Can strattera be taken at night

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III

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1999

Europe

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20000 9000 9000 9000

Japanese Japanese Japanese, Japanese, Japanese.

III

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2000

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2004

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60 9000 5, 10

There are sufficiently grounds for the use of Donpezil and other diseases that are developing and leaving for developing and leaving for developing and leaving for developing Thus, its effectiveness in Lewy body disease has been shown [14, 15]. Donepezil is used for traumatic brain injury [16], vascular dementia [17], and Parkinson's disease with dementia [18]. However, the prescription of donepezil for these nosologies remains off-label.

Most clinical studies show comparable efficacy and safety of the three cholinesterase inhibitors (donepezil, rivastigmine and galantamine) [19].

2017 meta-analysis by L. Blanco-Silvente et al. [20] showed a greater improvement in overall experience with donepezil compared with galantamine and rivastigmine. It has also been shown that all cholinesterase inhibitors improve cognitive functions, functional activity, and increase life expectancy. Their influence on neuropsychiatric symptoms could not be identified.

Similar data presented in a 2018 Cochrane review. Donepezil was effective in improving cognitive function, functional activity, and overall clinical impression. There was no effect of donepezil on behavioral disorders, which is associated with the short duration of clinical trials included in the review (most of them lasted no more than 6 months) [21].

The use of cholinesterase inhibitors is considered symptomatic therapy. But some data indicate that cholinesterase inhibitors may also have a nosomodifying effect. For example, a decrease in the increase in the degree of atrophy of the hippocampus, according to MRI of the brain, was shown against the background of taking 10 mg of donepezil for 1 year. However, in this study, despite slowing down atrophy, there was no clinical improvement in patients according to neuropsychological testing [22].

Donepezil has a long half-life, which is 70-100 hours. This allows you to take the drug once a day. The systematic use of single doses leads to the achievement of an equilibrium state within 2-3 weeks after the start of therapy. Communication with plasma proteins 95%. If the patient forgets to take the drug once, this does not significantly affect the therapeutic effect. At the same time, the long half-life and the relationship with plasma proteins require a more responsible approach to monitoring the development of side effects.

Donepezil is metabolized in the liver with the participation of cytochrome P450 isoenzymes CYP2D6 and CYP3A4, undergoes glucuronidation. Four major metabolites of donepezil have been identified, two of which are active. Unlike tacrine at therapeutic doses, donepezil is not hepatotoxic. Hepatic enzyme inducers (phenytoin, carbamazepine, phenobarbital, dexamethasone) may accelerate and hepatic enzyme inhibitors (ketoconazole) may slow down the metabolism of donepezil. Donepezil is excreted by the kidneys both unchanged (15-20%) and in the form of numerous metabolites [23].

Donepezil is a reversible acetylcholinesterase inhibitor. It also affects the expression of nicotinic receptors in the brain, which may be especially important in severe dementia. The drug selectively inhibits acetylcholinesterase: its activity against acetylcholinesterase is approximately 1000 times higher than against butyrylcholinesterase. This explains the good tolerability of donepezil and the rare occurrence of peripheral cholinergic side effects. When using donepezil at a dose of 5 mg/day, the average activity of acetylcholinesterase is reduced by 63.7%, at a dose of 10 mg/day - by 77.3% [24].

In the instructions, only hypersensitivity and children's age appear in the contraindications for use, which in itself indicates the relative safety of the drug. The tolerability and safety of donepezil are well described in S. Jackson et al. [25]. The frequency of side effects depends on the dose of the drug.

The most common adverse events are gastrointestinal manifestations (nausea and vomiting, diarrhea, abdominal pain). In most cases, they pass on their own and do not require discontinuation of the drug. Nausea can be avoided by slowly titrating the dose. The recommended starting dose is 5 mg. With the development of nausea, it can be recommended to take 2.5 mg / day for 4-6 weeks, then for another 4-6 weeks - 5 mg / day, then 10 mg / day. It is recommended to switch to a dose of 23 mg/day no earlier than after 3 months of taking donepezil at a daily dose of 10 mg [26]. The effectiveness of a gradual increase in the dose of the drug to reduce the risk of side effects has been shown in comparative studies of rapid and gradual increase in the dose of donepezil [27, 28].

Since the maximum blood concentration is reached after 3-5 hours, taking in the evening also improves its tolerability. The decrease in peak concentration is facilitated by taking the drug after a meal. However, if the evening reception provokes sleep disturbances (insomnia, nightmares), the reception should be postponed to the morning. The development of sleep disorders is associated with excessive cholinergic stimulation during the peak dose of the pedunculopontine and dorsolateral nuclei of the brainstem, which are responsible for the development of the REM sleep phase. No sleep disturbances have been reported with donepezil in the morning. If sleep disturbances develop on the background of an increase in the dose of the drug, returning to the previous dose for a few more weeks may also contribute to the regression of side effects.

Cardiovascular adverse events include the risk of bradycardia and QT interval prolongation. The possibility of developing bradycardia often leads clinicians to refrain from prescribing cholinesterase inhibitors in elderly patients. However, these concerns are based on reports of isolated cases of arrhythmia, while in clinical studies there was no increase in the incidence of bradycardia while taking donepezil. The incidence of bradycardia while taking donepezil does not exceed 1% and is comparable to the incidence of bradycardia while taking placebo. And serious consequences are even rarer. Monitoring heart rate (HR) at the beginning of taking the drug and with increasing doses allows you to timely detect bradycardia and adjust therapy.

Administration of cholinesterase inhibitors may induce bradycardia or exacerbate existing cardiac arrhythmias. Therefore, sick sinus syndrome and impaired sinoatrial conduction are relative contraindications for the appointment of cholinesterase inhibitors. Morning administration of the drug is more preferable in patients with an increased risk of developing bradycardia. If the patient has a pacemaker implanted, one should not be afraid of the development of a heart rhythm disorder during cholinergic therapy.

Theoretically, the risk of developing bradycardia may be influenced by the use of other drugs that slow the heart rate, such as digoxin and beta-blockers. When prescribing cholinesterase inhibitors, dose adjustment or withdrawal may be required. However, according to clinical studies, the simultaneous use of donepezil with digoxin or beta-blockers does not lead to an increase in the incidence of bradycardia [29]. Particularly revealing are the results of donepezil tolerance studies in patients with vascular dementia receiving a large number of drugs at the same time [30, 31].

No randomized controlled trial showed differences in heart rate, blood pressure, ECG values ​​between cholinesterase inhibitors and placebo. The use of cholinesterase inhibitors does not increase the frequency of ischemic attacks.

In a number of studies, while taking donepezil, a decrease in heart rate by 2 beats per 1 min and an increase in the duration of the PR interval by 3 ms have been shown. However, there were no clinically significant manifestations. It has also been shown that the risk of progression of atrioventricular block I degree to II degree while taking donepezil does not increase. Patients with pre-existing cardiovascular disease are no more likely to develop cardiovascular side effects than those with an uncomplicated history. Thus, at present, there are no sufficient grounds for identifying a high-risk group that would require a preliminary examination of the cardiovascular system before prescribing cholinesterase inhibitors [32-35].

There are reports that donepezil can provoke the development of epileptic seizures. In some cases, convulsive seizures develop against the background of cardiac arrhythmia, asystole. Considering that donepezil is used mainly in patients of the older age group with neurodegenerative diseases, the development of an epileptic seizure may not always be associated with taking the drug. Perhaps epileptic seizures are a manifestation of the disease itself.

In a large, multicenter, randomized clinical trial, there was no difference in the incidence of side effects between the donepezil and placebo group. Against the background of donepezil, gastrointestinal side effects developed more often, but they were transient and not severe. The incidence of bradycardia did not differ between donepezil and placebo [36].

When using donepezil at a dose of 23 mg / day, 8.4% of patients showed a decrease in appetite, leading to a decrease in body weight. High doses of donepezil also increase the risk of gastrointestinal bleeding and bradycardia. Whereas the risk of arousal, hallucinations and falls does not increase with increasing dose [37].

The frequency of dizziness and fainting while taking cholinesterase inhibitors is also higher compared with taking placebo, part of the cases can be explained by the development of bradycardia. But the risk of falls while taking donepezil not only does not increase, but also decreases [38, 39]. On the one hand, walking disorders, like cognitive impairments, can develop as a result of cholinergic deficiency. On the other hand, the improvement in walking may be mediated by the correction of a dysregulatory cognitive defect (primarily by improving attention).

There is an opinion among clinicians that memantine is a safer drug for the treatment of dementia compared to other cholinesterase inhibitors. Perhaps it should be preferred in patients with an increased risk of developing cholinergic side effects (in patients with sick sinus syndrome, atrioventricular blockade, gastric ulcer, bronchial asthma). However, in patients not burdened with concomitant somatic pathology, the question of which drug is safer remains controversial. A French study compared serious side effects between donepezil and memantine monotherapy. It turned out that the frequency of side effects did not differ significantly: bradycardia was noted in 10 and 7% of cases, respectively, general weakness - in 5 and 6%, epileptic seizures - in 4 and 3%. It should be noted that such phenomena in elderly patients often develop even without taking antidementia drugs, and it is not always possible to unambiguously establish the relationship between deterioration in well-being and taking the drug [40].

Patients with severe dementia often receive combination therapy with donepezil and memantine. When adding memantine to donepezil, it is necessary to monitor heart rate, since memantine can potentiate the effect of donepezil on heart rate [41]. It is especially necessary to carefully monitor heart rate in patients receiving memantine simultaneously with high doses of donepezil (23 mg/day) [42].

We conducted a study on the efficacy and safety of donepezil in the treatment of dementia in neurodegenerative diseases. The aim of the study was to find out whether a gene polymorphism 9 is a predictor of the development of side effects of cholinesterase inhibitors.0280 CYP2D6 and MDR1 .

As mentioned above, hepatic cytochrome CYP2D6 is involved in the metabolism of donepezil. Slowing down the metabolism of the drug can lead to an increase in its plasma concentration above the therapeutic one and be accompanied by the development of side effects associated primarily with excessive peripheral cholinergic stimulation.

Gene MDR1 encodes p-glycoprotein, which is involved in the absorption of the drug in the gastrointestinal tract, in its elimination by the kidneys and bile, and also in the penetration of donepezil through the blood-brain barrier. With its low activity, it is possible to slow down its excretion from the central nervous system. Increasing the concentration of donepezil in the brain tissues above the therapeutic level may lead to an increased risk of developing central side effects.

The study included 62 patients with dementia due to various neurodegenerative diseases: 16 with AD, 25 with dementia with Lewy bodies and 21 with Parkinson's disease with dementia. The mean age of the patients was 76. 6±5.3 years with a range of 59-86 years. The gender distribution is 40 (64.5%) women and 22 (34.5%) men. The baseline score on the Mini Mental Status Assessment (MMSE) was 22.0±6.0. In patients with mild dementia - 20-23 points, with AD - 20-30 points, with Lewy body disease and Parkinson's disease with dementia - 19(30.6%), with moderate dementia (11-19 points) - 43 (69.4%). Patients with severe dementia (10 points or less on the MMSE scale) were not included in the study.

All patients were treated with donepezil at an initial dose of 5 mg/day for 1 month followed by an increase in daily dose to 10 mg. All patients took donepezil in the evening. Along with a cholinesterase inhibitor, 58.5% of patients were taking memantine, the duration of treatment at a stable dosage was at least 6 months before the start of the study.

Of the 62 patients included in the study, 59.7% ( n = 37) started on donepezil. Particularly low compliance was observed in patients with Parkinson's disease, 23. 8% ( n = 5) started taking donepezil, which may be due to the need for a large number of anti-Parkinsonian drugs during the day at an advanced stage of Parkinson's disease. Some patients stop taking it because they do not see the same obvious effect as from taking antiparkinsonian drugs. Among patients with dementia with Lewy bodies, 44.0% were started on donepezil ( n =11), among patients with BA - 62.5% ( n =10). The greater adherence to treatment of patients with primary dementing diseases compared with patients with Parkinson's disease is undoubtedly associated with the control of medication intake by patients' relatives.

Of all the follow-up patients, only 26 patients took donepezil during the entire period between examinations. The effectiveness of treatment was assessed based on the dynamics of the score on the MMSE scale. The interval between examinations was 6.8±3.1 months. At the same time, a poor response to treatment was noted no earlier than 6 months after the start of therapy. If the improvement was evident already after 3 months of therapy, the patient was considered to have responded well to treatment.

Since there is no consensus on what change in MMSE score is considered a good response to treatment, we took two approaches.

In the first, more stringent, analysis, only those patients who had an increase or decrease on the MMSE scale of 2 points or more were included in the analysis. Eight patients did not respond to donepezil treatment, 9 responded well. Thus, when applying strict criteria, 34.6% of patients who started donepezil responded well to treatment. When analyzing gene polymorphism CYP2D6 GA/GG ratio among those who responded well to treatment was 6/3, among those who did not respond - 4/4. When analyzing the polymorphism of the MDR1 gene, the ratio of CC/TC/TT among those who responded well to treatment was 2/5/2, among those who did not respond — 2/5/1. The data obtained allow us to reject the hypothesis that the presence of the CYP2D6 mutant A allele and the MDR1 mutant T allele of the MDR1 gene is associated with a poor response to treatment.