Exelon Transdermal therapist sist 9.5 mg/24h N30 (Novartis)

Exelon is a selective inhibitor of brain acetyl- and butyrylcholinesterase used to treat Alzheimer's disease and dementia in Parkinson's disease. Rivastigmine slows down the destruction of the neurotransmitter acetylcholine produced by functionally intact neurons. At the same time, rivastigmine selectively increases the content of acetylcholine in the cerebral cortex and hippocampus, and thus helps to improve cholinergic nerve transmission. Exelon may have a positive effect on cognitive decline associated with acetylcholine deficiency, in particular in dementia associated with Alzheimer's disease and Parkinson's disease. In addition, there is evidence that inhibition of cholinesterases can slow down the formation of fragments of the amyloid-beta precursor protein involved in amyloidogenesis, and thus slow down the formation of amyloid plaques, which are one of the main pathological hallmarks of Alzheimer's disease. Rivastigmine interacts with the target enzyme with the formation of a covalent bond, which leads to temporary inactivation of the enzyme. In young healthy men, after taking Exelon 3 mg, cerebrospinal fluid (CSF) acetylcholinesterase activity has been shown to decrease by approximately 40% during the first 1.5 hours. After reaching the maximum inhibitory effect, enzyme activity returns to its original level after approximately 9 hours. It has been shown that butyrylcholinesterase activity in the CSF of young healthy volunteers is inhibited reversibly and is restored to its original level after 3-6 hours. In patients with Alzheimer's disease, the inhibition of acetylcholinesterase activity in the CSF by rivastigmine is dose-dependent over the dose range studied (up to the highest dose of 6 mg twice daily). Inhibition of butyrylcholinesterase is also dose-dependent: a dose of 6 mg 2 times a day causes a decrease in enzyme activity by more than 60% compared to the original. This effect of Exelon persisted for 12 months of therapy (the maximum period studied). Statistically significant correlations have been shown between the degree of inhibition of both CSF enzymes by rivastigmine and changes in cognitive function in patients with Alzheimer's disease; Moreover, it is the inhibition of butyrylcholinesterase in the CSF that reliably and consistently correlates with improved results of tests of memory, attention and reaction speed. The effectiveness of Exelon therapy for Alzheimer's disease has been shown in patients with mild to moderate dementia (10-24 points on the Mini Mental State Examination, MMSE). According to clinical studies, Exelon therapy leads to a significant improvement in cognitive functions (attention, memory, speech, etc.), functional status and activity in everyday life, as well as a decrease in the severity of the disease and the severity of mental and behavioral manifestations (such as agitation, tearfulness, illusions, hallucinations, etc.). Studies have shown that the effect of Exelon therapy is observed approximately at week 12 and persists for 6 months of therapy, while during the control period in the group of patients receiving placebo, a deterioration in the corresponding indicators was observed. In dementia associated with Parkinson's disease, the effectiveness of Exelon was demonstrated in a placebo-controlled study lasting 24 weeks in patients with mild to moderate dementia (MMSE score 10 - 24). Patients receiving Exelon showed a statistically significant improvement in cognitive functions (attention, memory, speech, etc.), while in patients receiving placebo, similar indicators worsened.

Exelon®

Absorption

Absorption of rivastigmine from TTC Exelon® occurs slowly. After using the first dose of the drug, the time to achieve a detectable concentration of rivastigmine was 0.5-1 hour. The maximum concentration (Cmax) in plasma is achieved after 10-16 hours. After reaching Cmax, the concentration in the blood plasma slowly decreases during the remaining 24-hour period of use of TTS Exelon ®.

The equilibrium concentration of rivastigmine in the blood plasma after replacing the used Exelon® TTC with a new one slowly decreases over an average of approximately 40 minutes, until the absorption of the active substance from the newly glued Exelon® TTC begins to prevail over elimination. Thereafter, the plasma concentration of rivastigmine begins to rise slowly and again reaches a maximum after approximately 8 hours. At steady state, the lowest concentration is approximately 50% of the maximum, in contrast to oral administration, in which the plasma concentration is virtually zero between doses. Similar temporal characteristics of plasma concentrations of rivastigmine were observed with the use of TTC Exelon®, in the dose range from 4.6 mg/24 hours to 13.3 mg/24 hours. Despite the fact that the exposure (Cmax and area under the “first pass” curve through the liver).

Removal

EXELON TTC transderm patch. 9.5 mg/24 h pack. No. 30

Pharmacokinetics

inhibition of butyrylcholinesterase is also dose-dependent: a dose of 6 mg 2 times a day causes a decrease in enzyme activity by more than 60% compared to the original. This effect of Exelon persisted for 12 months of therapy (the maximum period studied). Statistically significant correlations have been shown between the degree of inhibition of both enzymes in the CSF by rivastigmine and changes in cognitive function in patients with Alzheimer's disease, while it is the inhibition of butyrylcholinesterase in the CSF that significantly and consistently correlates with improved results in tests of memory, attention and reaction speed. The effectiveness of Exelon therapy for Alzheimer's disease has been shown in patients with mild to moderate dementia (10-24 points on the Mini Mental State Examination, MMSE). According to clinical studies, Exelon therapy leads to a significant improvement in cognitive functions (attention, memory, speech, etc.), functional status and activity in everyday life, as well as a decrease in the severity of the disease and the severity of mental and behavioral manifestations (such as agitation, tearfulness, illusions, hallucinations, etc.).

Studies have shown that the effect of Exelon therapy is observed approximately at week 12 and persists for 6 months of therapy, while during the control period, a deterioration in the corresponding indicators was observed in the group of patients receiving placebo.

In dementia associated with Parkinson's disease, the effectiveness of Exelon was demonstrated in a placebo-controlled study lasting 24 weeks in patients with mild to moderate dementia (MMSE score 10 - 24). Patients receiving Exelon showed a statistically significant improvement in cognitive functions (attention, memory, speech, etc.), while in patients receiving placebo, similar indicators worsened.

Rivastigmine (Exelon) in the treatment of Parkinson's disease with dementia

In the pathogenesis of dementia in PD, critical importance is currently attached to the development of acetylcholinergic deficiency. Moreover, many researchers report a more significant severity of acetylcholinergic deficiency in PD with dementia than in Alzheimer’s disease [15]. According to pathomorphological studies, patients with PD and dementia exhibit a significant decrease in the number of cells in the basal nucleus of Meynert, where neurons producing acetylcholine are located [17,31]. The results of some studies indicate that Alzheimer's changes (neurofibrillary tangles, senile plaques) make a certain contribution to the pathogenesis of dementia in PD [5,9,26]. According to pathomorphological studies, with long-term blockade of muscarinic receptors (for example, when taking anticholinergic drugs), the density of senile plaques and neurofibrillary tangles in the cerebral cortex of patients with PD increases by 2.5 times [12]. This suggests that cholinergic drugs may have a neuroprotective effect in patients with PD. The concentration of acetylcholine in the brain is regulated by the enzymes choline acetyltransferase (participates in the formation of acetylcholine), acetylcholinesterase and butyrylcholinesterase (destroy acetylcholine). In patients with PD and dementia, a decrease in choline acetyltransferase activity is found in the cortical regions of all lobes of the brain, while the degree of decrease in its activity in the temporal lobes correlates with the severity of cognitive disorders [27]. The role of acetylcholine deficiency in the genesis of cognitive impairment in PD is also evidenced by positron emission tomography (PET) data, revealing a decrease in the activity of cortical acetylcholinesterase [15]. Acetylcholinergic deficiency in PD with dementia is associated with the development of psychotic disorders and, in particular, hallucinations [6]. To compensate for acetylcholinergic deficiency, drugs from the group of acetylcholinesterase inhibitors are currently used. The effectiveness of these drugs was initially proven in mild to moderate Alzheimer's type dementia, after which acetylcholinergic drugs became the standard treatment for this disease [2,8]. Rivastigmine (Exelon) is a drug from the group of acetylcholinesterase inhibitors, the specific difference of which is the selective inhibition of acetylcholinesterase and butyrylcholinesterase, the enzymes responsible for the destruction of acetylcholine in the cholinergic synapse [8,12]. It is believed that during therapy with rivastigmine, an increase in movement disorders rarely occurs, which is associated with the selective effect of the drug on the G1 isoform of acetylcholinesterase, which is more abundant in the hippocampus and cortex and less in the caudate nucleus [16]. The results of a number of studies suggest that the use of Exelon contributes to a significant improvement in cognitive functions and a reduction in the severity of behavioral and psychotic disorders in patients with PD [21,30]. Of greatest interest are the results of a recent randomized placebo-controlled study of the effectiveness of Exelon in PD with dementia (EXPRESS study). The effectiveness of Exelon was evaluated in 68 centers in 12 countries. The study included 541 patients. After 6 months of therapy with Exelon at a dose of 3-12 mg per day, a positive effect was obtained that exceeded placebo in relation to cognitive and behavioral disorders, as well as psychotic disorders. Analysis of motor disorders showed the absence of a negative effect of Exelon on the main symptoms of PD [19]. Subsequent studies of the effectiveness of Exelon confirmed that the reduction in the severity of cognitive impairment in PD persists even with long-term courses of therapy [28]. Thus, international studies conducted to date have shown that Exelon is an effective drug for PD with dementia. We analyzed our own experience of using Exelon in this category of patients. The purpose of this study was to further study the effect of Eselon on cognitive and motor functions in PD with dementia, as well as to assess the safety and tolerability of this drug. Patients and research methods The main group included 15 patients with PD and dementia (8 men and 7 women) aged from 54 to 80 years (mean age 71.3±6.6 years). The diagnosis of PD was established in accordance with the criteria of A. Hughes et al. and the UK Brain Bank [23]. 14 patients had higher education, 1 had specialized secondary education. The average duration of the disease was 7.8±4.3 years. The distribution of patients according to the form of the disease was as follows: the akinetic-rigid form was observed in 8 patients, in 5 – rigid-tremorous, in 2 – tremulous-rigid. The stage of the disease according to the Hoehn and Yahr scale was on average 3.0±0.5 (2.5 in 4 patients, stage 3.0 in 9 patients, stage 4.0 in 2 patients). Exelon was prescribed according to the following regimen: from 1 to 4 weeks: 1.5 mg twice a day, from the 4th week – 3.0 mg twice a day. The duration of treatment was 6 months. Simultaneously with the study drug, patients in the main group received levodopa. The comparison group (control) included 15 patients with PD (9 men and 6 women, average age 70.0±7.4 years, average disease duration - 9.5±5.8 years), who received only standard antiparkinsonian therapy . Patients in the main group and the comparison group were comparable in age, gender, level of education, severity of cognitive and motor disorders. In the main group, 1 (6.7%) patient had vivid dreams, 5 (33.3%) had illusions and hallucinations with a critical attitude towards them, and 1 (6.7%) had hallucinations with impaired criticism. Patients in the control group had no psychotic disorders at the time of the examination. All patients underwent clinical neurological and neuropsychological examination before starting Exelon and after 3 and 6 months from the start of treatment. To assess motor disorders, the Unified Parkinson's Disease Rating Scale (USPDS) and the Hoehn and Yahr scale were used. The neuropsychological study included the following methods: the Brief Mental Status Scale (MSMS) [20], the Battery of Tests for the Assessment of Frontal Dysfunction (BTLD) [18], the Mattis Dementia Scale (MDS) [25], the Clock Drawing Test, the Verbal Association Test (literal and categorical), test of repetition of series of numbers in forward and reverse order according to the Wechsler method, tracking test, test for symbolic-digital substitution [24], test “12 words” [22]. To assess the severity of psychotic disorders, the USHOBP scale was used (Part I – “Mental disorders”). To assess the safety and tolerability of the study drug, all adverse health events that occurred to the patient after taking the first dose of Exelon and until the end of observation were recorded. Diagnosis of dementia was carried out in accordance with the ICD-10 and DSM-IV criteria for dementia [7,14]. The obtained results were processed using the SPSS statistical package, version 10.0, using Wilcoxon–Mann–Whitney nonparametric statistics methods. Results A repeat clinical and neuropsychological study at the end of a 6-month follow-up period was carried out in 13 patients; 2 patients stopped treatment with Exelon before the end of follow-up. In 1 case, treatment discontinuation was due to adverse events (see below); another patient discontinued therapy independently for reasons unrelated to side effects. The average dose of Exelon was 5.8±0.7 mg per day. 12 patients received the drug at a dose of 3 mg 2 times a day, in 1 patient the dose of Exelon was 1.5 mg 2 times a day. During therapy with Exelon, there was a significant decrease in the severity of cognitive impairment, as evidenced by the positive dynamics of the results of the main neuropsychological scales in the main group of patients with PD: BTLD and SDM (Table 1, Figs. 1 and 2). In the control group, negative dynamics were noted (a significant decrease in the overall SDM score). Treatment with Exelon helped to reduce the severity of dysregulatory disorders. This was evidenced by a significant improvement in the total score of the test for symbolic-digital substitution (Table 1, Fig. 3). At the same time, there were no significant changes in speech fluency indicators (literal and categorical associations). In the control group, after 3 months of observation, a significant decrease in associative fluency was observed (Table 1). During therapy with Exelon, a significant improvement was observed in the “memory” subtest of the SDM, in which, along with the study of memorization and reproduction of individual words and pictures, memory for sentences and general memory (orientation in place, time and current events) are examined. It should be noted that this subtest involves the mechanisms of long-term memorization and retention of information and requires the stability of memory traces in relation to interference. Also, during treatment, there was a significant increase in the volume of free delayed reproduction in the “12 words” test and the total indicator of delayed reproduction in the same test. At the same time, the indicators of immediate reproduction (both free and with a hint) and delayed reproduction with a hint did not undergo statistically significant dynamics (Table 1, Fig. 4). Thus, according to our data, Exelon helps to increase the resistance of the memory trace to interference. In the control group after 3 months, a significant decrease in the volume of free direct reproduction was noted. Therapy with Exelon contributed to an improvement in concentration: we noted significant positive dynamics in the “digit repetition” test (Table 1). At the same time, treatment with the drug did not have a significant effect on the time required to complete the tracking test. We did not note any significant dynamics in the performance of the clock drawing test, which may indicate a minor influence of Exelon on spatial functions (Table 1). During treatment with the drug, there was a decrease in the severity of psychotic disorders, as evidenced by a significant decrease in the total indicator of the “psychotic disorders” section of the USHOBP (Part I) (Fig. 5). In 4 patients there was a complete regression of psychotic disorders, in 2 the severity and frequency of hallucinations decreased, in 1 patient the therapy contributed to the disappearance of vivid dreams. Analysis of the dynamics of motor disorders showed that Exelon therapy does not lead to an increase in the severity of parkinsonism symptoms. There was no significant decrease in either the total indicators of the “motor functions” section of the USOBP (part III, assessment in the “on” period) (p>0.05), or its individual indicators (bradykinesia, rigidity, resting tremor, postural disturbances). In the control group, after 3 months of observation, a significant increase in the severity of bradykinesia was revealed (initial - 16.31±5.76; after 3 months of observation 17.23±5.34; p<0.05). The remaining indicators of the “motor functions” section were stable and did not undergo significant changes in the subsequent 3 months of observation of the patients. During therapy with Exelon, 3 adverse events were recorded; in 1 case, discontinuation of the study drug was required. In one case, the adverse event was the occurrence of nausea in the 1st week of therapy, which went away on its own and did not recur with an increase in the dose of the drug. In 2 cases, an increase in anxiety and restlessness was noted, which, however, could not be unambiguously associated with the study drug, since similar phenomena had occurred in patients before. In one of these patients the drug was discontinued. During therapy, there were also no clinically significant changes in vital signs (changes in blood pressure, pulse, heart rate). Discussion Thus, the results of the study indicate the effectiveness and safety of using Exelon in PD with dementia. The data obtained are consistent with the results of a large multicenter study, which demonstrated the high effectiveness of Exelon in the treatment of severe cognitive impairment in PD [19]. In the group of patients receiving the drug, a significant decrease in the severity of cognitive impairment was noted, while in the comparison group an increase in the severity of cognitive impairment was detected. Exelon therapy helped reduce the severity of dysregulatory disorders, improve attention and memory. The data obtained suggest that in PD with dementia, the drug mainly affects the cognitive symptoms of frontal dysfunction and neurodynamic disorders, which are the main ones in the structure of the cognitive defect characteristic of PD. Similar results were obtained by other researchers [19,30]. The study showed that Exelon therapy is accompanied by a significant decrease in the severity of psychotic disorders. Atypical antipsychotics are usually used to correct psychotic disorders in PD, but their use is associated with a negative effect on motor functions. In addition, the anticholinergic effect inherent in these drugs can increase cognitive impairment and cause complications from the cardiovascular system [6,12]. The study suggests that the use of Exelon may reduce the need for antipsychotics in patients with PD and dementia. The absence of a negative effect of Exelon on the main symptoms of PD is of great practical importance. According to the results of studies conducted to date, no significant worsening of movement disorders was noted when taking the drug [19,21,30] (only in some cases there was a slight increase in tremor) [19]. The literature describes one case of increasing hypokinesia in a patient suffering from PD with cognitive impairment following a single dose of 3 mg rivastigmine. However, the noted negative effect on the motor sphere was not recorded using a unified scale for assessing PD [29]. It should be noted that in our study we used lower doses of Exelon than in international studies - an average of 5.8 mg per day, while in the EXPRESS study, for example, the average dose of Exelon was 8.6 mg per day. Thus, Exelon may be effective in PD with dementia when administered in a minimal therapeutic dose. Meanwhile, according to international studies, the clinical effect of AChE inhibitors on cognitive functions is dose-dependent. Treatment is carried out up to the optimally tolerated dose, which can be 12 mg per day [19]. Considering that cholinergic deficit is detected even in PD without dementia [15], it is important to evaluate the effectiveness of cholinergic drugs in patients with mild cognitive impairment [8]. The study confirmed that Exelon was well tolerated. An adverse event in only 1 case was associated with gastrointestinal dysfunction and did not require a reduction in the drug dose or additional therapy. No changes in indicators reflecting the state of vital functions were noted. According to the EXPRESS study, patients receiving Exelon were significantly more likely to develop nausea and vomiting than those receiving placebo. This is consistent with the safety and tolerability profile of this drug in Alzheimer's disease [19]. Thus, the results of the study showed that Exelon is an effective and safe drug for PD with dementia. The use of this drug promotes regression of the severity of cognitive and behavioral disorders without affecting the motor symptoms of parkinsonism. Considering the undoubted negative impact of mental disorders on the quality of life of patients with PD and their relatives, the obtained positive effect of Exelon is of great clinical significance.