6 fetal donors are required for 1 Parkinson’s patient, and it is unknown how to solve several problems such as limited transplantation donors, low survival rate of transplanted cells, and tumorization. There are also problems of uncertain post-transplant efficacy, immune rejection and post-transplant dyskinesia that need to be addressed. stem cell transplantation therapy, which began in the 1990s, has shown a promising future in which stem cells can be used not only as a replacement resource for dopaminergic neurons lost in Parkinson’s disease patients, but also as target cells for gene therapy. In one study, it was found that an important link in the differentiation from embryonic stem cells to dopaminergic neurons, which drives overexpression of Nurr-1 in mouse embryonic stem cells, most of these cells differentiate into a dopaminergic neuronal phenotype, express their markers, release dopamine in vitro and exhibit electrophysiological properties of dopaminergic neurons [20]. In addition, Swedish scientists found that two genes, Lmx1a and Msx1, play an important role in the formation of midbrain dopaminergic neurons during embryonic development of the central nervous system. lmx1a induces the expression of Msx1, which causes the expression of the preneural protein Ngn2 and neuronal differentiation, and more importantly, the expression of Lmx1a leads to the production of a large number of dopaminergic neurons and the embryonic emergence of the midbrain, demonstrating that Lmx1a and Msx1 are key endogenous determinants of dopaminergic neurons [21]. These studies offer hope for future gene therapy for Parkinson’s disease, but this approach is still at the laboratory research stage and is not yet ready for large-scale clinical application.
Thus, cell replacement therapy using stem cells and others is still in its infancy, and there are many experimental studies and clinical trials to be done before it can be used as an ideal cell replacement resource for clinical treatment of a range of neurodegenerative diseases, including Parkinson’s disease, and further exploration and extensive investigations are needed. The current experimental observations reinforce the hope for stem cells as a potential resource for cell replacement therapy.
2.3 Summary of Western medical treatment for Parkinson’s disease
After the efforts of many experts, in 2006, the Movement Disorders and Parkinson’s Disease Group of the Chinese Medical Association Neurology Branch issued the Guidelines for the Treatment of Parkinson’s Disease, which emphasizes comprehensive and individualized (including staging) treatment, and the applied treatments, whether drugs or surgery, can only improve symptoms, not stop the progression of the disease, much less cure it, and must not magicalize or generalize one treatment measure. Each treatment has its limitations, and to date, there is no realistic and feasible way to completely cure Parkinson’s disease. The goal of drug therapy is to slow disease progression, control symptoms, and extend the number of years of symptom control as long as possible, while minimizing side effects and complications of the drugs [22]. In contrast, the clinical manifestations of advanced Parkinson’s disease (H-Y grades IV to V) are extremely complex, with adverse drug reactions and the involvement of progressive factors in the disease itself. Clinicians should consider the long-term effects of advanced Parkinson’s disease in the early stages of treatment to avoid “mending the fold”. Treatment of patients with advanced Parkinson’s disease continues to seek to improve motor symptoms on the one hand, and to address some of the possible motor complications and non-motor symptoms on the other. Surgery may be considered for those who have early drug therapy that is effective, but whose long-term treatment has significantly diminished, and who have atopic symptoms that are difficult to improve with drug therapy. It should be emphasized that surgery only improves the symptoms, but does not cure the disease. Patients with Parkinson’s superimposed syndrome who do not have primary Parkinson’s disease are contraindications to surgery. Surgery is not recommended for patients who are in the early stages of the disease and who have demonstrated efficacy with drug therapy. Also, education, psychological support, support, nutrition and exercise are emphasized as adjunctive measures in the treatment of Parkinson’s disease that should not be neglected [23].
In conclusion, the clinical treatment of Parkinson’s disease is still drug-based, emphasizing the principles of comprehensive treatment, individualization and staging, and clinical efficacy has been achieved, which is not yet able to hinder disease progression and cure the disease, and its adverse effects and other problems have not been solved. At the same time, the market and demand show that the price and growth rate of anti-Parkinson’s disease drugs continue to climb, the current compound growth rate of this market has reached an average rate of 13%, and by 2010 the global market size is expected to exceed $2.3 billion. Levodopa, which has brought about a fundamental shift in the treatment of Parkinson’s disease, is still the basic drug in this field, and the clinical treatment drugs for Parkinson’s disease are currently dominated by levodopa combination and dopamine agonists, and the major market shares are held by imported drugs and joint ventures, with less market for domestic drugs [24].
3. Analysis of the current status and expectations of Chinese medicine treatment for Parkinson’s disease
By retrieving and analyzing 25 experiments including 620 patients and 810 experimental animals on the treatment of Parkinson’s disease in Chinese medicine from 0l 1994 to 08 2005 in the full-text database of Chinese journals and Wipu Chinese journal database, Zhang Lin et al. concluded that the effect of Chinese medicine in the treatment of Parkinson’s disease is clear and good, with calm medicinal properties and little toxic side effects, while the treatment is still aimed at the control of its symptoms. There is no effective means to slow down the disease process [25].
The advantages and characteristics of TCM are its evidence-based treatment, which is similar to the individualized treatment currently proposed in clinical practice. As previously discussed, for Parkinson’s disease, drug therapy is still the main treatment, emphasizing the combination of comprehensive treatment and individualization, and individualized treatment varies according to the patient’s stage of disease (mostly according to H-Y classification) and combined medication, etc. In advanced patients, due to the characteristics of the disease itself, patients are basically or completely unable to take care of themselves, and it is difficult to save the disease with drug therapy. Therefore, based on the current status of Western medical diagnosis and treatment of Parkinson’s disease and the efficacy of Chinese medicine and combined Chinese and Western medicine in the treatment of Parkinson’s disease and its possible potential characteristic advantages, we believe that patients with early and mid-stage Parkinson’s disease should be treated individually and comprehensively using the evidence-based treatment of Chinese medicine according to their clinical etiology and clinical evidence characteristics, and using multifaceted indicators that can better reflect the characteristic efficacy of Chinese medicine for The comprehensive efficacy of Chinese medicine and its safety evaluation.
The State Food and Drug Administration announced on December 31, 2004 the 2004 “National Essential Drugs” (State Food and Drug Administration [2004] No. 266) preparation varieties catalog, Chinese patent medicine for 1260 varieties, there is no proprietary Chinese medicine dedicated to anti-shock paralysis (secondary category) [26]. In the Eleventh Five-Year Plan for the Development of Chinese Medicine, it is pointed out that: to give full play to the advantages of Chinese medicine in the prevention and treatment of major and difficult diseases, to research, optimize and promote the Chinese medicine treatment protocols and efficacy evaluation systems for these diseases, to develop innovative drugs that are safe, effective and controllable, to enhance the independent innovation capability of Chinese medicine and the international competitiveness of the Chinese medicine industry. It is a key task and project to achieve comprehensive, coordinated and sustainable development of TCM and to better serve people’s health. We must build on the existing effective therapies and guidelines of Chinese and Western medicine for the treatment of Parkinson’s disease, use Chinese medicine treatment methods or protocols with proven efficacy, and clarify their efficacy and safety as well as their therapeutic indications through clinical evaluation study designs such as randomized controlled trials, based on the characteristics of different stages of Parkinson’s disease and the treatment of Chinese medicine (individualized) evidence-based interventions and their advantages and disadvantages of Chinese and Western medicine treatment. Form clinical practice guidelines and promote their application nationwide, and gradually standardize the treatment of Parkinson’s disease in the field of using Chinese medicine, and also develop drugs with independent intellectual property rights to serve the majority of Parkinson’s disease patients and continuously improve our competitiveness in the field of Parkinson’s disease treatment.
4. Analysis of the current situation of the evaluation of the efficacy of Parkinson’s disease and the expectation of Chinese medicine intervention research
4.1 Current status of efficacy evaluation of Parkinson’s disease
For the evaluation of the efficacy of TCM intervention in Parkinson’s disease, the Chinese National Association of Traditional Chinese Medicine Geriatrics (CNCTG), with reference to the Webster’s Parkinson’s disease dysfunction equivalence score, after years of clinical practice mapping and summarizing, published the Diagnostic and Efficacy Assessment Criteria for TCM Geriatric Fibrillation (Trial) in 1991 at the 3rd CNCTG Geriatric Brain Disease Symposium, after discussion and demonstration [27 ], which provides a platform for the exchange of research results in the industry, but has not yet fully met the needs of TCM clinical practice. The efficacy criteria developed and used by some national research projects reflect the level of efficacy evaluation research of Parkinson’s disease in China. The National Ninth Five-Year Plan Medical Science and Technology Project (No96-906-05-08) group [28,29] selected some of the motor function scores from the UPDRS combined with Webster scores, and also selected some ADL items to form the ” Motor Function Rating Scale for Parkinson’s Disease (MDRSPD)”, so that the distribution in the scale of the four main disorders of Parkinson’s disease is approximately equivalent and can reflect the motor dysfunction of patients more comprehensively. By assessing the consistency and sensitivity of the scale, it was concluded that it could be used to assess the severity of the disease and the efficacy of treatment in patients with Parkinson’s disease. However, the scale is more subjective in the assessment of limb tonicity and resting tremor, and its precise quantification is not yet satisfactory, so it has not been widely used so far.
4.2 Expected analysis of research on the evaluation of the efficacy of Chinese medicine intervention in Parkinson’s disease
Chinese medicine has distinctive characteristics and unique theoretical system, and the evaluation and confirmation of its clinical efficacy has been a hot spot for research in Chinese medicine. Scholars [30,31] believe that the evaluation system of TCM efficacy should include: (i) evaluation criteria for the efficacy of TCM diseases; (ii) evaluation criteria for the efficacy of TCM evidence; and (iii) a quantitative scale for the evaluation of survival quality in accordance with the characteristics of TCM. And in the combined treatment of Chinese and Western medicine, the advantages of the two types of medicine should be integrated to explore the best integrated treatment of diseases by Chinese and Western medicine (which is superior to both single Western medicine and single Chinese medicine and forms an organic whole), and the characteristics of Chinese medicine in the integrated treatment of Chinese and Western medicine should be evaluated scientifically and objectively. Based on the holistic characteristics of TCM, it is difficult to reflect the efficacy of TCM comprehensively and objectively using a single alternative index. A reasonable selection of intermediate indexes such as important clinical symptoms, combinations of several symptoms, patients’ subjective feelings, overall satisfaction with treatment, and survival quality will help to objectively evaluate the efficacy of TCM interventions.
When evaluating the efficacy of TCM for Parkinson’s disease, the focus should be on its ability to improve the quality of survival. Although the Unified Parkinson’s Disease Rating Scale (UPDRS) contains part of the content of survival quality, it is not a survival quality scale in the strict sense. The British Parkinson’s Disease Measurement Questionnaire (PDQ-39) and Parkinson’s Disease Quality of Survival Questionnaire (PDQL) have been developed abroad for clinical outcome evaluation, of which the PDQ-39 is more commonly used. Universal scales have also been applied abroad: the Nottingham Health Scale (NHP); the “Health Status Questionnaire” (SF-36) for the evaluation of Parkinson’s disease. Due to the different economic, cultural and social backgrounds, foreign scales have failed to adapt to the Chinese context and are difficult to accurately reflect the quality of survival of patients in China. Moreover, the understanding of the content of survival quality in Chinese and Western medicine is not exactly the same, and the dimensions, entries and their expressions of the Western Parkinson’s disease survival quality evaluation scale cannot fully cover the relevant content of Chinese medicine, and do not contain certain important content (symptoms) of Chinese medicine, which makes it difficult to objectively reflect the efficacy of Chinese medicine.
5.Problems and countermeasures
At present, the domestic use of Chinese medicine, Chinese herbal medicine, acupuncture and other therapies in the treatment of Parkinson’s disease, initially showed some efficacy, most of them did not find obvious toxic side effects, and used with Western drugs, most of them have a synergistic effect, and can reduce the toxic side effects of Western drugs. Therefore, Chinese medicine has shown good prospects for the treatment of this disease, and is increasingly valued by patients and physicians. At present, the problems of TCM in the treatment of Parkinson’s disease are: ① lack of multicenter, large sample randomized controlled trial studies of TCM; ② most of the trials do not use unified, domestic and foreign recognized criteria for determining efficacy (such as UPDRS, etc.); ③ the staging of TCM intervention targets is not clear, leading to its ambiguous scope of adaptation; ④ lack of TCM preparations with independent property rights that are suitable for long-term use in Parkinson’s disease; ⑤ The lack of recognized criteria for diagnosis and identification of TCM; (6) failure to reflect the evidence-based treatment of TCM and to combine the characteristics of TCM in research; (7) failure to use efficacy evaluation indexes (systems) that can reflect both clinical reality and the advantages of TCM.
Therefore, based on the existing status of TCM and TCM treatment of Parkinson’s disease, we must adopt safe and effective TCM and TCM treatment methods or protocols, further clarify their efficacy and safety as well as their therapeutic indications through a clinical evaluation study design of a large sample multicenter double-blind randomized controlled trial, form clinical TCM evidence-based treatment protocols and promote their application nationwide, and gradually standardize the treatment of Parkinson’s disease within the field of using TCM [32-35].