Material and methods
At the city office for extrapyramidal diseases of the nervous system (Voronezh), the effectiveness of treatment of patients with PD with the drug stalevo was assessed.
The study included 47 patients, 21 men and 26 women, with stage 3-4 PD (according to Hoehn and Yahr). The age of the patients ranged from 58 to 76 years, the duration of the disease was 6-18 years.
The patients had clinical signs of motor fluctuations with the presence of dose depletion and on-off phenomena. 7 patients had disturbances in the form of choreiform dyskinesia or painful dystonia, 8, in addition, had “night” symptoms (akinesia, myoclonus, restless legs syndrome, urinary disorders). Patients received two-component levodopa preparations for 3 years or more (levodopa dose from 600 to 1500 mg) in combination with non-ergoline dopamine receptor agonists and/or amantadines.
All patients were prescribed the drug stalevo (100-150 mg) in combination with two-component levodopa preparations (¼-½ tablets of levodopa-carbidopa or levodopa-benserazide 3-4 times a day) taking into account the equivalent daily dose of levodopa. For patients on quadruple levodopa dosing, ¾ to a full tablet of levodopa-carbidopa or levodopa-benserazide was prescribed. In the treatment regimen for patients with nocturnal symptoms, the third dose of Stalevo was prescribed before bedtime. For patients with an increased daily dose and frequency of levodopa administration (more than 5 times a day), the treatment regimen was optimized (no more than 1000 mg of levodopa per day).
The effectiveness of treatment was assessed using the Unified PD Rating Scale (UPDRS), the patient's self-monitoring diary, and a questionnaire of motor function fluctuations. Control examinations were carried out after 1, 4 and 6 weeks of treatment.
The use of levodopa in the treatment of Parkinson's disease
Levodopa drugs have been used to treat Parkinson's disease (PD) since the late 1960s. It is difficult to find drugs in the history of neurology that would make such a radical revolution in the treatment of the disease as dopa-containing drugs. After their implementation, thousands of patients with Parkinson's disease who were bedridden were able to move around and lead an active lifestyle for a long time. Today, levodopa drugs are called the “gold standard” for the treatment of PD, since to this day they are the most effective against all the main symptoms of parkinsonism.
Table 1. Dopa-containing drugs
Table 2. Distribution of patients receiving Syndopa (Group I) and Nakom (Group II) by gender, age, clinical form and stage of the disease
Table 3. Evaluation of the effectiveness of therapy with syndopa and nacom according to the USHOBP scale, part III (motor activity)
Figure 1. Changes in quality of life indicators on the PDQ-39 scale (total score) in patients in the syndopa and nacoma groups
Figure 2. Changes in quality of life indicators on the PDQ-39 scale (total score) in patients in the syndopa and nacoma groups
Table 4. Side effects when using syndopa and nacom drugs in patients with Parkinson's disease
The most important event in the use of levodopa drugs was the discovery in the late 50s by the Swedish scientist A. Carlsson of dopamine in the brain (7), for which he was awarded the Nobel Prize in 2000. At the same time, I. Sano et al. (40) showed that dopamine is localized predominantly in the lenticular nucleus, caudate nucleus, thalamus, and hypothalamus. The next step towards understanding the causes of Parkinson's disease was made by H. Ehringer and O. Hornykiewicz (15). In 1961, examining the brains of patients who died from PD, they found a significant decrease in dopamine in the basal ganglia. But dopamine itself could not be used to treat Parkinson's disease, because. does not penetrate the blood-brain barrier (BBB). Then they remembered its metabolic predecessor levodopa. Back in the 50s of the last century, A. Carlsson showed that levodopa can prevent akinesia caused by the administration of reserpine in experimental animals (7). These reports led to a small, open-label study in Vienna (20 patients) conducted by W. Birkmayer and O. Hornykiewicz with single (2 g) intravenous levodopa in PD patients, the results of which were published in 1961 (5). 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 (4) independently tested the effectiveness of levodopa in patients with PD and also noted the therapeutic effect of levodopa. A few years later (1967), G. Cotzias reported an improvement in the condition of patients with PD treated with high doses (up to 16 g/day) of oral levodopa. He was the first to propose a technique for gradually increasing the dose of levodopa during treatment in order to reduce the severity of side effects, which is successfully used to this day (11). 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/day. – contribute to the development of choreiform and athetoid hyperkinesis (44). Industrial production of levodopa was established by 1970, and from the same year levodopa was approved for use in the United States.
However, the use of “pure” levodopa was accompanied by a large number of side effects such as nausea, vomiting, blood pressure fluctuations, and heart rhythm disturbances. The solution to this issue was found by W. Birkmayer, who was the first to use levodopa in combination with a DOPA decarboxylase (DDC) inhibitor. The combined use of a DDC inhibitor and levodopa increased the therapeutic efficacy of levodopa and improved tolerability. The mechanism that increases the bioavailability of levodopa against the background of a DDC inhibitor was discovered much later by A. Pletscher and M. DaPrada (1993) (35). DDC inhibitors - carbidopa and benserazide - do not penetrate the blood-brain barrier, but block the transformation of levodopa into dopamine in the periphery, as a result of which the number of adverse gastrointestinal and cardiovascular effects is reduced, and the dose of levodopa is reduced by 60-80% (8, 30 ). The combination of levodopa and a DDC inhibitor was launched in 1975 (43). The first drug released in Europe was madopar (levodopa in combination with benserazide). Almost simultaneously with madopar, Sinemet (levodopa/carbidopa) was released in the United States.
Levodopa (an aromatic acid) taken orally is almost completely absorbed in the small intestine through the amino acid transporter system. Amino acids contained in food may compete with levodopa for transport across the intestinal wall. Therefore, levodopa should be taken before or after meals with an interval of 45-60 minutes. Levodopa can be taken on an empty stomach. In this case, the effect of the drug occurs faster. If this is not possible, then it is better to take levodopa with a small amount of carbohydrate food (25). At the same time, 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 and helps achieve its peak concentration. Part of levodopa, despite the use of DDC inhibitors, is metabolized in the periphery in the gastrointestinal tract, capillary endothelium, parenchymal organs with the formation of dopamine (24). An excessive concentration of dopamine is created in the bloodstream, which affects the receptors of the cardiovascular system, causing arrhythmias, blood pressure fluctuations, tachycardia, orthostatic hypotension, angina pectoris, and also stimulates the receptors of the vomiting center of the medulla oblongata that are not protected by the blood-brain barrier, which is manifested by nausea, vomiting, loss appetite. Gradual titration of the dose of levodopa over 2 weeks makes it possible to reduce the number of side effects. You can also recommend taking domperidone (Motilium) 10 mg over 20-25 minutes. before taking levodopa. Cardiac arrhythmias are 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.
Levodopa, having crossed the blood-brain barrier, 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. At the same time, 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 DOPA decarboxylase. The release of dopamine from these cells occurs chaotically. The progression of the disease leads to a critical decrease in the number of nigrostriatal neurons. An increasing amount of levodopa supplied from outside is processed in glial cells. The remaining dopaminergic neurons lose their buffering capacity, causing dopamine release to passively follow the fluctuations of levodopa in the blood (9, 10, 43). 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, as well as against the background of an aggravated somatic disease or infection.
The timing of levodopa administration is widely discussed among specialists. On the one hand, there is an element of levodopaphobia associated with fears of neurotoxicity, as well as an increased risk of developing motor fluctuations and dyskinesias. Proponents of this tactic recommend delaying the initiation of levodopa therapy in young patients until significant motor impairments that are not controlled by taking low-dose medications. 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 (12, 19, 28, 33, 36, 38, 41, 42). 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 the drug and the quality of life of such patients is lower (26).
Concerns about the neurotoxicity of levodopa are based on the fact that in the process of enzymatic oxidation of dopamine, potentially neurotoxic substances are formed - hydrogen peroxide, quinones, semiquinones, levodopa-neuromelanin compounds, therefore levodopa, potentially increasing dopamine levels in the brain, can theoretically activate oxidative stress mechanisms, i.e. .e. exhibit neurotoxicity (32). in
vitro
experiment with cultured dopaminergic neurons did show that levodopa causes neuronal death, but the culture media used in these studies had either reduced numbers or complete absence of potentially neuroprotective glial cells (45). In animal experiments with MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) and 6-OHDA (6-hydroxydopamine)-induced parkinsonism, conflicting results were obtained. A number of researchers, S. B. Blunt (1993), T. Fukuda (1996), showed that chronic use of levodopa caused loss of nigrostriatal neurons compared to a control group of animals that did not receive levodopa (6, 18). On the other hand, 6-month administration of levodopa to 6-OHDA-induced parkinsonism in rats actually promoted restoration of striatal innervation (29). A number of other researchers agree with this opinion - F. Hefti (1981), TL Perry (1984), KP Datla (2001) (13, 23, 34). H. Okazawa and colleagues (1992) showed that levodopa is able to increase the content of brain-derived neurotrophic factor mRNA in the striatum of mice (31). Another study found that levodopa may activate the natural antioxidant glutathione (22). It is possible that the conflicting results of the studies are a consequence of the different ages of the animals included in the experiment. Young animals have great potential for neuronal detoxifying mechanisms. Thus, to simulate parkinsonism in old rats, the dose of MPTP required is 2 times less than in young animals (1, 2). In addition, we do not fully know the potential capabilities of natural defense systems in in vivo conditions. In clinical studies, high-dose levodopa in patients without PD did not lead to the development of parkinsonism (3, 37). 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 family members receiving levodopa had a 2-fold longer life expectancy (15 years versus 7 years) (20).
The large, multicenter, placebo-controlled ELLDOPA trial was conducted at 35 centers in North America. The main objective of this study was to evaluate the effect 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 (150/32.5; 300/75; 600/150 mg/day in three divided doses) or placebo for 40 weeks. The study results were assessed 2 weeks after discontinuation of the drug. In the placebo subgroup, the degree of increase in motor disorders was significantly greater than in patients receiving levodopa (17).
Levodopa preparations can be divided into 2 groups depending on the inhibitor of peripheral DOPA decarboxylase they contain - carbidopa and benserazide (Table 1). Drugs containing carbidopa include nacom, sinemet, tidomet, duellin, sindopa. Benserazide is part of the only drug madopar. As a rule, 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/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.
Along with standard levodopa preparations, long-acting and fast-acting preparations are used. Long-acting drugs include madopar HBS and sinemet CR. The peculiarity of the action of these drugs is the delayed onset of action compared to standard drugs and the gradual release of the active substance. If, when taking conventional forms of levodopa preparations, the peak concentration is observed after 30-60 minutes. after administration, the absorption of prolonged forms lasts for several hours. At the same time, the bioavailability of prolonged forms is lower, which requires an increase in the single dose by 25-30%. Typically, long-acting forms are prescribed at night to relieve nighttime stiffness, as well as in cases of motor fluctuations due to dose depletion (27, 16, 21, 39). To ensure faster onset, especially in the morning, a standard form of the drug is added to the long-acting form.
Fast-acting dispersible madopar ensures faster activation - 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 switch on the patient - morning or night akinesia, akinesia during the “off” period, etc. The drug may be indispensable in patients with swallowing disorders (27).
In clinical practice, there is often a need to transfer patients from one dopa-containing drug to another due to poor tolerability of the drug or economic necessity. When changing the drug, it should be taken into account that dopa-containing drugs may have different levels of levodopa, therefore, when switching from a drug with a higher content of levodopa to a drug with a lower content, the dosage must be slightly increased. The transition is carried out the next day after an overnight break. The frequency of drug intake remains the same. Today on the Russian market, along with European drugs that have been used for a long time in our clinical practice, new drugs from other manufacturers are appearing (generic drugs, i.e. drugs produced by various pharmaceutical companies after the patent on the original drug has expired). When switching from one dopa-containing drug to a similar one to another, you need to be sure that their clinical effect is comparable.
As part of a comparative open study, we assessed the comparability of the clinical effects and tolerability of syndopa and nacom. Sindopa and Nacom contain the same DDC inhibitor, carbidopa, and the levodopa/carbidopa ratio in these drugs is also the same (10 to 1).
The patients were divided into two groups. Patients of group I (25 patients) received syndopa, patients of group II (20 patients) received nacom. The distribution of patients into groups was random. Patients of groups I and II were comparable in gender, age and severity of the disease.
The criteria for inclusion of patients in the study were the presence of an established diagnosis of PD with ineffectiveness of previous therapy with dopamine receptor agonists at the age of 50-60 years; intolerance to initially prescribed other drugs containing levodopa; severe manifestations of parkinsonism at the age of 50-70 years and age over 70 years with the initial prescription of levodopa.
Exclusion criteria were: severe cognitive impairment (MMSE score less than 18); decompensation due to concomitant somatic diseases (coronary heart disease, hypertension, exacerbation of gastric/duodenal ulcer). For patients who had not previously received levodopa, an additional exclusion criterion was orthostatic hypotension (decrease in systolic blood pressure ≥ 20 mm Hg 2-3 minutes after taking a standing position). For patients already receiving levodopa drugs, an additional exclusion criterion was inadequate dose (not corresponding to the individual optimal dose) administration of levodopa drugs before the patient was included in the study and the ineffectiveness of previous levodopa therapy at the individual optimal single and, accordingly, daily dose (no more than 400 mg per day) , i.e. at the dose that most significantly reduces the symptoms of parkinsonism and does not cause side effects or an increased risk of their development.
The stage of the disease was determined using the modified Hoehn & Yahr scale. The effectiveness and tolerability of therapy were assessed on the basis of the subscale (motor activity) of the Unified Scale for Assessing the Severity of PD Manifestations (USSBP), the Clinical Global Impression scale (CGI, subscales severity, improvement, severity of side effects), and the quality of life indicator according to the PDQ questionnaire - 39. The safety of therapy was monitored by the results of ECG, laboratory blood and urine tests (before and after the study).
The average age of the patients was 70.07 ± 4.32. The average age of onset of the disease was 66.21 ± 5.38 years. Among the patients, 55% (25 patients) were women, 45% (20 patients) were men. The duration of the disease ranged from 1 year to 6 years. According to the form of the disease, 23 patients (51%) had a predominantly tremor-rigid form, and 22 patients (49%) had an akinetic-rigid form of the disease. The stage of the disease corresponded to stage 1-2.5 according to the Hoehn & Yahr scale (Table 2).
Of the 45 patients with PD, 29 patients (64.4%) received antiparkinsonian therapy. 23 patients - dopamine receptor agonists, amantadines, 6 - levodopa drugs, 16 (35.6%) did not receive previous therapy.
An adequate daily dose of syndopa and nacoma drugs was selected individually by titration. The study included a screening visit with the selection of patients into the group and prescription of the drug, a visit after 2 weeks while taking the drug with the determination of the individual optimal single and daily dose of the drug, a visit after 4 weeks and a control visit at the end of the study. The duration of the study was 8 weeks. The intake of other antiparkinsonian drugs did not change during the dose selection phase and throughout the entire period.
The results of the study showed that the average daily dose of syndopa was 334.68 ± 53.58 mg, nacoma 320.79 ± 57.47 mg. Comparative dynamics of the main symptoms of PD before and after treatment for patients in both groups is presented in Table 3.
As can be seen from the presented results, both syndopa and nacom were effective against all the main symptoms of PD: hypokinesia, rigidity, tremor. There were no significant differences in motor activity indicators after the end of therapy between patients in groups I and II. Taking dopa-containing drugs led to a significant improvement in the quality of life of patients, assessed by the PDQ-39 scale (Figure 1). According to the “general clinical impression” scale – the “improvement of condition” subscale – in the group of patients receiving Syndopa, “improvement” was noted in 20 patients (87%). Of these, “noticeable improvement” was detected in 11 patients (48%), “no improvement” – in 2 patients (8.7%), “minor deterioration” – in 1 patient (4.3%). In group II, “improvement” was noted in 21 patients (95%), of which “noticeable improvement” was observed in 10 patients (45%), “no improvement” was observed in 1 patient (5%), and no deterioration of the condition was noted. According to the Clinical Global Impression (CGI) scale, a significant decrease in the severity of the condition was noted in patients of both groups (p
Side effects of therapy were assessed using the CGI subscale - “severity of side effects.” According to the severity of the side effect, the average score in patients of group I was 1.56 ± 0.52, in patients of group II – 1.03 ± 0.43.
In total, the presence of side effects was noted in 8 patients of group I (35%) and 5 patients of group II (23%). The most common side effects in both groups were dizziness, headaches, nausea, pain, abdominal discomfort, and sleep disturbances. In the group of patients receiving syndopa, nausea, dizziness, and headaches were more common (Table 4). In all cases, the negative effect was reduced by adjusting the dose of the drug taken.
Thus, a comparative study of the effectiveness of dopa-containing drugs Sindopa and Nakoma showed the comparability of the clinical effect of the drugs in terms of the effect on the main symptoms of parkinsonism, quality of life indicators and global clinical impression scales. The incidence of side effects was slightly higher in the group of patients receiving Syndopa. Side effects were predictable and typical for the entire group of dopa-containing drugs; they were identified during the period of syndopa dose selection and were eliminated by dose adjustment and a slower titration regimen. Of course, in patients taking dopa-containing drugs for a long time, it is necessary to adhere to treatment and approach drug changes with caution. At the same time, for patients who have not previously received treatment with levodopa, syndopa can be recommended as a starting therapy with dopa-containing drugs.
results
After 6 weeks of treatment, 45 of 47 patients experienced a decrease in the severity or complete disappearance of the dose “depletion” phenomenon, and a decrease in the duration of the “off” phenomenon during the day. In 5 patients the severity and duration of dyskinesia decreased; 2 patients noted a significant decrease in painful cramps and manifestations of restless legs syndrome; 4 patients noted improved sleep and decreased urgency to urinate. In 10 patients, it was possible to reduce the daily dose of levodopa without worsening general symptoms.
When analyzing the observed undesirable side effects, it turned out that 1 patient experienced dyspeptic symptoms in the first 2 days of taking the drug, and 2 patients experienced an increase in dyskinesia, which was stopped by reducing the daily dose of Stalevo. In 3 patients, orthostatic hypotension occurred, which was relieved by correction of antihypertensive therapy.
During treatment, there was a significant decrease in the severity of motor disorders in 42 patients according to part 1 of the UPDRS scale; 33 – in part 2 (everyday activities); in 23 - in the 3rd part (motor disorders) and in 37 - in the 4th part (dyskinesia).
Here is an example of a clinical observation.
Patient X.
, born 1942. In 2006, he consulted a neurologist at his place of residence with complaints of tremors in his right hand, changes in gait (“shuffling with his right foot”), changes in handwriting, and slowness of movements. PD was diagnosed and the drug Nakom was immediately prescribed at a dose of 125 mg 3 times a day. Over the course of 4 years, the patient independently increased the dose of Nakoma to 8 tablets of 250 mg per day. During treatment, the patient developed “twisting” in the limbs, swaying of the head, usually 1-2 hours after taking levodopa, severe trembling (before taking the medicine, and sometimes without connection with taking Nakoma) lasting from 2 to 4 hours, according to several times a day, muscle pain, leg cramps, more often in the evening, frequent urge to urinate, episodes of a sharp drop in blood pressure. The patient was referred for consultation to the office of extrapyramidal diseases of the nervous system.
The examination revealed: tremulous-rigid syndrome, predominantly expressed in the right extremities, motor fluctuations with the phenomena of “depletion” of the dose, “on-off”, drug-induced dyskinesias, postural disorders, the presence of autonomic dysfunction.
Concomitant diseases: coronary heart disease, atrial fibrillation. In 2007, a pacemaker was installed. Hypertension 11A, risk 111. Chronic heart failure. Prostate adenoma. Takes medications: nacom 250 mg 8 tablets, concor, omnic, cordarone, warfarin.
Recommended taking into account concomitant pathology: at 8 o'clock - madopar GSS 1 capsule + stalevo (150 mg) 1 tablet; at 10 a.m. - mirapex PD 0.75 mg; at 12 noon - Stalevo (150 mg) 1 tablet + ½-¼ Nakoma tablets; at 17:00 - ¾ Nakoma tablets; at 21:00 - Stalevo (150 mg) 1 tablet + ½ tablet of Nakoma.
After 1 month, there was a significant improvement in the condition in the form of regression of drug-induced dyskinesias and motor fluctuations, and the severity of autonomic dysfunction decreased. There was good tolerability of the drugs and a lasting therapeutic effect.
