What are the treatment options - coping with Parkinson's disease (EPDA)

Translation of Booklet No. 1 from the series (cf www.parkinsonpoly.com)
Release date unknown

Parkinson's disease
Parkinson's disease is a common neurological disorder, it is estimated that four million people worldwide suffer from it.

1. Parkinson's disease is a slowly developing disorder. It affects lifestyles but is not life-threatening. The progress in medical research allows the doctor and the treated patient to have better control over the living conditions in the holocaust of the past
   Parkinson's disease is caused by the loss or degeneration of nerve cells that produce dopamine in the brain. The main area of ​​the brain affected is called the nucleus accumbens.
2. Dopamine is a neurotransmitter. Loss of nerve cells that contain dopamine impairs control of movement in the body.
3. The first signs of Parkinson's disease occur when the level of dopamine in the brain drops below 20% of normal.

Parkinson's disease is not just a disease of old people
- Although the average age at which the disease is diagnosed is 60, 5% of patients are diagnosed at an age younger than 40 years
- People diagnosed at the age of 21-40 years are defined as having Parkinson's disease of young people

The signs (symptoms) of Parkinson's disease
Not every person has the same signs at the same time. The disease can affect each patient differently, and in some cases many years pass before limitations or severe problems in daily activities become apparent.
In the first stage of the disease, the signs usually appear on one side of the body and later move to the other side of the body
Typical symptoms of Parkinson's disease:

1. Trembling in hands, arms, legs, jaws and lips
2. Muscle problem
3. Slowness of movement (bradykinesia), difficulty in starting movement (akinesia) such as when getting up from a chair
4. Problems with balance, these characterize the later stages of the disease

Other symptoms unrelated to movement may also appear. These include sleep disorders, difficulty speaking and swallowing, impaired memory. Most of these symptoms can be overcome with medication.

The treatment of Parkinson's disease

1. It is not yet known exactly how Parkinson's disease is caused. In many cases it appears for no apparent reason and is therefore called idiopathic Parkinson's disease (of unknown origin)
2. Currently, there is no way to prevent or cure Parkinson's disease. On the other hand, the symptoms can be effectively controlled with pharmaceutical and/or surgical means.

Maintaining a correct medicinal balance
• Work with the attending physician to find the appropriate medicinal balance individually
• Treatment usually starts with a low drug dosage level. The dose is gradually increased until the desired result is achieved
• The doctor recommends a specific treatment according to the individual symptom picture. Different people will therefore receive different medicines. In the early stages of the disease, medication may not be required at all
• The doctor may examine a reaction to the drugs while taking them. The dosage level of the drugs and the time to take them may change depending on the reaction (or the appearance of side effects)
• The most effective symptom control is usually achieved through a combination of several medications

Getting the most out of medication
Regardless of the type of drug, it is important to understand:
- the dosage of the medicine and the date(s) of taking it during the day
- Conditions of taking the medicine (for example, before or after the meal)
- Which medicines should not be consumed with the current medicine
• It is necessary to share the side effects caused by taking the medicine with the attending physician
• It is advisable to avoid taking a new medicine when the doctor is not available (weekends, holidays, the doctor's or the patient's vacation)
• In addition to the doctor, it is advisable to use additional professionals (paramedical) (see brochure no. 2)

Dopaminergic healing
• Since the symptoms of Parkinson's disease result from a lack of dopamine in the brain, most of the research focuses on dopaminergic solutions (related to dopamine). These drugs are aimed at correcting the results of the missing natural dopamine, by copying or imitating its action or by inhibiting proco.

Levodopa treatment - supply of dopamine to the brain
• Dopamine cannot penetrate the brain (through the blood - after administration through the vein or food), therefore it is supplied indirectly. The substance levodopa (or L-dopa) is able to penetrate the brain, where it turns into dopamine. Levodopa is usually given as a pill or capsule.
• Levodopa is very effective in controlling most of the symptoms of Parkinson's disease. After 30 years since the development of this drug, it is still the main axis of treatment for the disease, most patients receive this drug.
• When the patient does not respond to levodopa, this suggests that the disease is not typical Parkinson's disease. There are several other diseases that accompany the symptoms of Parkinson's disease. In this situation, additional tests are needed to diagnose the disease (see brochure no. 5)
• In the body, there are enzymes (biological catalysts) that break down levodopa, so the duration of the substance's action is limited.
• Two enzymes break down levodopa: Dopa-decarboxylase (DDK Dopa-decaboxylase) and catechol or methyl transferase (COMT catechol-O-methyltransferase)
• The use of inhibitors of these enzymes will slow down the release rate of levodopa, increase its availability in the brain and its positive effect on symptom control
• On the other hand, the positive effect of levodopa decreases after several years of treatment. Later in the booklet, a reference to the challenge of long-term treatment of Parkinson's disease is included.
• The DDK inhibitor was developed in the 70s close to the introduction of Budopa for use
• The inhibitory use of DDK allows the introduction of larger amounts of levodopa, and reduces the side effects (such as dizziness and vomiting) caused by high concentrations of levodopa in the blood. The existing inhibitors are carbidopa (carbidopa) and benzeraside (benzeraside)
• A COMT inhibitor developed in the 90's, it enables continuous and prolonged exposure of levodopa in the brain. As a result, the effective duration of Levodopa's activity is extended and the duration of the symptoms of Parkinson's disease is shortened

Dopamine agonists - substances that mimic the action of dopamine
• Dopamine agonists (competitors) mimic the action of natural dopamine (compared to budopa which replaces natural dopamine)
• Since long-term treatment with levodopa may cause complications (as will be described later), in some cases doctors prefer to start the treatment with dopamine agonists first, to allow the treatment with levodopa later
• Agonists can be an effective treatment alone or in combination with levodopa. Levodopa is usually eventually required
• The choice of which treatment should be started (levodopa or dopamine agonist) is based on the patient's individual situation and is subject to joint consideration by the doctor and the patient
• Some people find it difficult to accept, or respond weakly to, dopamine agonists, so for them giving levodopa as an initial drug is the preferred option
• Some of the side effects of dopamine agonists such as nausea and low blood pressure can be dealt with by titration - start taking the drug at a low dose, and slowly increase the dose gradually until the desired control of the symptoms is achieved

MAO-B inhibitors - reduce the breakdown of dopamine in the brain
• Monoamine oxidase type B is an enzyme that breaks down dopamine in the brain. Substances that inhibit the activity of this enzyme can be used alone (usually in the initial stages of the disease) or together with levodopa to prevent the release of dopamine and increase the activity of levodopa

Non-dopaminergic treatments
• There are drug treatments for Parkinson's disease that are not directly aimed at affecting the dopamine system. This includes the anticholinergic substances that inhibit the activity of the nerve hormone acetylcholine. In the healthy brain there is usually a balance between dopamine and acetylcholine. In a Parkinson's patient there is a relative excess of acetylcholine, due to the depletion of dopamine. Anticholinergic agents can work towards achieving balance, but their effectiveness falls short of that of levodopa.
• Amantadine is a substance that releases dopamine or suppresses another neurotransmitter - glutamate. Amantadine use is common at the beginning of the disease, or in continuation to treat involuntary movements (dyskinesia) that originate from prolonged dopamine treatment
• A short guide to drug treatments for Parkinson's disease is presented below

future treatments
• The ongoing goal is to provide a drug that will help Parkinson's patients maintain as normal a lifestyle as possible. Researchers and clinicians are constantly looking for ways to improve the control of symptoms, as well as to prevent the development of side effects
• Much research effort was invested in the past in the development of drugs that allow a natural (physiological) and prolonged activation of the dopamine receptors in the brain
• In the future, most of the research into curing Parkinson's disease will be spent on developing measures that will protect or restore the brain's ability to produce dopamine
• Researchers are examining the application of brain cell transplantation, in surgical efforts, replacing the damaged cells that produce dopamine. Measures based on genetic engineering are also being tested

A short guide to drugs intended for the treatment of Parkinson's disease
Drug (1) Examples of existing drugs (2) Notes
Drugs that replace dopamine
Levodopa + DDC inhibitor Sinemet (levodopa + carbidopa
Medopar (levodopa+benserazide) levodopa is served together with the inhibitor DDC, thus preventing its conversion to dopamine in the bloodstream before reaching the brain
Drugs that increase the availability of levodopa - COMT inhibitors
Entacapone (Entacapone) Comtan/Comtess A combination of COMT inhibitors and DDC inhibitors to achieve the maximum utilization of levodopa
Tolcapone 3 Tasmar
Drugs that mimic the action of dopamine - dopamine agonists
Lisurid Revanil Dopergin • Dopamine agonists are recognized by the dopamine receptors in the brain and they mimic the dopamine signal that is lost in Parkinson's disease
• Treatment usually starts with a low dose, which is increased later, to reduce side effects
Bromocriptine (Bromocriptine) Parlodel Parlodel-MR
Cabergoline (Cabergolin) Cabaser
Pergolide (Pergolide) Celance Permax
Pramipexol (Pramipexol) Mirapex Mirapexin
Ropinirole (Ropinirole)) Requip
Apomorphine (Apomorphine) Apo-go • In some patients, apomorphine is very helpful as a means of rescue that allows controlling the symptoms
• Usually given by injection or continuous infusion under the skin, in the abdomen, thigh or hand
Drugs that prolong the duration of dopamine availability4
Selegiline (Selegiline) Eldepryl Eldeprine Movergan
Zelapar • Type B monoamine oxidase inhibitor, given alone or in combination with levodopa
Drugs that inhibit the action of acetylcholine
Trihexiphenidyl Artane • Anticholinergic drugs have a low effect on Parkinson's symptoms, especially tremors
Since the frequency of side effects (forgetfulness, hallucinations, confusion) is higher in older patients, these drugs are given to younger patients
Benztropine mesilate (Benztropine mesilate) Cogentin
Orphenadrine Disipa
Procyclidine (Procyclidine) Kemadrin
Drugs that inhibit the action of glutamate
Amantadine (Amantadine) Symmetrel used to be used only at the beginning of the disease. Today also used in more advanced stages to control involuntary movements
1- Most medications for Parkinson's disease are given as tablets
2- Only examples are given. Any Tarnpa can exist under another name not mentioned here
3- Telefon has severe usage restrictions in the USA and Switzerland. It is not available in most European countries and Canada. When it is used, it is accompanied by constant monitoring of blood enzyme levels that indicate liver functions
4- [Translator's Note] Resjalin (Azilect) also belongs to this group

Long-term coping with Parkinson's disease
• Over time as the disease progresses, its treatment may become less effective, additional symptoms may appear that do not respond to the current treatment
• Medicines such as dopamine agonists may be effective as a sole measure in the early stages of the disease when the symptoms are mild and moderate. As symptoms progress, treatment with levodopa is usually required
• Although the use of levodopa allows good control of the symptoms of the disease, the effectiveness of the drug wanes after several years of use. As a result, in certain periods of time the signs, including tremors, tremors and hypomotility, are no longer controllable. This condition is known as "wearing off". In Booklet No. 4 there is a broader reference to this phenomenon
• In several patients, this may lead to sharp transitions between a state in which the symptoms are under complete control ("on" periods) and a state in which the symptoms are not under control ("off" periods) - the "on-off" phenomenon
• Additional movement disorders may appear such as involuntary movements. They can usually be treated in consultation with the doctor by using an appropriate variety of medications.

An explanation for the decrease in levodopa's effectiveness over time
The researchers currently assume that the complications that accompany levodopa treatment are due to a combination of several factors:
- As Parkinson's disease progresses, the number of dopamine cells in the brain continues to decrease, therefore the number of cells in the brain capable of absorbing and storing the drug decreases - the brain loses its buffering capacity
- As a result of losing this regulatory ability, the fluctuations (ebb and flow) in the level of levodopa in the blood as a result of standard administration of the drug can no longer be controlled and these fluctuations translate into large fluctuations in the level of dopamine in the brain
- According to the researchers, fluctuations in the level of levodopa in the blood and in the brain in advanced stages of Parkinson's disease cause electrical changes in the brain. This affects the processing of data in the brain and causes the development of involuntary movements
- It is common to think that by maintaining stability in the level of levodopa in the blood and reducing the fluctuation in its level in the brain, these disorders can be reduced, postpone their appearance and possibly even eliminate them
- Dopamine agonists provide more stable stimulation of the dopaminergic axis because of their ability to mimic the action of dopamine in the brain
- In experiments in which levodopa was administered intravenously to Parkinson's patients, a more stable level of the substance was obtained in the blood and brain
- Practically, it is possible to continuously achieve a stable level of levodopa through the use of substances such as DDC and COMT inhibitors, these substances reduce the release of levodopa and improve its therapeutic effect.

Surgery in Parkinson's disease
The first surgeries for Parkinson's disease began in the 50s and 60s of the last century, even before the development of Levodopa. In recent years, there has been renewed interest in the surgical approach to Parkinson's patients. This is due to technical progress in the means of surgery, improvement in the understanding of the events in the brain caused during the disease, improvement in imaging methods (such as CT - computerized tomography and MRI - magnetic resonance imaging). CT is an X-ray test that provides images of the brain, while MRI uses magnetic fields to obtain detailed and sharp images of the brain.
Due to a certain risk, the surgical approach is used only after levodopa treatment is not effective enough in controlling the signs of the disease.

Excisional treatments Surgical treatments for Parkinson's disease previously included "excisional" treatments designed to remove or destroy specific areas of the brain. The treatments are aimed at three main areas:
• Thalamotomy – demolition of a small part of the area called the thalamus (level). This is done to treat tremors that cannot be controlled by medication
• Pallidotomy - destruction of part of the area called globus pallidus. This is done to relieve difficult situations of involuntary movements
• Subthalamic nucleotomy destruction of an area of ​​the brain called the subthalamic nucleus (sublevel). This is the area that is mainly treated today, since by changing its function it is possible to improve many of the Parkinson's symptoms
Deep brain stimulation • Instead of destroying a certain area of ​​the brain, electrodes are implanted in defined areas of the brain that send electrical stimulation
• Deep brain stimulation, mainly in the area of ​​the subthalamic nucleus, is given to patients whose symptoms of the disease are not properly controlled by drugs
Transplants (reconstructive surgeries) • A new surgical technique is based on the transplantation of fetal nerve cells as a replacement for the loss of dopamine-producing cells.
• There is promising progress in the field, but the subject is still in the research stage
• Implants of embryonic cells (in which the cells can be induced to become dopamine-producing cells that are implanted in the brain) are also currently being studied as a future therapeutic measure

Frequently asked questions about Parkinson's disease and its treatment

How do I know if I have Parkinson's disease?
The first signs of Parkinson's disease are mild and appear gradually. At first the patient may feel tired, unsteady or sluggish in general. Usually friends or family members feel the change first. They can feel, for example, changes in facial expression or reduced speech. As the disease progresses, the more typical signs of the disease begin to appear. Usually the appearance of tremors is the first sign of the disease that causes the patient to consult a doctor. On the other hand, these signs may also appear in a healthy person, so the definition of the disease is based on a complex combination of signs and reactions. There is currently no specific test to characterize Parkinson's disease.
Is Parkinson's disease inherited?
Only a small number of disease cases (2-3%) are familial. Several genes related to the disease have been identified so far. The most common hereditary disorder is related to the Parkin gene and manifests itself in an early onset of the disease. The cause of most cases of the disease is unknown and therefore called idiopathic (of unknown origin). According to many researchers, most Parkinson's cases are related to a combination of aging, genetic susceptibility and environmental factors.

Can exercise help Parkinson's patients?
Consistent practice can help maintain flexibility, good posture, strengthen muscles, joint flexibility and improve blood flow to the heart and eyesight. In addition, the practice may help in dealing with stress on a daily basis, and gives the practitioner a sense of achievement and control over his situation. A physical therapist can help determine an appropriate exercise and stretching program. Other methods such as the Alexander method, yoga, tai chi can also help. The Alexander technique strengthens through individual lessons the connection between the thinking and the muscles. This method can help control balance and movement in patients with Parkinson's disease. Complementary treatments are sometimes part of an overall rehabilitation plan for the patient.

Tools for dealing with Parkinson's disease
It is important to keep in touch with the doctor and other professionals and work with them as a team. It is important to take the medicines according to the instructions and report to the doctor how they work and if problems arise because of them. Providing full information to the doctor, for example by keeping a diary, may greatly help the doctor, and the patient, in making the right decisions. It is very important to maintain an adequate level of activity, as the activity increases, so will the ability to perform the activity. If you receive an exercise plan from your doctor or physical therapist, try to follow it, even if it seems difficult at first. Through proper coping and a positive attitude, Parkinson's patients can expect to lead a full and satisfying lifestyle.
Translated from English by Ami Arieli