To date, there are anticholinergic agents, L-DOPA agents, amantadine, dopamine receptor agonists, DOPS, etc. as anti-Parkinson’s disease drugs, and some other new drugs are under development and research. However, there is no agent superior to L-DOPA at present. Currently, it can be said that L-DOPA
is still the most effective drug for the treatment of Parkinson’s disease, and this is recognized by the world.
The diagnosis of Parkinson’s disease can be made almost at the first visit based on the patient’s characteristic expressions, posture, and voice, and treatment is started afterwards. L-DOPA is usually given to patients in just 2 weeks to a month to receive good results, so that patients can express themselves freely and gait easily. However, such a good effect can only be maintained for 4 to 5 years, and after 5 years, the phenomenon of wearing-off and on-off will occur, which will reduce the effect of treatment and cause symptoms such as instability, dyskinesia and hallucinations. The following describes the countermeasures for these phenomena.
I. Wearing-off phenomenon
The wearing-off phenomenon (w0) refers to the shortening of the duration of the therapeutic effect after each dose of L-DOPA and the fluctuation of the symptoms with the change of the concentration of L-DOPA in the blood, and the degree of the change of the symptoms is predictable. The incidence varies. The incidence has been reported differently.
In the 1980s, when L-DOPA was most used, the incidence was reported to be 50-70 over 5 years in Europe and the United States, and recently reported to be 20 9/6-25 over 5 years and 40-50 over 10 years.
The half-life of L-DOPA is very short, only one hour, but in the early stage, because the patient still has considerable residual dopamine nerve terminals, so the drug can be administered twice a day to maintain a stable and good effect. However, as the disease progresses, the residual dopamine in the nerve terminals gradually decreases, making the reuptake, storage and retention of dopamine more and more difficult. This is due to the rapid change in the peak blood concentration of L-DOPA due to the long-term administration of large amounts of L-DOPA and the shortening of the half-life of L-DOPA, which makes it easy to develop the w-O phenomenon. This change in the peak blood concentration of L-DOPA can be seen in normal rats, so it is not related to Parkinson’s disease itself, but is due to the absorption changes caused by the long-term administration of large amounts of L-DOPA. The reason for considering w-O is related to the progressive reduction of dopamine nerve terminals, the large amount of L-DOPA long I administration, coupled with dopamine receptor changes. The change in dopamine receptors (DR) is presumed to be due to an increase in the receptor sensitivity threshold as a result of prolonged dopamine-like stimulation. Dopamine neuroterminal is progressively reduced with age, but in practice, the w-O phenomenon is more likely to occur in younger patients and less likely to occur in older patients. This suggests that w-O is not only associated with a decrease in dopamine nerve terminals, but also suggests a close relationship with dopamine uptake and receptor sensitivity. The countermeasure to the wearing-off phenomenon is to prolong the effective time of L-DOPA, which is usually done as follows. ①L-DOPA is administered in small amounts several times L-DOPA combination is usually 1 tablet of 100mg, but such a dose is too large for Japanese people, and long-term administration will lead to a higher and higher peak blood concentration and become the cause of the later mentioned dyskinesia. Therefore, the method of increasing the number of doses by 1/2~3/4 tablets each time is used. If the daily dose is increased, the symptoms may improve in a short period of time, but after 1 to 2 years, there will be a sharp change in the blood concentration curve, causing a serious w-O phenomenon, so avoid increasing the daily dose as much as possible. ②Addition and increment of dopamine agonist Although the effect of dopamine agonist is much less than L-DOPA in people’s impression, it has the advantages of long half-life and stable efficacy, and the purpose of using it is to play the role of crossing and elevating the trough in OFF period. Although these drugs are not yet available in Japan, it is believed that they will soon be put into clinical use. c0MT-1 is a drug that blocks the metabolism of L-DOPA to 3-O-methyldopa (3OMD) at the nerve endings. ) metabolism at the nerve end to extend the half-life of L-DOPA. In addition, it is currently believed that 3OMD can be significantly reduced due to the action of COMI-1, but a certain degree of 3OMD can be generated due to the administration of L-DOPA.
MAOB I1 inhibits the metabolism of dopamine in the brain, allowing the synaptic gap dopamine effect to achieve a sustained presence. These drugs are currently in the summary stage of observation, and it is believed that they do have efficacy in the control of W-O and look forward to their release. But here is a
However, it is important to note that the effect of these two drugs on dopamine receptors is the same as that of increasing L-DOPA dosage, i.e., if C0MT-1 and MA0B-1 are added casually without any adjustment of L-DOPA dosage, there is a possibility of significant W-0 phenomenon after 1 to 2 years. This drug must be used with caution.
This method of continuous administration of L-DOPA is not used in Japan. Although, the cause of the occurrence of W-0 is due to changes in the blood concentration of L-D0PA
in a sense, it is an excellent method in terms of the fluctuation of symptoms due to changes in the blood concentration of L-DOPA. However, it was observed in clinical practice that patients who were given L-DOPA in a continuous 24-hour sedative drip for 7 days had a significantly lower response when the same amount of L-DOPA was used after 1 week. The above results suggest that the problem of 24-hour intermittent stimulation of dopa receptors suggests that the longer the duration of action of anti-Parkinsonian drugs is not simply better.
Second, on-off phenomenon (on-on off phenomenon), reduced efficacy and instability
If the duration of L-D0PA treatment continues to be prolonged, unpredictable symptom fluctuations (unpredictabl off) will occur. In one case, when L-DOPA blood concentration is supposed to be high and effective, it suddenly turns off and on like a power switch, causing symptoms to fluctuate and change accordingly. Another situation is that in the past, the effect will definitely appear after the patient takes the drug for 30 minutes, but not at this time, when the effect has become unpredictable, or sometimes no effect at all, which causes the phenomenon of reduced and unstable drug efficacy.
As for the reason of on-off, it is not very clear yet, but it may be related to the receptor. The reduced efficacy and instability are considered to be due to changes in dopamine receptors and changes in L-DOPA uptake. Since the absorption of L-DOPA, like tyrosine and phenylalanine, relies on a large neutral amino acid delivery system, absorption through the intestinal tract and passage through the blood-brain barrier, diet has a significant impact on its absorption and efficacy. Generally speaking, the blood concentration rises faster when taken before meals than after meals, and the effect is obvious but not lasting. The blood concentration of drugs taken after meals does not rise sufficiently, so it is not easy to appear on phenomenon, and most of them have better effect due to changing the drug delivery before meals. In order to improve the symptoms during the day, we should adopt a diet that restricts protein intake in the morning and lunch, but sufficient protein in dinner. However, most people in Japan already have a low protein diet at breakfast and lunch, so there is no need to emphasize this point to prevent the occurrence of low protein. In addition, the absorption of L-D0PA is related to the acidity of the stomach, so it is recommended to use it with lemon juice. However, by experimental comparison, the solubility of L-DOPA preparation was observed by placing it in liquid at pH 1.6-7.6, and it was found that although the solubility of L-D0PA was high at pH 1.6. However, the difference in solubility at pH 3.6-7.6 was not significant. L-DOPA is insoluble in water and easily forms a suspension, so it can be absorbed quickly by gently cracking it and mixing it with water. Also, it can be used in combination with vitamin C to form acidic salts that can increase solubility. To avoid lemon juice complicating gastric ulcers, lemon juice can be used instead of water to dissolve into a suspension and good results can be received.
Three, involuntary movements
Involuntary movements in Parkinson’s disease are caused by excessive stimulation of the cholinergic system, and one of the more common symptoms in young Parkinson’s patients is dystonia. The drug-induced involuntary movements are mostly manifested in the increase of slow movements at the end of the extremities, and can also be seen around the trunk and mouth. Such involuntary movements can manifest as slow tardive dyskinesia, dystonia to chorea, and then violent tremor-like movements. These abnormal movements are related to the duration (or blood concentration) of L-D0PA administration and include peak dose dyskinesia, beginning and end of dose (biphasic) dyskinesia [-onset and end of dose (biphasic) dyskinsia], early morning dystonia ( morn-ing dystonia), etc. Regarding peak dose dyskinesia, it is not only associated with the period of L-DOPA administration, but also occurs if overdose is administered. Early morning dystonia is the toe pacing and flexion of the lower extremities that occurs early in the morning and during the off period prior to daytime dosing, and is often associated with pain. These involuntary movements may disappear after thalamic and pallidum destruction with the disappearance of trunk extremity dystonia, so it is considered to be caused by the same systemic lesion as dystonia. When seeing dyskinesia, it is important to first clearly understand from the patient’s complaints whether it is tremor or dyskinesia. It is also important to clarify when this dyskinesia occurs and the degree of impairment in the ability to perform activities of daily living (ADL). Peak dose dyskinesia is basically an overstimulation of the L-DOPA or dopa (DA) tract that reverses the threshold for the appearance of effects from that of dyskinesia due to long-term treatment. In addition, when dyskinesia occurs, the patient does not feel abnormal or often feels relaxed because the body, which was originally muscularly tense, becomes easy to move. In addition, young patients with Parkinson’s syndrome are highly susceptible to high levels of dyskinesia, which is often the cause of walking impairment. In this case, the dosage of L-DOPA should be reduced as much as possible, either by small and multiple doses or by adding dopamine agonists, etc. It is very important to be careful not to cause a sharp peak of dopamine stimulation. Depending on the situation, a dopamine receptor antagonist (TABILA, tiapride) can be added. Also, L-DOPA can be increased in small amounts or dopamine receptor agonists can be added during biphasic dyskinesia and early morning dystonia off or just after the onset of off or on, and sometimes symptoms can be improved using. For early morning symptoms, a bedtime addition of a long-acting dopamine agonist may be used.
IV. Hallucinations and delirium
Particularly in elderly patients with Parkinson’s disease, there are often hallucinations and delirium symptoms, which may be caused by the disease itself, or may be symptoms due to the combination of dementia, in addition to those caused by taking drugs. Because D3 and D4 dopamine receptors, which work with anti-Parkinsonian drugs, are located in the limbic system, which is associated with emotions, when this part of the brain is stimulated by drugs, psychotic symptoms such as hallucinations or delirium can occur, and there are distinctive hallucinations of small animals and people, which are considered by many authors to be characterized by hallucinations.
As in the case of dyskinesia, it occurs when the dose of the drug is reversed in relation to the effect dose. If the hallucination disappears and the dose is reduced, the patient will return to the original inactive state, which will make the patient uncomfortable. Therefore, it is important to reduce the dosage of anti-Parkinsonian drugs as much as possible to improve these symptoms, if the patient and family can accept it. If necessary, dopamine receptor antagonists such as Tebilox can be added, but of course, the more toxic drugs should not be taken. For patients who cannot eat and have hallucinations and delusions, it is important to improve the hallucinations and delusions and other psychiatric symptoms as soon as possible, even if the original symptoms are slightly aggravated.
3.3.1 Fluctuation of symptoms
The so-called “end-of-dose phenomenon” is characterized by a shortening of the duration of the therapeutic effect of levodopa, with a decrease in efficacy occurring after approximately every 4 h. As the disease progresses, the “onset of symptoms” may be reduced. As the disease progresses, the “on” period becomes shorter and the “off” period becomes longer. “Morning stiffness” is an end-of-dose phenomenon that occurs in the early morning. It is believed that it may be due to the progressive decrease of dopaminergic neurons in the brain and the reduced ability to convert levodopa and to store and release dopamine.
Treatment.
(1) Adjust levodopa: e.g., increase the number of levodopa doses, switch or alternate levodopa controlled-release agents.
(2) Drugs to enhance the efficacy of levodopa: use Cetinine 5mg once every morning and afternoon or use Entacapone (which has been tried in China but not marketed) to stabilize the concentration of levodopa in the blood and dopamine in the brain.
(3) Add or increase the dose of dopamine receptor agonists.
(4) Improve the absorption of levodopa: reduce protein intake, apply gastrointestinal motility drugs, and promote gastrointestinal motility