Essay: Side effects of the drug levodopa against Parkinson's disease

Abstract
Parkinson’s disease is a neurodegenerative disease that will become more prevalent in the future, why?. The main treatment is the drug levodopa, a dopamine precursor, but this medicine has a lot of side effects. This thesis describes Parkinson’s disease, the neurotransmitter dopamine, levodopa and the side effects that levodopa causes. Finally, solutions for these side effects of levodopa and new ways of treatment are proposed.
Introduction
Parkinson’s disease (PD) is a severe neurodegenerative disease that has a big impact on patients and their families. My grandfather suffered from this disease and he experienced serious side effects from the medication he used. That is the reason why this thesis will focus on the side effects of the medication that is most often used by patients that suffer from this disease. Levodopa is the medicine that is predominantly prescribed to patients that have PD.
Epidemiology
PD was first described by James Parkinson almost 200 years ago and therefore the disease was named after him. It is a disease that becomes more prevalent when people get older. The occurrence of PD increases exponentially with age, the main prevalence is between 65 and 90 years; around 0.3 percent of the general population and 3 percent of people older than 65 years have PD . Age is the main risk factor and as the general population is getting older, the prevalence of PD will rise steadily in the future. other neurodegenerative diseases (PD, motor neuron disease and dementia) are projected to surpass cancer as the second most common cause of death among elderly by the year 2040 [1]. PD occurs in all ethnic groups, throughout the world and affects both sexes roughly equally with only a slight predominance in males.[1]
Approach (Materials and Methods)
This bachelor thesis is a literature study, because the thesis has to be completed in a short time frame. Search engines that were used to find relevant articles are: Scopus, Web of Science, PubMed, Science direct and Google Scholar. When using these search engines, keywords were used to conduct these searches:
Parkinson’s disease, Parkinson treatment, Levodopa side effects, Parkinson medication side effects, Levodopa treatment, Levodopa problems. Also articles older than 1970 were excluded from usage by using inclusion and exclusion criteria and to find the appropriate articles, often the ‘relevant articles’ option was used when searching for articles.
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This literature study will review the different side effects of Levodopa and investigate if there are things that can be done to counter these effects. The scientific relevance of this thesis will be an article that can be submitted to the PLOS Biology journal. Maybe this thesis will be a little help for Parkinson patients, maybe they learn some things that they didn’t know about. This accounts for the societal relevance of my thesis.
Clinical features of Parkinson’s disease
PD has many different symptoms that can be categorized in two groups: motor symptoms and non-motor symptoms. Motor symptoms consist of rigidity, trembling and slowness/poverty of movement (bradykinesia), flexed posture, freezing when walking and instability of posture [2]. To give a few examples: once a person with PD is seated, he or she finds it difficult to rise. Once this same person starts walking, he or she has difficulty stopping. A person with PD cannot easily pace back and forth across the room. Reaching for an object can be accurate, but his movement usually begins only after a considerable delay. Writing is slow and difficult to read and the letters gt smaller and smaller as it progresses. Postural movements are impaired. A normal person who is bumped while standing will quickly move to restore balance by taking a step in the direction of the forthcoming fall or by reaching out with the arms to grasp onto a piece of furniture. However a person with PD cannot perform these action and will simply fall. It is unlikely even that a person with PD will put out his or her arms to break the fall. PD also produces a resting tremor, vibratory movements of the arms and hands that diminish somewhat when the person makes movements on purpose. This tremor is accompanied by rigidity, the joints appear stiff [3]. There are also several non-motor symptoms like delusions, depression, anxiety and cognitive impairment [4]. Dementia occurs very often in PD, in approximately one third of the patients [5].
Diagnosis of Parkinson’s disease
The best way to diagnose PD remains neuropathological examination. There is still no viable biological marker that can diagnose PD . More than 90 percent of patients with PD have a good initial response to levodopa treatment. So the absence of such a response is an important clue to an alternative diagnosis. Still other diseases that show similar symptoms as in PD, may initially respond well to levodopa, especially multiple-system atrophy . Misdiagnosis is an important problem, because the symptoms that occur with PD are also seen in other neurodegenerative diseases, drug users and Wilson’s disease [1].
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Risk factors
There are several risk factors that can increase the chance of getting PD. First the exogenous factors, that come from the environment and second the endogenous factors, that come from the inside of patients (genes etcetera), will be described. A rural environment is generally, but not always, an elevated risk for PD. Exogenous factors such as the use of herbicides, pesticides and exposure to well water can support this relation between a rural environment and PD. Strange enough smoking is associated with a reduced risk of PD. A history of smoking reduced the risk of PD by half, but recently it was found that this reduced risk was limited to those with a relatively young age at the onset of the disease. Diet was also investigated to see whether it has a relation with PD in patients, the role of inadequate intake of anti-oxidants was checked. The anti-oxidants were investigated, because they might influence the patients, predispose patients to insults from other exogenous or endogenous risk factors of PD . One community-based study in the Netherlands found that vitamin E intake was significantly lower among patients with Parkinson’s disease than among people in the control group [6]. However, all other attempts to prove a relation between diet and PD were generally unsuccessful [1].
Endogenous factors can play a role too in the onset of PD. There is more and more evidence that genetic factors can play an important role in PD. It was found that, apart from age, a family history of PD is the strongest indicator of an increased risk of the disease . However, the role of shared environmental exposure in some families must be considered as well [1]. PD is mostly a sporadic disease, but rare inherited forms of PD offer clues to possible underlying genetic factors and mechanisms that might be relevant to sporadic PD [7]. The available evidence supports an inheritance of PD that is autosomal dominant, even in families where only a small number of members is affected. However most patients do not have a clear family history of autosomal dominant diseases, probably because either the genes that can cause PD have a low penetrance (these genes are not easily causing a change in phenotype or the cause of PD is composed of multiple factors: a combination of a genetic disadvantage and environmental exposure [1].
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Dopamine and the brain
In the next paragraph the role of dopamine in the brain is discussed, so a better understanding of what is wrong in PD patients is gained. Dopamine functions primarily as a neurotransmitter and belongs to the catecholamine family. The catecholamines contain a catechol group, a six-carbon ring and they are derived from the amino acid tyrosine. Dopamine is primarily released by neurons in the central nervous system. It binds to specific receptors, the so called dopaminergic receptors [8]. Dopamine produces both excitatory and inhibitory postsynaptic potentials, depending on the postsynaptic receptor. It is one of the more interesting neurotransmitters because it has been involved in several important functions, such as movement, learning, attention and the reinforcing effect of drugs that people tend to abuse. In figure 1 the synthesis of dopamine is shown. The precursor tyrosine is an essential amino acid that must be obtained from diet. Tyrosine receives a hydroxyl group (OH-group: an oxygen atom and a hydrogen atom) from the enzyme tyrosine hydroxylase to become levodopa (L-DOPA in the picture). Levodopa then loses a carboxyl group (COOH-group: one carbon atom, two oxygen atoms and one hydrogen atom) through the activity of the enzyme DOPA decarboxylase and becomes dopamine [3].
Figure 1 The biosynthesis of dopamine. From [3] adjusted by the author
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There are several dopamine systems in the brain. The mesolimbic system has cell bodies of neurons located in the ventral tegmental area and the axons of these cell bodies are projected to several parts of the limbic system, including the hippocampus, the amygdala and the nucleus accumbens. The nucleus accumbens is important for the reinforcing, rewarding effects of certain categories of stimuli, including the drugs that people abuse. The mesocortical system has also its cell bodies of neurons located in the ventral tegmental area. The axons from these cell bodies are projected to the prefrontal cortex and influence functions such as planning, strategy preparation for problem solving and formation of short-term memories
The focus in this thesis is on the nigrostriatal system, because that is the largest dopaminergic system and it is damaged in humans with PD. The other two systems are described, because they are important to understand certain parts of the next paragraph about dopamine and PD. The nigrostriatal system mediates the initiation of movement. It originates in neurons within the substantia nigra (see figure 2) of the midbrain and whose axons project into the striatum of the forebrain to control motor functions [9]. To be more precise these axons connect the substantia nigra with the neostriatum: the caudate nucleus and the putamen. The neostriatum is an important part of the basal ganglia, which is involved in the control of movement [3].
Figure 2 The location of the substantia nigra in the brain [10]
Dopamine and Parkinson’s disease
In this next paragraph the things that are wrong in humans with PD are mentioned. In humans with PD there is degeneration of the dopaminergic neurons that connect the substantia nigra with the caudate nucleus. The cell bodies of these dopaminergic neurons are as previously described located in the substantia nigra, that literally means ‘black substance’. This region in the brain is normally stained black with melanin, the substance that gives colour to the skin. This melanin is produced by the breakdown of dopamine. Pathologists that discovered the brain damage that causes PD, saw that the substantia nigra of a diseased PD patient was pale rather than black. Further examination of these brains of patients that had PD showed, of course, the near-disappearance of nigrostriatal dopaminergic neurons. Many of the surviving dopaminergic neurons showed Lewy bodies, abnormal circular structures found within the cytoplasm. Lewy bodies have a dense protein core, surrounded by a ring of radiating fibers [3].
As previously mentioned most cases of PD do not appear to have a genetic origin, but it was discovered that a mutation on chromosome 4 of a particular gene will produce PD. This gene produces the protein ??-synuclein, which is normally found in the presynaptic terminals and is thought to be involved in synaptic transmission in dopaminergic neurons. The mutation produces a toxic gain of function, it produces a protein that results in effects that are toxic to the cell. Mutations that produce toxic gain of function are normally dominant because the toxic substance is produced whether one or both members of the pair of chromosomes contain the mutated gene. Abnormal ??-synuclein becomes misfolded and forms aggregations, especially in dopaminergic neurons. The dense core of Lewy bodies consists of these aggregations, along with synaptic vesicle proteins and neurofilaments [3].
There is another rare hereditary form of PD. It is caused by mutation of a gene on chromosome 6 that produces a gene named parkin. This mutation causes a loss of function which makes it a recessive disorder. If a person has the mutated parkin gene only on one chromosome, the normal allele on the other chromosome can produce a sufficient amount of normal parkin for normal cellular functioning and this person will not get PD. Normal parkin plays a role in transporting defective or misfolded proteins to the proteasomes, organelles that destroy these proteins. This mutations allows high levels of defective protein to accumulate and in dopaminergic neurons and ultimately damage them. Figure 3 shows how parkin and the proteasomes work. Parkin helps tagging the abnormal or misfolded proteins with numerous molecules of ubiquitin, a small compact globular protein. This process is ubiquitination and it targets the abnormal proteins for destruction by the proteasomes, which break them down into their basic amino acids. When parkin is defective, it fails to ubiquinate the abnormal proteins and these proteins accumulate in the cell, eventually killing it. For some reason dopaminergic neurons are especially sensitive to this accumulation [3].
Figure 3 The Role of Parkin in PD [3]
Almost all cases of PD, approximately 95 percent, are sporadic. These cases occur in people that do not have a family history of PD. However, ??-synuclein does also accumulate in these cases and the dopaminergic neurons are destroyed. Research suggests that these sporadic cases of PD are caused by toxins from the environment, by faulty metabolism or by unrecognized infectious disorders. For example, the insecticides paraquat and rotenone can cause PD and maybe other unidentified toxins can do this too. These chemicals inhibit mitochondrial function, which leads to the aggregation of misfolded ??-synuclein, especially in the dopaminergic neurons. The accumulation of proteins eventually kills the neurons [3].
Of the three systems of dopaminergic neurons in the brain, only the nigrostriatal system is damaged by PD. The mesolimbic and the mesocortical system are not affected by PD. This means that there must be an important difference between the dopaminergic neurons in these three systems. It is suggested that there is a critical difference in the calcium channels that are involved in regulating the spontaneous activity of dopaminergic neurons in the nigrostriatal system and the sodium channels that are involved in the activity of dopaminergic neurons in the mesolimbic and in the mesocortical system. Research suggests that the presence of ??-synuclein, elevated levels of intracellular dopamine and elevated levels of intracellular calcium ions combine to kill the dopaminergic neurons. Interference with any of these three factors prevents damage to the dopaminergic neurons. Because the dopaminergic neurons of the mesolimbic and the mesocortical system do not contain elevated levels of calcium ions, they are not damaged.
Therapy
Now the strategies and therapies that are used by patients that suffer from PD will be described.In early cases of PD it is acceptable to not use any drugs and to observe the patient very regularly. If the symptoms of PD start to interfere with daily life, the therapy can be started with other medication than levodopa. However this thesis keeps its focus on levodopa, because that is the drug that every PD patient eventually gets. If the patient is in danger to lose his job, then levodopa therapy can be needed in a very early state of PD. If the disease is disabling the patient, levodopa treatment must be started [5]. When some patients eventually do not longer respond to levodopa, treatment can be continued with several stereotaxic procedures performed by neurosurgeons. These treatments are not often performed and will unfortunately not be described any further in this thesis. Scientist are developing a gene therapy strategy but this is still in clinical trials [3].
Before levodopa was used by patients with PD, the disease was usually a relentlessly progressive condition. After five years from onset of the disease about 60% of the patients were severely disabled, and after ten years this amount had risen to more than 80%. On average the disease shortened life and mortality was about three times that of the general population.[11]
The initial response to levodopa therapy is variable, some patients show a huge improvement and others don’t show any reaction. As seen in figure 4, maximum benefit with plain levodopa may not be achieved until one to two years after the start of the therapy, because the optimal dosage has to be found [11].
Figure 4 Average outcome of long-term levodopa therapy. The mean percent improvement in total disability scores from pre-treatment values is shown on the y-axis against duration of the therapy on the x-axis over a five-year period. The dotted extension predicts later events[11].
Levodopa has been used against PD for more than 40 years [12]. It is used in dopamine-replacing therapies and is very effective in countering the symptoms of the disease and is still the standard drug with which other therapies are compared [2]. Levodopa has multiple problems/side effects that can be seen in table 1. These side-effects will be further described in the side effects section [5]:
Table 1 side effects of levodopa [5]
Early (‘peripheral’) side-effects Psychiatric disturbances Oscillations in motor performance after long-term treatment Dyskinesia
nausea, vomiting
toxic confusional state
end-of-dose akinesia (absence, poverty or loss of control of voluntary muscle movements)
peak-dose dyskinesia (involuntary muscle movements)
cardiac arrhythmias
dementia
nocturnal and early-morning akinesia
peak-dose dystonia (sustained muscle contractions cause twisting and repetitive movements or abnormal postures), Improvement-Dystonia-Improvement response
postural hypotension
hallucinations random on-off phenomenon, from mobile to immobile and back
biphasic dystonia, Dystonia-Improvement-Dystonia response
peak-dose akinesia (loss of speech when the medicine takes effect) early-morning dystonia
akinesia paradoxa (freezing, start hesitation, “frozen on the spot”)
Myoclonus, jerks of the limbs and occur most frequently during sleep.
Asterixis, tremor of the hand when the wrist is extended (flapping bird tremor)
Levodopa is a dopamine precursor and is used to counter the symptoms of PD [2]. The medicine is taken orally by the patient with the purpose of replenishing depleted stores of dopamine [5]. An increased level of levodopa in the brain causes the remaining dopaminergic neurons to produce and secrete more dopamine and for a time alleviate the symptoms of PD. However this compensation does not work indefinitely, the number of nigrostriatal dopaminergic neurons will eventually decline to such a low level that the symptoms get worse. The levodopa will now activate the dopaminergic neurons in the mesolimbic and the mesocortical system and causes side effects such as hallucinations and delusions [3].
Dopamine cannot cross the blood-brain barrier, but its precursor levodopa can. In the brain levodopa is decarboxylated to dopamine by decarboxylases, but elsewhere in the human body there are decarboxylases too. These compounds convert plasma levodopa to dopamine and this dopamine is not useful because it cannot cross the blood-brain barrier. This is the reason why levodopa is often used with a decarboxylase inhibitor. This inhibitor inhibits the decarboxylation of levodopa to dopamine in the periphery, outside the brain. In this way it helps a greater amount of levodopa to reach the brain and be effective in countering the symptoms of PD [5].
Now the chemical and medicinal properties of levodopa will be mentioned. The official name of levodopa is 3,4-dihydroxy-L-phenylalanine. It is a large neutral amino acid that is chemically synthesized for pharmaceutical use. This stereoisomer can be found in nature in a few species of broad beans (such as cacao and Mucuna pruriens), but in the average diet there is only levodopa in very small amounts. Orally administered levodopa is taken up in the duodenum and the jejenum. Once it is absorbed, it is rapidly distributed and also rapidly removed. Only a small fraction of levodopa reaches the brain, most of it is taken up by the liver, the kidneys and skeletal muscle. If there is no decarboxylase inhibitor, levodopa is converted to dopamine. The levodopa that reaches the brain restores dopaminergic transmission through the same mechanism as the endogenous synthesis of dopamine (see figure 1). Because of the rapid transit of levodopa through the brain, it is necessary that the drug is continuously delivered to get a constant dopaminergic effect. A daily levodopa dose of 300-600 mg is needed to treat the symptoms of PD [13]. In the next paragraphs the side-effects from the previous paragraph are explained and possible solutions are described.
Side effects
Early (‘peripheral’) side-effects
Nausea and vomiting that is induced by Levodopa, should first be controlled by gradually increasing the dose when starting therapy. Furthermore it can also help to take the levodopa with meals [2].
Cardiac arrythmias are not very common and can be reduced by using a decarboxylase inhibitor or by propanolol. Peripheral decarboxylase metabolizes a great part of the absorbed levodopa to dopamine. This dopamine is in the plasma, cannot cross the blood-brain barrier and is therefore not effective in the treatment of PD. This plasma dopamine may even induce dopaminergic activity in other places in the body and may lead to the occurrence of side effects. A peripheral decarboxylase inhibitor allows a greater portion of levodopa to reach the brain and minimizes peripheral side effects such as cardiac arrhytmias [2].
Postural hypotension is a side effect where both peripheral and central mechanisms play a role. This side effect is also decreased by taking decarboxylase inhibitors. If this is not sufficient dihydroergotamine (Dihydergot) or etilefrine (Effortil) may be prescribed. In general, it is always wise to give patients with cardiac problems or hypotension a combination preparation containing a decarboxylase inhibitor. [2]
Psychiatric disturbances
Pychiatric distubances like hallucinations, toxic confusional state and dementia are a special kind of side effects of levodopa treatment. These problems are often reversible because they are caused by overdoses of anti-parkinsonian drugs like anticholinergics, amantadine, levodopa, dopamine agonists. Symptoms do not immediately go away after people stopped using the drug but they diminish in days or sometimes weeks. It is considered that a patient that already has a psychiatric illness, more susceptible is to the psychiatric side-effects during levodopa treatment [14]. In Parkinson patients cognitive functions decline but the impairment seems to be related to the progression of the disease and not to the levodopa treatment [14]. After levodopa treatment the intellectual functions may even be improved but this effect is only for a short period of time[15]. But anti-parkinson drugs may result in dementia and confusion, especially in the intellectually impaired Parkinson patient [16]. Drug induced loss of cognition may do more harm to the patient and his/her partner than the original motor symptoms. Confusional states and hallucinations should be treated by lowering the dose of the anti-parkinson drugs. Mild neuroleptics may alleviate the psychiatric symptoms but many times at the expense of reappearance of the symptoms of PD[2].
Oscillations in motor performance after long-term treatment
Akinesia includes two different motor disorders. One of them is bradykinesia, slowness of movement. It occurs at the same time as rigidity and impaired skilled movements in PD patients and is considered as secondary akinesia. The other part of akinesia is hypokinesia, the absence of movement. Any unconscious movements or actions such as gestures and swallowing food are limited, although the elemental functions are maintained. Hypokinesia is an essential feature of PD and can categorized as primary akinesia. [17]
Akinetic periods occur when the dose of levodopa taken by the patient wears off. In advanced PD it takes one to three hours until the akinesia symptoms reappear after levodopa intake. These symptoms persist until the positive effect of a new levodopa dose appears. Increasing the frequency of levodopa doses decreases the number and shortens the time that symptoms of PD are experienced so that the patient can move more easily for a greater part of the day. But in advanced PD this is often accompanied by an emergence or increase of dyskinesia. It is often not possible to decrease each levodopa intake without inducing akinesia or other symptoms of PD again, but nearly all patients prefer this hyperkinesia to akinesia except when the hyperkinesia is very severe. Sometimes patients take a dose of levodopa when they feel that the effect of the previous one is wearing off. The patients have to notice this effect reliably, otherwise they will get a dopa intoxication. Unfortunately a lot of these patients have signs of dementia so doing this method has a great risk of intoxication[2].
Akinesia does also occur in the night and in the early morning. This is caused by the long time period between the last levodopa dose in the evening and the dose in the morning. An extra dose in the night or a long lasting dopamine agonist can help to counter this effect.[5]
Akinesia that occurs at the end of a working levodopa dose can be explained by low levodopa plasma levels. This can be treated with an increased frequency of levodopa intake. By increasing this frequency and therefore increasing the total dosage in per day, dyskinesias can take place easily. This often occurs in patients who are on levodopa for a long period of time [5]. A constant levodopa plasma level could be maintained by continuous intravenous levodopa infusion. But levodopa cannot be taken in with an insulin pump because levodopa has to be diluted to large volumes [5]. Long acting dopamine agonists can also be useful against the akinesia that occurs at the end of a levodopa dose. If these drugs are used together with levodopa, the levodopa dosage must be reduced to prevent dyskinesia. Also the dosages of the agonists and the dosages of levodopa should be reduced because of side effects like confusion and dyskinesia [5]. Another way of prolonging the effect of each levodopa dose is slowing down the breakdown of dopamine. A selective inhibitor, deprenyl, can do this when added to levodopa treatment. If the akinesia is related to meals, a low-protein diet has to be tried or the levodopa must be ingested on an empty stomach[5].
Most of the occurrences of motor symptoms are related to levodopa plasma levels and the timing of the levodopa dose. But after some years of levodopa treatment, patients may show a random occurrence of motor symptoms, that is not related to levodopa levels or timing of the dose. These patients change from being mobile, which is often accompanied by hyperkinesia (extra involuntary muscle movements), to sudden immobility in seconds to minutes. After a few minutes they return to being mobile again. These periods of being immobile can end without taking levodopa. This switching between mobile and immobile is very disabling because it is very unpredictable. The mechanism that causes this switching is not known yet so it is very difficult to treat.[5]
The random periods with switching between mobile and immobile states are temporarily improved by reducing levodopa intake or a drug holiday (not using any drugs in this period). Stopping with all the dopaminergic medicines for two days each week may improve hallucinations, dyskinesias and sleep disorders, but is not effective in treating the random switching between mobile and immobile. A drug holiday may be very disabling and humiliating for the patient and is most of the time feasible only in hospitalized patients. Patients with the random switching symptom treated with intravenous infusion of levodopa show an improved response that suggests that central dopamine receptors are still available for stimulation. This method can unfortunately not be used for long term treatment. Lithium carbonate can reduce akinesia in some cases, but scientists disagree about this [5].
Another kind of akinesia is freezing also called akinesia paradoxa. A sudden freezing occurs when the patient meet an obstacle such as a doorstep or a line on the ground that they have to pass. This akinesia can last for seconds to hours. Patients say that there is a strong link between external trigger factors which can provoke or relieve episodes of freezing. To overcome this immobility patients use many tricks, dancing or walking to music, marching on command like a soldier etcetera. There is no agreement about what is causing the freezing: PD itself or levodopa treatment [5].
The last form of akinesia is peak-dose akinesia. Patients that show this symptom have a loss of speech when the medicine takes effect. It may be caused by spasms of the muscles that are used to talk. There are no recurrences of other PD symptoms[5].
Dyskinesia
Dyskinesia related to levodopa is most occurring as peak-dose, it occurs when the medicine is doing its job. The patient makes continuous movements, usually starting as a slight twisting movement of the neck, so that the head is in an instable position. First the patient does not seem to notice it. Dyskinesia can also start in the legs, the face or other parts of the body. When the patients benefits maximally from levodopa , the abnormal involuntary movements usually occur. It is not rare that the patient stays mobile only at the expense of continuous dyskinesia during the whole period. The patient has to make a choice between mobility and dyskinesia on one hand and akinesia and immobility on the other hand. Most patients do prefer the dyskinesia with mobility. Dyskinesia is also influenced by psychological factors like stress, fear and behavior. These factors affect the severity of the dyskinesia [5].
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Peak dose dyskinesia is the most frequent form of abnormal involuntary movements induced by levodopa. Reducing of each dose leads to a decrease in huge peaks of plasma levodopa levels but the patient may show PD symptoms again. Taking levodopa more often may help, but in most patients the dyskinesia will come back. If levodopa is carefully increased during treatment, this may lead to alleviate the symptoms of PD without leading to more dyskinesias [5].
In patients with advanced PD that react to levodopa in a short time period, peak-dose dystonia is seen. The patients show a sequence that starts with improvement, they feel better and show lesser symptoms of PD. Then they show dystonia, with muscle contractions that cause twisting and repetitive movements or abnormal postures. And after that they show improvement again. This sequence is a special type of peak-dose dyskinesia occurring at the time when the patients benefits maximally from levodopa. Reduction of the levodopa dose is maybe the solution for peak dose dystonia and peak-dose akinesia [5].
Other patients can show this sequence in a different order: first they show dystonia, then improvement and then dystonia again. This is rare and occurs in patients that got PD very early in their life and show severe akinesia. The phases of dystonia may be prevented by maintaining a sufficient high blood level of levodopa by giving doses of levodopa quickly after one another. The dystonia occurs at the end of the period between two doses of levodopa and is directly followed by akinesia that occurs when the effect of a dose wears off [5]. Patients with this rare response of first dystonia, then improvement, then dystonia again, need an increase of the levodopa dose to prevent the major dystonia symptom. This is not practical because patients may experience levodopa intoxication [5].
Dystonia can also occur in the early morning before the first dose of levodopa when the patient shows akinesia. It only lasts for two hours and primarily affects the legs and feet [5]. Early-morning dystonia can be treated with the drug baclofen taken at bedtime[5].
Myoclonus is another symptom of PD patients that take levodopa. The abrupt movements of the limbs occur most often during sleep. The arm and the leg on the same side can move at the same time [5]. Myoclonus that is induced by levodopa is related directly to the levodopa dosage. To treat this side effect, the daily dosage of levodopa should be reduced. Myoclonus is also blocked specifically by methysergide, the serotonin antagonist [5].
Asterixis that is induced by levodopa is a part of a toxic confusional state on top of the Parkinson state with dementia. These patients show often insomnia, hallucinations and myoclonus [5]. When the patient stops taking levodopa or reduces using it, the asterixis will go away [5].
New ways of treatment
The control of PD with improved levodopa products has been very difficult for years. Two widely distributed levodopa products were developed that release levodopa continuously: Sinemet CR and Madopar HBS. Both products are capable of giving a more gradual rise and decline in plasma levodopa concentration than products that release levodopa instantly. However neither of these products have shown consistency in levodopa release. So levodopa that is released immediately taken at close intervals can be the best way to deliver the drug for consistency of action [13].
One succesful strategy for extending the effect of levodopa and keeping the plasma concentrations constant by continuous infusion is Duodopa. This product was under development for more than a decade and is now marketed in Europe. Duodopa is a microsuspension of carbidopa (a decarboxylase inhibitor) and levodopa and can be infused by a portable pump at a rate that fits the need of the patient. The levodopa plasma concentration can be kept in within a window to maintain the mobile state of the patient without rising to a level that causes dyskinesias. This is an effective method compared to orally taken levodopa, but it requires the adaptation of a tube that is permanently inserted through the stomach [13].
Apart of decarboxylase inhibitors there is another way of improving the bioavailability of plasma levodopa and deliver it to the brain. The peripheral metabolism of levodopa can be inhibited via the catechol-O-methyltransferase (COMT) pathway with entacapone. Entacapone is a COMT inhibitor and enhances the transportation of levodopa across the blood-brain barrier and the conversion to dopamine. This results in an increase in the bioavailability of the drug of approximately 30%. When a patients uses both a decarboxylase inhibitor, like carbidopa, and a COMT inhibitor, this results in a significant longer time that the patient is mobile and a corresponding decrease of the time that the patient is immobile. But increasing the bioavailability of levodopa with co-administration of COMT inhibitors is also linked with an initial increase in dyskinesias. These dyskinesias can generally be controlled by adjusting the doses of levodopa [12].
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Discussion
It is apparent that levodopa still is an important medicine. Most of the side effects can be treated. However different side effects require sometimes opposite treatments. For example if a patient suffers from the side effects myoclonus or asterixis, he or she would want to reduce the dose of levodopa. However when the patient also shows the dystonia, improvement, dystonia response, he or she would want to increase the levodopa dose to counter this symptom [5]. This is the main point of difficulty with levodopa: once you treat one side effect you will get another one back. This is the reason why it would be interesting to search for new adjustments/therapies to treat PD, because levodopa as it is used now, is still not an optimal drug.
Acknowledgements
Of course I want to thank my supervisor, Ruth Adriaansen. Without her I could not have put a decent structure in this thesis and the thesis ring meetings where very helpful for me. My grandmother and family I would like to thank. They are the inspiration for this thesis. I want to thank my rowing crew, Zwaar 2015. These are the friends I train with every day and they helped me with planning fun activities around this thesis. Furthermore Kevin Walgering and Joep Smits are very important friends to me and they wanted to be in this acknowledgements section. There is nothing better than coming home after a long day of studying and a very harsh rowing training to find out that your nuts have been eaten. Special thanks go to my friends Jorrit Colenberg and Pam Toten. Without these people I would not have survived the long sessions in the Forum library.
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