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The history of the creation of levodopa preparations began in 1911, when the Polish biochemist C. Funk synthesized D,L-dopa in the laboratory [32]. In 1913, M. Guggenheim obtained an isolated fraction of L-dopa from the broad bean Vicia faba [6]. However, at that time, the role of dopamine in the development of Parkinson's disease (PD) was not known and levodopa was considered as a vasopressive and even antibacterial drug, but these properties were not confirmed, and levodopa was forgotten for several decades.

At the end of the 50s, the Swedish scientist A. Carlsson identified dopamine in the brain [12]. For this important discovery he was awarded the Nobel Prize in 2000. At the same time, I. Sano et al. [55] showed that dopamine is localized predominantly in the lenticular, caudate nuclei, thalamus and hypothalamus. In 1961, H. Ehringer and O. Hornykiewicz [20], examining the brains of patients who died from PD, revealed a significant decrease in dopamine in the basal ganglia. But dopamine could not be used to treat PD because it does not cross the blood-brain barrier (BBB). Then they remembered its metabolic predecessor levodopa. Back in the 50s of the last century, A. Carlsson et al. [12] showed that levodopa was able to prevent reserpine-induced akinesia in experimental animals. These reports served as the basis for W. Birkmayer and O. Hornykiewicz [10] to conduct a small open study (20 patients) in Vienna with a single (2.0 g) intravenous administration of levodopa to patients with PD. Administration of levodopa for 2-3 hours significantly reduced the severity of akinesia. The effect lasted up to 24 hours. At the same time, in Montreal, A. Barbeau et al. [7] tested the effectiveness of levodopa in patients with PD and also noted its therapeutic effect. In 1967, G. Cotzias et al. [16] reported an improvement in the condition of PD patients treated with high doses (up to 16 g per day) of oral levodopa and were the first to propose a technique for gradually increasing the dose of levodopa during treatment in order to reduce the severity of side effects. In 1969, the first double-double placebo-controlled study was conducted demonstrating the effectiveness of levodopa on akinesia, tremor and rigidity. At the same time, it was already noted that high doses of levodopa (8 g per day) contribute to the development of choreiform and athetoid hyperkinesis [62]. Industrial production of levodopa was established by 1970, and from the same year levodopa was approved for use in the United States.

The use of “pure” levodopa was accompanied by a large number of side effects (nausea, vomiting, fluctuations in blood pressure, heart rhythm disturbances). A solution to this issue was found by W. Birkmayer [10], who was the first to use levodopa in combination with a DOPA decarboxylase (DDC) inhibitor, which increased the therapeutic effectiveness of levodopa and improved its tolerability. Gradual titration of the dose over 2 weeks also makes it possible to reduce the number of side effects. The mechanism that increases the bioavailability of levodopa against the background of a DDC inhibitor was discovered by A. Pletscher and M. DaPrada in 1993 [49]. DDC inhibitors - carbidopa and benserazide - do not penetrate the BBB, but block the transformation of levodopa into dopamine in the periphery. As a result, the number of side gastrointestinal and cardiovascular effects is reduced, and the dose of levodopa is reduced by 60-80% [13, 41]. Production of the combination of levodopa and a DDC inhibitor began in 1975 [61]. The first two-component levodopa preparation (Madopar) was released in Switzerland and contained levodopa and benserazide. Almost simultaneously, another levodopa drug (sinemet) was created in the United States, containing another DDC inhibitor, carbidopa.

Since that time, levodopa drugs have become the basis for the treatment of PD; they are called the “gold standard”.

Subsequently, in the 80s of the 20th century, the development of levodopa therapy followed the path of creating drugs with controlled release in order to overcome the development of motor fluctuations and dyskinesias and provide a more “physiological” stimulation of dopamine receptors, as well as fast-acting, dispersible forms. The next step was the creation of three-component drugs containing levodopa, a DDC inhibitor and a COMT (catechol-o-methyl-transferase) inhibitor, which appeared at the beginning of the 21st century. The basis for their creation was research demonstrating that several months after blocking the DDC pathway, another pathway of levodopa metabolism is activated using the enzyme catechol-o-methyl-transferase. The resulting metabolic product 3-OMD (3-hydroxy-methyl-dopa) competes with levodopa for absorption in the small intestine, which is an additional factor in reducing the bioavailability of levodopa. In addition, the use of three-component forms provides more uniform stimulation of dopamine receptors in the striatum. In 2003, the first such drug, stalevo (levodopa/carbidopa/entacapone), was approved for use in the United States and European countries. The combination of levodopa with DDC and COMT inhibitors allows increasing the half-life of levodopa by 85%, bioavailability by up to 45%, and reducing fluctuations in the concentration of levodopa in the blood plasma by up to 50%. The consequence of this is an increase in the duration of action of levodopa and a significant increase in the effectiveness of fluctuation therapy, which has been proven by multicenter controlled studies.

Pharmacokinetics of levodopa

Levodopa taken orally is almost completely absorbed in the small intestine. Only 1% of ingested levodopa actually enters the brain; the remaining amount is metabolized in the periphery under the influence of peripheral DDC in the gastrointestinal tract and capillary endothelium [33]. Amino acids contained in food may compete with levodopa, which is an aromatic acid, for transport across the intestinal wall, so levodopa should be taken before or after meals, 45-60 minutes apart. It is possible to take levodopa on an empty stomach, in which case the effect occurs faster. If this is not possible, then it is better to take levodopa with a small amount of carbohydrate food [35]. For patients with motor fluctuations, most often at peak dose, it is better to recommend taking levodopa with protein foods, which slows down the absorption of the drug.

Levodopa, having crossed the BBB, is taken up by nigrostriatal neurons and, under the influence of cerebral DDC, is metabolized into dopamine. Levodopa has a short half-life - on average 30-60 minutes, however, neurons of the substantia nigra are able to capture levodopa coming from outside, accumulate and gradually release it, i.e. have buffer capacity. Exogenous levodopa does not completely compensate for dopamine deficiency. The pharmacotherapeutic effect of levodopa is explained by the hypersensitivity of denervated postsynaptic dopamine receptors in the striatum. Some of the levodopa is taken up by nondopaminergic neurons (serotonergic neurons, glial cells), which also contain DDCs. The release of dopamine from these cells occurs chaotically. The progression of the disease leads to a critical decrease in the number of neurons in the substantia nigra. The remaining dopaminergic neurons lose their buffering capacity. As a result, the process of dopamine release passively follows fluctuations in the level of levodopa in the blood [14, 15, 61]. Pulsatile stimulation of dopamine receptors in combination with their denervation hypersensitivity are the most important causes of the development of motor fluctuations and dyskinesias. In addition, activation of dopamine receptors in the limbic system and cortex contributes to the development of visual hallucinations, agitation, sleep disturbances, depression, the so-called central side effects of levodopa, which are not affected by the peripheral DDC inhibitor. Most often, these phenomena are the result of an overdose, but can be observed against the background of a stable dose, especially in elderly patients, against the background of somatic diseases, infections.

Neurotoxicity of levodopa

The problem of levodopa toxicity is extremely important, since it determines the timing of the initiation of levodopa therapy, the duration of its use, and the dosages used. In the process of enzymatic oxidation of dopamine, neurotoxic substances are formed - hydrogen peroxide, quinones, semiquinones, levodopa-neuromelanin compounds, therefore, levodopa, by increasing the content of dopamine in the brain, can activate oxidative stress mechanisms [44]. In an in vitro

with cultured dopaminergic neurons, levodopa was shown to induce neuronal death, but the culture media used in these studies had either reduced numbers or complete absence of potentially neuroprotective glial cells [63].
In experiments on animals with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-OHDA (6-hydroxydopamine)-induced parkinsonism, conflicting results were obtained. Thus, S. Blunt, T. Fukuda [11, 25] showed that long-term use of levodopa caused the loss of nigrostriatal neurons compared to animals in the control group that did not receive levodopa. At the same time, 6-month use of levodopa in 6-OHDA-induced parkinsonism in rats contributed to the restoration of striatal innervation [39]. Other researchers agree with similar conclusions [18, 31, 48]. H. Okazawa et al. [43] showed that levodopa is able to increase the content of brain-derived neurotrophic factor mRNA in the striatum of mice. Another study found that the use of levodopa may lead to activation of the natural antioxidant glutathione [30]. It is possible that the inconsistency of the research results obtained is a consequence of the different ages of the animals used in the experiments. Young animals have stronger neuronal detoxifying mechanisms. Thus, to simulate parkinsonism in old rats, a 2-fold lower dose of MPTP is required than in young animals [1, 2]. In addition, we do not fully know the potential capabilities of natural defense systems in vivo
. In clinical studies, administration of high doses of levodopa to patients without PD did not lead to the development of parkinsonism [3, 52]. A comparison of the survival of patients with an autosomal dominant form of PD before 1969 (before the introduction of levodopa) and against the background of levodopa therapy showed that patients receiving levodopa had a 2-fold longer life expectancy (15 years versus 7 years) [28].

The multicenter placebo-controlled ELLDOPA trial was conducted at 35 centers in North America to evaluate the effects of different dosages of levodopa and placebo on the rate of progression of PD in 360 untreated patients with early-onset disease. Patients received one of three dosages of levodopa/carbidopa (150/37.5; 300/75; 600/150 mg per day in 3 divided doses) or placebo for 40 weeks. In the group receiving placebo, the degree of increase in motor disorders was significantly higher than in patients treated with levodopa [22].

Time to start therapy

The timing of levodopa administration is widely debated. Thus, among some specialists there is a certain element of levodopaphobia, associated with fears of the above-mentioned neurotoxicity, as well as with an increased risk of developing motor fluctuations and dyskinesias. Proponents of this point of view recommend delaying the initiation of levodopa therapy in young patients until significant motor impairments are not controlled by taking insufficient drugs. Most often, dopamine receptor agonists, amantadines, and MAO-B inhibitors are called among the starting therapy drugs for PD, due to their possible neuroprotective effect [17, 27, 38, 46, 50, 53, 57, 59]. Patients over 70 years of age are recommended to begin treatment for PD with levodopa, since their effectiveness is higher, and the side effects of levodopa do not have time to develop. This tactic is in accordance with the recommendations of the EFNS/MDS-European Section. At the same time, a number of other experts believe that delayed initiation of levodopa therapy does not allow for maximum benefit from using the drug, and the quality of life of such patients is lower [36].

Levodopa preparations and recommended doses

Levodopa preparations can be divided into 2 groups depending on the peripheral DDC inhibitor they contain - carbidopa and benserazide (see table).

Carbidopa contains nakom, sinemet, tidomet, duellin, sindopa. Benserazide is part of the only drug madopar. Treatment with levodopa drugs begins with a minimum dose, gradually increasing the dosage to an effective one. Typically, the average dose of dopa-containing drugs ranges from 300 to 750 mg per day. The frequency of administration in the initial stages is 3-4 times a day.

The results of clinical studies show that the risk of developing motor fluctuations and dyskinesias depends on the dose of levodopa taken, so the daily dosage should usually not exceed 1000 mg/day.

To reduce gastrointestinal complications, domperidone (Motilium) 10 mg 20-25 minutes before taking levodopa can be recommended. Cardiac arrhythmias can be controlled with beta blockers. To correct orthostatic hypotension, it is recommended to increase fluid and salt intake, as well as prescribe the synthetic corticosteroid fludrocortisone.

Side effects of levodopa drugs on the central nervous system include agitation, confusion, hallucinations, delusions, hypersexuality, and depression [24]. If they occur, it is recommended to reduce the daily dose of levodopa, as well as other antiparkinsonian drugs, primarily dopamine receptor agonists, amantadine, anticholinergics, and MAO-B inhibitors. If side effects persist within 2 days, atypical antipsychotics (clozapine, ondasetron, olanzapine, quetiapine) are prescribed, since they do not increase the main symptoms of parkinsonism [8].

Along with standard levodopa preparations, long-acting and fast-acting preparations are used. The first include madopar HBS and sinemet CR. The peculiarity of their action is the delayed onset of action and the gradual release of the active substance. If, when taking conventional forms of levodopa preparations, the peak concentration is observed 30-60 minutes after administration, then the absorption of prolonged forms is extended for several hours. The bioavailability of prolonged forms is lower, which requires increasing the single dose by 25-30%. Typically, long-acting forms are prescribed at bedtime to relieve nighttime stiffness, as well as in case of “dose depletion” motor fluctuations [19, 21, 29, 54]. To ensure a faster “on”, especially in the morning, a standard form of the drug is added to the prolonged form.

Fast-acting dispersible madopar provides faster “switching on” - on average after 15-20 minutes (standard form - after 30-45 minutes). The drug is intended for use in cases where it is necessary to quickly “turn on” the patient - morning or night akinesia, akinesia during the “off” period, etc. The drug may be indispensable in patients with swallowing disorders [37].

In 2005, a new generation of levodopa drug, Stalevo (levodopa/carbidopa/entacapone), appeared in Russia. The drug is available in 3 dosages (based on levodopa content): stalevo - 50, stalevo - 100, stalevo - 150. Each tablet, regardless of the dosage, contains a fixed amount of entacapone - 200 mg, so the tablets cannot be divided when taken. The main indication for prescribing stalevo is motor fluctuations - the phenomenon of “dose depletion”, “on-off”, etc. There is data from comparative clinical studies on the use of two-component drugs levodopa and levodopa/carbidopa with entacapone, indicating an improvement in daily activity and quality of life of patients, and also allowing to reduce the daily dose of levodopa drugs when using a combination of levodopa/carbidopa/entacapone.

Switching from one levodopa drug to another

It should be taken into account that in such drugs as nacom, duellin, sindopa, etc., there is less DDC inhibitor compared to madopar, and there is more levodopa. Therefore, when switching from these drugs to Madopar, you need to slightly increase the dosage. The transition is carried out the next day after an overnight break. The frequency of drug intake remains the same.

When converting from two-component levodopa preparations to Stalevo, choose a form of Stalevo with an equivalent levodopa content. A slight reduction in the dose of levodopa is allowed (by 5-10%). When switching to Stalevo from a slow-release drug, the dose of levodopa is reduced by 20-30%. The transfer is also carried out after a night's sleep. If a single dose of a 2-component drug in a patient exceeded 200 mg, then when switching to Stalevo, a combination of Stalevo with a small amount of a two-component drug is possible. To ensure stability of levodopa concentrations, the frequency of administration of Stalevo, as well as other levodopa preparations, should not be less than 3 times a day.

Motor fluctuations and dyskinesias

The stable effect of levodopa (the so-called “honeymoon”) lasts for 2-4 years. Subsequently, the patient develops specific changes in the response to standard doses of levodopa—motor fluctuations and dyskinesias [23, 51, 52, 56]. The risk of developing motor complications depends on the total cumulative dose of levodopa received as a result of treatment, duration of treatment and age at initiation of therapy. The incidence of motor fluctuations and dyskinesias, according to a review of 74 publications [4], after 5 years of levodopa therapy is 40%. According to the prospective DATATOP study, after 20.5 ± 8.8 months of therapy, the “dose depletion” phenomenon was observed in almost half of the cases, dyskinesia in ⅓ of patients, and a severe “on-off” phenomenon in approximately 10% of cases [47]. In most patients, motor fluctuations and dyskinesias develop within the first year of levodopa therapy [40]. The ELLDOPA study showed that 40 weeks of high-dose (600 mg/day) levodopa resulted in fluctuations more frequently than lower doses (150 and 300 mg/day). When taking 600 mg per day after 40 weeks, the phenomenon of “dose depletion” was noted in 29.7% of patients [22]. To determine the effect of age at treatment on subsequent disease course and response to levodopa, 48 patients with early-onset PD (<40 years of age) were compared with 123 patients with late-onset PD (60 years or later). Patients with early onset of the disease had a better response to levodopa, but the risk of developing motor complications was higher. On average, the risk of motor fluctuations and dyskinesia increases by 10% every year of taking dopa-containing drugs [34].

Changes in the motor response of levodopa are associated with progressive loss of neurons in the substantia nigra. The remaining neurons are unable to accumulate and retain incoming levodopa. As a result, dopamine begins to be released into the synaptic cleft randomly. Due to the short half-life of levodopa, stimulation of dopamine receptors becomes pulsatile, leading to fluctuations in the patient's motor state [14, 15, 61]. Against the background of dopamine deficiency, denervation hypersensitivity of dopamine receptors in the striatum develops, which is the cause of the development of “dose peak” dyskinesia. Pulsatile stimulation of dopamine receptors leads to changes in the production of preproenkephalins A and B, which affect the functional activity of GABAergic pathways [9, 25]. The result of these changes is disruption of the functional activity of the basal ganglia system and destabilization of cortical-subcortical interactions caused by the pharmacokinetics of dopamine in the striatum and periphery. An additional factor contributing to the development of motor fluctuations and dyskinesias are disturbances in the absorption of levodopa in the gastrointestinal tract (GIT) and intestinal motility.

Fluctuations in the motor state can be divided into predictable and unpredictable (in relation to levodopa administration).

Predictable fluctuations

: the phenomenon of “dose depletion” - a decrease in the duration of action of levodopa with an increase in motor, sensory vegetative symptoms by the time of the next dose of the drug; the “on-off” phenomenon is sudden changes in motor activity of the “all or nothing” type.

Unpredictable fluctuations

: “missing a dose” - lack of effect from the dose of levodopa taken; “Yo-yoing” is chaotic fluctuations in well-being from hypo- to hyperactivity.

The deterioration of motor symptoms during the “off” period is accompanied by an increase in non-motor symptoms of PD - vegetative (sweating, tachycardia, shortness of breath, frequent urination), sensory (pain, paresthesia), emotional and affective disorders (anxiety, irritability, depression, confusion). During the “on” period, euphoria, hypomania, and hypersexuality may be observed. Often it is non-motor symptoms that have a greater destabilizing effect on the patient than fluctuations in motor activity.

According to the classification of C. Olanow [45], the following types of dyskinesias are distinguished: “peak dose” dyskinesia. Most often in the form of choreiform hyperkinesis of the muscles of the face, trunk, and limbs. Observed against the background of a peak concentration of levodopa in the blood; biphasic dyskinesia that occurs at the beginning and end of the action of the next dose of levodopa. Usually it has the character of either choreiform hyperkinesis or dystonia of various localizations; dystonia of the “off” period occurs at the end of the drug’s action against the background of a drop in the concentration of levodopa in the blood. Most often it occurs in the morning in the form of dystonia of the feet, muscles of the face and neck.

To correct motor fluctuations and dyskinesias, several strategies are used aimed at maintaining the stability of the concentration of levodopa in the basal ganglia: 1) increasing the frequency of administration and reducing the single dose of levodopa (the daily dose remains the same). The frequency of administration should not be more than 5-6 times, otherwise a single dose will be insufficient to “switch on” the patient. This approach is possible at an early stage of fluctuation development; its effectiveness is temporary; 2) reducing the daily dose of levodopa by adding dopamine receptor agonists, amantadines, and MAO-B inhibitors to the treatment regimen; 3) replacing standard forms of levodopa with long-acting or fast-acting ones. Prolonged forms are often prescribed at night to correct nighttime akinesia and reduce the severity of morning akinesia. When replacing daily doses of standard levodopa, one must remember that the bioavailability of prolonged forms is lower and in some cases it is necessary to increase the dose of levodopa by 30-40%. The onset of improvement from taking such drugs is delayed and, due to the low peak concentration, is not so pronounced. In such cases, standard doses of levodopa should be added to the long-acting forms. Fast-acting forms are used to relieve morning akinesia, as emergency medications for sudden hardening; 4) the use of drugs that reduce the catabolism of levodopa - COMT inhibitors (entacapone, tolcapone), MAO-B inhibitors (selegiline, rasagiline).

Since COMT inhibitors are not available as stand-alone drugs in Russia, if fluctuations occur, patients should be transferred to the combination drug levodopa stalevo, which contains a COMT inhibitor (entacapone). This approach is most widespread in the world, as it has the highest level of evidence A; 5) impact on the adsorption and transport of levodopa in the gastrointestinal tract - normalization of intestinal motility, hypoprotein diet, taking the drug before or after meals with an interval of 45-60 minutes. If dyskinesia occurs, it is recommended to take levodopa after meals.

We should look at approaches to correcting the most common motor fluctuations and dyskinesias in more detail.

Therapy for the “dose depletion” phenomenon

: increasing the frequency of levodopa administration and, as a rule, the total daily dose; adding long-acting forms of levodopa; adding COMT inhibitors, switching to steel; adding dopamine receptor agonists, amantadine, and MAO-B inhibitors to levodopa therapy.

To relieve morning dystonia

used: late evening administration of levodopa drugs; evening intake of dopamine receptor agonists; prescription of “correctors” (baclofen 5 mg 2 times a day, clonazepam 1 mg 2 times a day).

In order to reduce “peak dose” dyskinesias

the following methods are used: withdrawal of MAO-B inhibitors, anticholinergics, COMT inhibitors; reducing the single dose of levodopa and increasing the frequency of administration; taking levodopa with meals; adding amantadine; reducing the dose of levodopa and adding dopamine receptor agonists.

Therapy of biphasic dyskinesias

most difficult. The most commonly used options are: reducing the dose of levodopa with the simultaneous addition of dopamine receptor agonists or COMT inhibitors, switching to Stalevo; discontinuation of long-acting forms of levodopa; increasing the frequency of levodopa administration; addition of amantadine.

Intraduodenal form of levodopa

A new direction in the strategy of continuous dopaminergic stimulation is the administration of levodopa drugs directly into the gastrointestinal tract [5, 42, 58]. Duodopa (a suspension of levodopa/carbidopa in a ratio of 20:5 mg/ml) in the form of a gel is administered through a special pump into the initial part of the small intestine. To install the system, percutaneous endoscopic gastrotomy with placement of a duodenal tube or gastrotomy is used. To select the required dose and rate of administration of the drug, a nasoduodenal tube is initially installed for several days. After this, the probe is removed, and duodopa from cassettes attached to the belt is delivered through a pump into the intestines according to an individual program. This system of levodopa administration has been used for several years to treat patients with advanced stages of PD in Europe, Australia, and Canada.

Conclusion

Despite the attempts of scientists to find drugs with neuroprotective properties, as well as certain successes in neurosurgical interventions, at present the main type of treatment for PD remains replacement therapy. Levodopa is an undoubted achievement of modern pharmacology and, in terms of its effectiveness, has no competitors among other drugs for the treatment of parkinsonism. The steady progression of the disease requires lifelong use of levodopa-containing drugs, which can be prescribed either in mono- or combination therapy. Further development of this area will apparently be associated with the search for new possibilities for delivering levodopa to the brain and maintaining a stable concentration of levodopa in the basal ganglia.