Abstract:Parkinson’s disease is a chronic progressive neurodegenerative disease with about 17,000 patients in our country. In the last decade, the treatment options and concepts of Parkinson’s disease have changed considerably due to advances in pharmacologic and surgical treatments for Parkinson’s disease. However, how to treat Parkinson’s disease in a systematic and holistic manner is still an issue that needs to be explored. Based on the current status of the treatment of Parkinson’s disease in China and the latest advances in the current treatment of Parkinson’s disease, this article describes the current strategies and programs that are appropriate for the treatment of Parkinson’s disease. Parkinson’s disease (PD) is a neurological disease commonly seen in middle-aged and old-aged people, and its pathology is characterized by the degeneration and death of dopaminergic neurons in the nigrostriatal system of the midbrain, leading to a reduction of dopamine neurotransmitters in the brain, and the appearance of clinical symptoms such as resting tremor, muscle stiffness, and bradykinesia. Although the cause of the disease is not completely clear and there is no cure for the disease, patients can still maintain their work and self-care ability for a relatively long period of time through rational treatment. This article introduces the current treatment status and progress of PD. First, drug therapy: 1, the principle of drug therapy: PD drug therapy belongs to symptomatic treatment, and in the early stage of its application of most of the side effects, digestive symptoms are the most common, such as nausea, vomiting and so on. Therefore, the application of each anti-PD drug should take a “titration” approach: that is, start with a small dose, slowly increase the dose, in the tolerable side effects of the dose range, to achieve the best therapeutic efficacy will be maintained at the dose of treatment. The “optimal efficacy” should be based on the patient’s specific situation to set the expected therapeutic goals. Generally speaking, there are three levels of therapeutic goals: ①The goal of treatment for young, early-stage PD patients is to maintain or regain the ability to work, i.e., the first goal. These patients are mostly in stages I and II according to the HoehnYahr staging; ② The minimum treatment goal for patients with intermediate and advanced PD is to maintain or restore the ability to take care of themselves, i.e., the second goal. These patients are mostly in stage III according to HoehnYahr staging; ③ The minimum treatment goal for patients with advanced PD is to reduce pain and prolong life, i.e., the third goal. These patients are mostly in stage IV and V according to HoehnYahr staging. 2, the early treatment of PD The development of the treatment program for PD is subject to the following factors, namely, age, severity of the disease, the patient’s economic ability and response to drugs. For newly diagnosed patients with early PD, if the symptoms are mild and do not affect function, they may not take medication first and strengthen functional exercise. When possible, some neuroprotective agents should be taken. Although, there is no definitive neuroprotective drug for PD, the hypothesis of oxidative stress is still an important theoretical theory for the etiology of PD, so patients can be put on antioxidant drugs such as vitamin E, coenzyme Q10, etc. The B-type monoamine oxidase inhibitor (MAO-BI)-silaginin, has a theoretical potential neuroprotective benefit, and also improves the symptoms of PD, delays the application of levodopa, and has a potential neuroprotective effect after diagnosis of PD. application, which can be used after a diagnosis of PD. For patients with motor function, the first step is to determine whether the patient has cognitive dysfunction; if so, levodopa should be used directly; if there is no cognitive dysfunction, age is the primary factor to be considered. For patients younger than 65 years old, non-DA drugs can be considered first: (1) amantadine: the drug has improved the main symptoms of most patients, and it is believed that the drug has a certain effect on the prevention of anisotropia, applicable to patients in the early stages or all stages. However, its effect on tremor is slightly worse, and the efficacy is maintained for a shorter period of time, about several months to more than 1 year. (2) Anticholinergic agents: the commonly used drug is Antan, which has a better effect on tremor, and thus is more suitable for early PD patients with predominantly tremor. The application of this drug should pay attention to the patient’s age and cognitive function. Usually it should be avoided for patients over 65 years old or with cognitive impairment. If, after the above treatment, the desired goal cannot be achieved, or the patient’s condition affects the function, the following two types of drugs should be considered: (1) Dopamine (DA) agonists: Although DA agonists are not as effective as levodopa, due to the ability of this type of drug to delay the application of levodopa and the possible existence of neuroprotective effects, they are now favored for the treatment of early-stage patients, especially for young patients with onset of PD before the age of 40 years. However, due to their ability to delay the application of levodopa and their possible neuroprotective effects, they are now favored for the treatment of early-stage patients, especially those with onset before 40 years of age. Domestic available DA receptor agonists include piribedil (Tysudan), Creepa, and Senforo. Piribedil agonizes D2/D3 DA receptors, and Tysudan is its extended-release agent, which is more effective for tremor, and also improves rigidity and bradykinesia to some extent. It can be taken as 50mg,once to three times daily. The disadvantage is the heavier side effects in the digestive tract, which are not tolerated by a few patients. Sensenflo is a newly released drug in China, which is more effective for tremor and has antidepressant effect. (2) Compound levodopa preparation: This kind of drug is the most efficacious and well-tolerated PD treatment drug, and compound levodopa should be considered to be given when the patient’s symptoms have affected daily life and work. Levodopa should be started at a very low dose, e.g., methyldopa 1/4 tablet three times a day, and then gradually “titrated” to be effective. In the early stages, a daily dose of 300-450 mg of compound levodopa is usually sufficient. The generic form of levodopa is fast-acting and relatively inexpensive. Controlled-release tablets have a long duration of effect and therefore provide good control of symptoms at night. Fixed 3 or 4 times daily dosing is better than pulsatile dosing. As for DA receptor agonists and levodopa preparations, which one to use first depends on the patient’s condition. For patients who are relatively young and mildly ill, DA agonists can be considered, and vice versa for levodopa preparations. If the drug alone is not effective, a combination of drugs can be considered, rather than just increasing the dose of one drug. For patients older than 65 years old or with severe symptoms and obvious functional impairment, levodopa preparation can be used directly, and later, according to the situation, the combined use of DA agonists or other drugs can be considered. 3.Middle and late stage treatment of PD: continuous dopaminergic stimulation (continuousdopaminergicstimulation,CDS)，Generally speaking, the honeymoon period of levodopa is about 5 years, after which complications such as motor fluctuation, anisotropia and psychiatric symptoms will appear. It is believed that the side effects of motor fluctuations are mainly due to the short half-life of levodopa, which causes significant fluctuations in blood and brain concentrations. As the disease progresses, neurons continue to degenerate and their buffering capacity disappears, resulting in pulsatile stimulation of dopamine receptors, which cause excessive high or low activation of the receptors, resulting in various symptoms of motor fluctuations. Therefore, the therapeutic strategy of CDS is proposed, which is the latest advancement in the therapeutic concept of PD. The realization of CDS can be achieved by the following ways: 1, changing the dosage form of levodopa, the mode or route of administration: such as switching to a slow-release agent, increasing the number of administrations, continuous intravenous infusion, and continuous enteral administration (implantation of duodenal or jejunum tubes by percutaneous gastrostomy, externalization of a micropump, and perfusion of carbidopa/levodopa: 5/20mg/ml colloidal suspension); 2, choosing DA receptor agonists with longer half-lives agonist; 3, intravenous or subcutaneous injection of apomorphine; 4, the application of catecholamine oxygen-site methyltransferase (COMT) inhibitor (COMTI): COMT is a degrading enzyme of levodopa, and the inhibition of its activity can stabilize the paddle concentration of levodopa, increase the bioavailability and duration of levodopa’s action, and increase the passage of levodopa through the blood-brain barrier, so as to avoid the generation of peak concentration and the cause of fluctuation of symptoms. Currently, the application of COMTI is the most ideal drug to realize CDS, and the drugs that have been listed include entacapone (trade name Kodan), which can significantly increase the “on” time and correspondingly reduce the “off” time, and it should be taken together with compound levodopa, and is ineffective when used alone. It should be taken in conjunction with levodopa and is not effective when used alone. Due to the price of Kodan, many patients can not afford, for patients with motor fluctuations, the following corresponding countermeasures can also be used. (1) Motor fluctuation (Motorfluctuation) end-of-dose phenomenon (wearing-off): this phenomenon is manifested as a shortening of the duration of the efficacy of levodopa, “morning stiffness” is the end-of-dose phenomenon that occurs in the early morning. Treatment: (1) Adjustment of levodopa: increase the frequency of levodopa administration; switch or alternate levodopa controlled-release agents. (2) Enzyme inhibitors: use MAO-BI or COMTI to stabilize blood levodopa and brain DA concentrations. (3) Adding or increasing the dose of DA receptor agonists. (4) Improve the absorption of levodopa: reduce protein intake and use gastrointestinal stimulants such as mosapride to promote gastrointestinal motility. “On-off” phenomena: Symptom fluctuations become more abrupt and unpredictable, usually unrelated to the timing of administration. Treatment: reduce the dose of levodopa and increase dopamine agonists. Xylocaine has dual agonism at D1 and D2 receptors and may be effective in some patients. In other patients, continuous administration of DA-agonists can be tried. Rectal infusion of levodopa and continuous subcutaneous administration of apomorphine are effective. Freezing: This phenomenon is characterized by transient difficulty in initiating movements. This phenomenon of drug effect is not good, can be solved by gait training. (2) Dyskinesia (dyskinesia) Dyskinesia is often manifested as involuntary or choreographic movements of the trunk and limbs or abnormalities of muscle tone, and there are the following three types: ① Peak-dose dyskinesia or dyskinesia is the most common form of dyskinesia, treatment: switching to extended-release dosage forms; or lowering the dosage of levodopa and increasing the number of times it is administered; increasing the number of dopamine receptor agonists; and adding COMTI. Individuals with significant anisocoria even with small doses of levodopa may be treated with dopamine agonists alone. If the above treatments are ineffective, a small amount of antipsychotic drugs, such as clozapine, can be used to control the peak-phase hyperactivity. (ii) Off-phase anisocoria or dystonia: it occurs when the effect of each dose of levodopa wears off, and is more common with leg and foot spasms. For patients with dystonia appearing at night or in the early morning, levodopa controlled-release agent or dopamine agonist can be added before bedtime; for early morning dystonia, a dose of methyldopa can also be taken immediately after waking up in the early morning (preferably water-soluble tablets – methyldopa fast); if it mainly appears during the daytime, the effect of using long-acting dopamine agonists – xylocaine is better. Good. Local injection of botulinum toxin is effective in relieving localized painful spasms. Biphasic anisotropia: the above two anisotropic disorders appear in the same patient, it is very difficult to deal with, mainly seen in patients with a younger age of onset, the adjustment of drug dosage and the previous discussion is similar. 4. Management of non-motor disorders: (1) Psychiatric symptoms: common in the late stages. Initially they may be nightmares, then disorientation, hallucinations and delusions follow. The best approach is to simplify the treatment, which can be tapered in the following order: anticholinergics, amantadine, MAO-B inhibitors, DA receptor agonists, COMT inhibitors, and switching from extended-release agents to levodopa generic preparations. In severe cases, the non-classical antipsychotic drug, molindone, can be used, with 5-10 mg at bedtime. others can be considered, such as clozapine, risperidone, and olanzapine, which have been shown to be effective in controlling psychotic symptoms. Clozapine has the effect of reducing granulocytes. Clozapine has the side effect of making granulocytes decrease, so the number of white blood cells should be monitored in the application. (2) Depression: it is more common, and drugs such as tricyclic antidepressant-Dozepin or reuptake inhibitors of 5-HT (SSRIs) can be used. (3) Anxiety and inability to sit still: if anxiety and inability to sit still are associated with off-phase or low levodopa levels, modulating the dose of levodopa will improve these symptoms; if the symptoms are not dependent on PD, consider a trial of benzodiazepines. (4) Insomnia: There are two types of insomnia associated with PD to be aware of. One is when the symptoms of PD are poorly controlled, leading to difficulty falling asleep or early awakening, which can be controlled by adding resting controlled-release tablets or xylazine at night. The other situation is caused by an overdose of anti-PD medication. Anticholinergic drugs and amantadine can be discontinued, dopamine agonists can be reduced, and the dose of levodopa can also be reduced if needed. If the above treatments are not effective, tricyclics, benzodiazepines, and chloral hydrate can be used for those who have difficulty falling asleep; tricyclics or clonidine can be used for those who wake up early in the middle of the day. The best way to deal with excessive daytime sleep is to improve nighttime sleep. In addition, treatment with Sigitonin, caffeine and methylphenidate can also reduce the above symptoms. Second, surgical treatment PD patients in the middle and late stages, there are many patients inevitably appear drug efficacy and serious complications, through drug adjustment can not be resolved, at this time, appropriate surgery will be a good choice. The disfiguring surgery represented by pallidocerebellar disfiguration has been largely eliminated due to its poor long-term efficacy and the possibility of unpredictable complications, such as swallowing, speech and balance disorders. Neural stem cell transplantation, on the other hand, is currently in the experimental stage. At this stage, deepbrain stimulation (DBS) is the latest advancement in the treatment of PD. DBS utilizes brain stereotactic surgery to implant electrodes in a special location in the brain, and through high-frequency electrical stimulation, inhibits the neurons with abnormal electrical activity, thus providing symptomatic relief. Studies in several clinical centers have shown that DBS in the thalamus subnucleus (STN) not only improves all symptoms of PD, including midline symptoms such as “difficulty in starting” and “stiffness”, but also reduces the dosage of levodopa, and has a positive effect on the side effects caused by levodopa, such as anisocoria. It also reduces the dosage of levodopa and is effective in treating the side effects caused by levodopa, such as anisocoria and painful spasms. However, medication should still be adhered to after surgery, and the parameters of electrode stimulation should be adjusted at regular intervals, and the combination of the two is necessary to achieve a better therapeutic effect. Indications for surgery: ① typical PD; levodopa has been effective; ② after systematic drug treatment, the symptoms can no longer be controlled or dyskinesia comorbidities appear, and the adjustment of drugs can not be improved; ③ there is no serious cognitive and psychiatric disorders as well as severe cerebral atrophy; ④ after diagnosis of levodopa treatment for at least 5 years. Other advances The application of adenosine A2A receptor antagonists in the treatment of PD has received attention. Adenosine A2A receptor antagonists can reduce the activity of the indirect striatal-pallidal pathway and alleviate the symptoms of PD.Istradefylline is a new A2A receptor antagonist, which can significantly shorten the off phase and lengthen the on phase, and it is well-tolerated and has a good safety profile. It can be used as monotherapy for early stage PD patients, or for the treatment of neuropsychiatric symptoms such as anxiety and depression in PD patients, and it can also reverse antipsychotic-induced rigidity and improve motor skills. Its side effects include anisocoria, dizziness and nausea.Rasagiline is a novel selective irreversible MAO-B inhibitor, which is efficacious in the improvement of symptoms in patients with both early and late PD. Rasagiline has been shown to have neuroprotective effects.