Dementia in Alzheimer's Disease: Treatment

To date, the FDA has approved the use of four inhibitors of acetylcholinesterase-tacrine, donepezil, rivastigmine and galantamine for mild and moderate Alzheimer's disease, with severe dementia, an antagonist of the NMDA subtype of glutamate memantine receptors.

[1], [2], [3]

Tacrine

Tacrine (9-amino-1,2,3,4-tetrahydroacridine) was the first cholinesterase inhibitor to be approved for use in Alzheimer's disease. It is a centrally acting non-competing reversible inhibitor of acetylcholinesterase. Although the drug was synthesized in 1945, its ability to inhibit acetylcholinesterase was detected only in 1953. Tacrine slows the increase in symptoms in some patients with Alzheimer's, but several months of titration are required to achieve a therapeutic dose. The use of tacrine in Alzheimer's disease is limited by the need for four times a day and frequent monitoring of the concentration of the drug in the serum, as well as the risk of hepatotoxic effect and side effects from the gastrointestinal tract.

Pharmacokinetics

Tacrine is well absorbed in the intestine, but its bioavailability can be reduced by 30-40% when taken with food. The concentration of the drug in the plasma reaches a peak 1-2 hours after ingestion. Constant concentration is achieved 24-36 hours after the start of regular intake. The volume of distribution of tacrine is 300 l / kg, and the half-elimination period is from 2 to 3 h. The drug is metabolized in the liver by the CYP1A2 HCYP2D6 isoenzymes. It undergoes hydroxylation and conjugation with the formation of 1-hydroxy-tacrine. Since only a very small amount of tacrine is excreted by the kidneys, correction of the dose is not required in patients with impaired renal function.

Pharmacodynamics

Based on the pharmacological action of tacrine, it can be assumed that its therapeutic effect is associated with an increase in the concentration of acetylcholine in the brain. The ratio between the concentration of tacrine in the plasma and the dose taken internally is nonlinear. The concentration of tacrine in the plasma in women is twice as high as that of men, possibly due to the lower activity of CYP1A2. Since the components of tobacco smoke induce CYP1A2, smokers have a serum tacrine level one third lower than non-smokers. Tacrine's clearance is independent of age.

Clinical trials

Attention is drawn to the considerable variability in the methodological correctness of various clinical studies evaluating the effectiveness of tacrine in Alzheimer's disease. So, the first studies gave promising results, but they were not controlled. The results of subsequent studies in the 1980s were ambiguous, which was explained by methodological miscalculations, including the use of inadequate doses or insufficient duration of treatment. And only after two well-planned 12- and 30-week studies demonstrating the effectiveness of tacrine, the drug was approved for use.

Problems associated with the use of the drug

To obtain a therapeutic effect, the daily dose of tacrine must be at least 80 mg and, as a rule, more than 120 mg. In this case, the minimum period of titration required to reach a dose of 120 mg / day should be at least 12 weeks. If there are side effects from the gastrointestinal tract or an increase in transaminase activity, the titration period may be increased. The intake of tacrine must be discontinued if the activity of the liver transaminases exceeds the upper level of the norm by a factor of 5. However, the administration of the drug can be resumed after the normalization of the transaminase level, since in this case a dose exceeding a baseline can be achieved in a significant number, provided that the titration is slower. During the clinical trials there were no lethal outcomes caused by hepatitis. Tacrine should be used with caution in supraventricular disorders of the heart rhythm and peptic ulcer disease, as the drug enhances parasympathetic activity.

Side effects

Most often, tacrine causes side effects from the gastrointestinal tract. These include dyspepsia, nausea, vomiting, diarrhea, anorexia, abdominal pain. When taking the drug, it is necessary to regularly monitor the activity of transaminases for the timely detection of liver pathology, but it often remains asymptomatic. Although the frequency of many side effects in patients taking tacrine was similar to their frequency in the placebo-treated control group, the exit from the study was much more common in the group receiving the test drug.

Drug Interactions

In the combination of tacrine with theophylline or cimetidine, serum concentrations of both drugs are increased, as they are metabolized by the enzyme CYP1A2. Tacrine inhibits the activity of butylcholinesterase, an enzyme that ensures the degradation of succinylcholine, which can prolong the effect of muscle relaxants.

[4]

Dosing

Takrin can be prescribed only after a careful physical examination and determination of the activity of hepatic transaminases. Treatment begins with a dose of 10 mg 4 times a day, then it is increased every 6 weeks by 10 mg to achieve a dose of 40 mg 4 times a day. Titration can be limited by side effects from the gastrointestinal tract, increased transaminase levels or other side effects. The tolerance of the drug can be improved if taken with food, but the bioavailability is reduced by 30-40%. With an increase in the level of transaminases, another dose increase is not carried out, and sometimes a dose reduction is required. If the intake of tacrine is discontinued for more than 4 weeks, then the treatment is resumed with a dose of 10 mg 4 times a day.

Monitoring the liver and reassignment

If the patient tolerates the administration of tacrine without a significant increase in the level of hepatic transaminases (the level of alanine aminotransferase (ALT) does not exceed the upper limit of the norm by more than 2 times), it is recommended to determine ALT activity once every 2 weeks for 16 weeks, then once a month in for 2 months, and then - once in 3 months. If ALT level exceeds the upper limit of the norm by 2-3 times, it is recommended to conduct this study weekly. If the ALT level exceeds the upper limit of the norm by 3-5 times, then the dose of tacrine should be reduced to 40 mg per day and the activity of the enzymes should be monitored weekly. When the ALT level is normalized, the dose titration can be resumed, and transaminase activity should be determined once every 2 weeks. If the ALT level is 5 times higher than the upper limit of the norm, stop taking the drug and continue to monitor for possible signs of toxic hepatitis. When jaundice develops (the level of total bilirubin usually exceeds 3 mg / dL) or of hypersensitivity symptoms (eg, fever), treatment with tacrine should be completely discontinued without further resumption. In studies of the hepatotoxic effect of tacrine, 88% of patients managed to resume taking the drug, and in 72% of cases a higher dose was achieved than that at which the drug had to be discontinued.

With the resumption of taking takarin, the level of enzymes in the blood should be determined weekly. After the normalization of the activity of transaminases, the intake of tacrine is renewed at a dose of 10 mg 4 times a day. After 6 weeks, the dose can be increased if there are no serious side effects, and the level of transaminases does not exceed three times and the upper limit of the norm. After the normalization of the level of transaminases, the resumption of treatment is allowed even in cases where the ALT level exceeds the upper limit of the norm up to 10 times. However, when hypersensitivity to tacrine, manifested by eosinophilia or granulomatous hepatitis, re-administration of the drug is not allowed.

[5], [6], [7], [8]

Therapeutic effect of tacrine

Tacrine can prolong life expectancy for patients with Alzheimer's disease and reduce the need to place the patient in care facilities. Two-year follow-up of 90% of the 663 patients who participated in the 30-week clinical trial of tacrine showed that those who took more than 80 mg of tacrine per day had a lower probability of death or placement in care facilities than in patients , who took lower doses of the drug - odds ratio> 2.7. Although the absence of a control group makes it difficult to generalize the results, the dependence of the effect on the dose makes them promising.

[9], [10], [11],

Donnezil

Donepezil hydrochloride (2,3-dihydro-5,6-demethoxy-2 [[1- (phenylmethyl) -4-piperenyl] methyl] -1H-indene-1-monohydrochloride), became the second inhibitor of acetylcholinesterase permitted in the US for use with Alzheimer's disease. Its advantage over tacrine is the possibility of a single administration per day, the absence of a significant hepatotoxic effect and the need to regularly monitor the activity of enzymes in the serum. In addition, there is no need for prolonged titration of the dose, and treatment can be started immediately with a therapeutic dose. In vitro donepezil relatively selectively blocks acetylcholinesterase and acts less on butylcholinesterase.

Pharmacokinetics

When administered, the bioavailability of donepezil reaches 100%, and food intake does not affect it. The concentration of the drug in the plasma reaches a peak 3-4 hours after ingestion with a stable volume of distribution of 12 l / kg. Donepezil is 96% bound to plasma proteins, mainly with albumin (75%) and acidic a1-glycoprotein (21%). A stable level in the plasma is reached after 15 days, with a possible 4-7-fold increase in donepezil concentration. The half-elimination period is 70 hours. Donepezil is metabolized in the liver by the enzymes CYP3D4 and CYP2D6 and is subjected to glucuronization. As a result, two active metabolites are formed, two inactive metabolites and many small metabolites - all excreted in the urine. According to the manufacturer, liver disease (for example, non-progressive alcoholic cirrhosis) hepatic clearance of the drug is reduced by 20% compared with healthy individuals. With kidney diseases, the clearance of donepezil does not change.

Pharmacodynamics

Donepezil is an uncompetitive reversible inhibitor of the hydrolysis of acetylcholine. Thus, it basically increases the synaptic concentration of this neurotransmitter in the brain. Donepezil more actively inhibits acetylcholinesterase than tacrine, and 1250 times more effectively blocks acetylcholinesterase than butylcholinesterase. There is a linear correlation between the dose taken inside (1-10 mg / day) and the concentration of the drug in the plasma.

Clinical trials

The effectiveness in the form of slowing the progression of BA symptoms has been demonstrated in several clinical trials. In a 12-week, double-blind, placebo-controlled study, donepezil at a dose of 5 mg / day caused a significant improvement in ADAS-Cog in patients with a probable diagnosis of Alzheimer's disease (Alzheimer's Disease Assessment Scale / Cognitive subscale - Alzheimer's score / cognitive subscale scale) compared with placebo. When using lower doses (1 mg and 3 mg per day), no significant effect was observed. In another 12-week, double-blind, placebo-controlled study, donepezil at doses of 5 mg and 10 mg caused significant improvement in ADAS-Cog compared with placebo. Differences between the groups taking 5 mg and 10 mg of the drug were not statistically significant. At the second examination after a 3-week wash-out period, the therapeutic effect of donepezil was not detected. By the end of the 12th week, patients who took donepezil also had a statistically significant improvement (in comparison with the placebo group) on the CIVIC-Plus scale, which made it possible to assess the clinical impression of the doctor following a conversation with the patient and caregiver.

The efficacy of donepezil was demonstrated in a 30-week study that assessed the status of patients on the scales ADAS and CIVIC-Plus. In the first 24 weeks, the study provided for active treatment and was administered by a double-blind, placebo-controlled principle, the last 6 weeks being a wash-off period organized according to a blind placebo-controlled principle. Patients were randomly assigned to three groups, in one of which they took donepezil at a dose of 5 mg / day, in another - 10 mg / day (after a weekly intake of 5 mg / day), in the third - placebo. By the end of the 24 weeks, there was a statistically significant (compared to placebo) improvement in the ADAS-Cog and CIVIC-Plus scales in both groups of patients taking donepezil. There were no significant differences between patients taking 5 mg and 10 mg of donepezil. However, by the end of the 6-week blind wash-out period, there were no significant differences between patients taking donepezil and placebo according to ADAS-Cog. This indicated that donepezil does not affect the course of the disease. Direct comparative studies of tacrine and donepezil were not conducted, but the highest degree of improvement in ADAS-Cog with donepezil was lower than in tacrine.

Problems associated with the use of the drug

Donepezil does not have a hepatotoxic effect. Since donepezil increases the activity of the parasympathetic system, care should be taken when prescribing the drug to patients with supraventricular heart rhythm disturbances, including the sinus node weakness syndrome. Due to the parasympatomimetic effect, donepezil is able to cause dysfunction of the gastrointestinal tract and increase the acidity of the gastric juice. Against the background of treatment donepezil should carefully monitor patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and having a history of peptic ulcer, in view of the risk of gastrointestinal bleeding. When taking 10 mg per day, nausea, diarrhea and vomiting are observed more often than when taking 5 mg per day.

Side effects

The most common side effects of donepezil are diarrhea, nausea, insomnia, vomiting, cramp, fatigue and anorexia (Table 9.6). Usually they are easy and go with the continuation of treatment. Side effects are more common in women and elderly patients. Nausea, diarrhea and vomiting are the most common side effects of donepezil, which are the cause of the cessation of treatment. In one of the studies mentioned above, patients taking 10 mg per day (previously they took 5 mg / day for a week) were more likely to refuse treatment than patients taking 5 mg per day. In the open phase of the study, when the dose was raised to 10 mg / day after 6 weeks, the described side effects were observed less often than with a faster titration-their frequency was the same as that of patients taking 5 mg / day.

Drug Interactions

In vitro studies show that a significant portion of the drug taken binds to plasma proteins and can displace other drugs (furosemide, warfarin, digoxin) from their association with proteins. However, whether this phenomenon is of clinical significance remains unclear. This issue is very significant, since many patients with Alzheimer's disease simultaneously take several drugs. Although the manufacturer reports that the binding of donepezil with albumin is not affected by furosemide, warfarin or digoxin, it remains unclear how the effect of dopenese in patients with nutritional deficiency or cachexia varies. The manufacturing company also reports that dopenysyl does not have a significant pharmacokinetic effect on the effects of warfarin, theophylline, cimetidine, digoxin, although data confirming this position are not given. Due to the blockade of butylcholinesterase, the action of succinylcholine is possible. Drugs that inhibit CYP2D6 or CYP3A4 can inhibit donepezil metabolism, which leads to an increase in the serum levels of both compounds. In contrast, inducers CYP2D6 or CYP3A4 can increase the elimination of donepezil.

Dosing and application

Donepezil is available in tablets containing 5 mg and 10 mg of dopenesyl hydrochloride. It is recommended to start treatment with a dose of 5 mg once a day. To minimize the side effects that occur against the background of the peak concentration of the drug, it is usually prescribed in the evening, while the peak concentration in the plasma falls at the time of sleep. The results of clinical trials do not allow to unequivocally solve the question whether it is expedient to increase the dose of donepezil from 5 to 10 mg per day. Although no statistically significant differences in the efficacy of these two doses were observed, a trend toward a higher dose efficiency of 10 mg / day compared with a dose of 5 mg / day was noted. The patient and the doctor must jointly decide whether it makes sense to increase the dose of the drug to 10 mg / day. The half-elimination period is 70 hours, but this indicator was determined in young people, and similar studies were not conducted in the elderly. Since pharmacokinetic and pharmacodynamic changes in elderly patients may lead to an increase in the half-elimination period of the drug, in patients of this age group it is preferable to use a dose of 5 mg / day. Experience shows that increasing the dose from 5 mg to 10 mg per day should be done no earlier than 4-6 weeks, carefully observing the therapeutic and possible side effects.

[12], [13], [14], [15]

Galantamine

Competitive reversible inhibitor of acetylcholinesterase, which does not affect butyrylcholinesterase. In addition, due to the allosteric effect, it is able to increase the sensitivity of nicotinic cholinergic receptors. In multicenter trials in the US and Europe, it was shown that the drug at doses of 16 mg / day and 24 mg / day improves the ADAS scale, reflecting the state of speech, memory, and motor functions. Side effects were observed in 13% of patients taking 16 mg / day, and in 17% of patients taking 24 mg / day. Currently, the use of the drug in Alzheimer's disease is approved by the FDA.

[16], [17], [18], [19]

Rivastigmine

"Pseudo-invertible" carbamate inhibitor of cholinesterase with selective action in the region of the hippocampus and the cortex of the brain. In a 26-week, double-blind, placebo-controlled study, the drug was more effective than placebo, having a beneficial effect on memory and other cognitive functions, as well as the patient's daily activities. Higher doses (6-12 mg / day) had a more significant effect than lower doses (1-4 mg). The last in one of the studies on efficacy did not differ from placebo. Treatment usually begins with a dose of 1.5 mg 2 times a day, then it can be sequentially increased to 3 mg 2 times a day, 4.5 mg 2 times a day, 6 mg 2 times a day, taking into account the effect. The interval between increases in doses should be at least 2-4 weeks. Side effects (including weight loss) are observed in about half of patients taking high doses of the drug, and in 25% of cases it is required to cancel it.

Memantine is an amantadine derivative, a low-affinity non-competitive NMDA receptor antagonist, and a glutamatergic transfer modulator. In double-blind, placebo-controlled trials, it has been shown that in patients with Alzheimer's disease with moderate to severe dementia, memantine is slowed by a slowdown in the progression of the cognitive defect, increased motivation, motor activity, household independence of patients, and reduced stress on caregivers. The initial dose of memantine is 5 mg / day, after a week it is increased to 10 mg / day, after 2-3 weeks, with insufficient effect - up to 20 mg / day. In the subsequent dose, if necessary, can be increased to 30 mg / day.

Experimental pharmacological approaches to the treatment of Alzheimer's disease

[20], [21], [22], [23], [24], [25], [26], [27]

Cholinesterase inhibitors

Physostigmine is a reversible cholinesterase inhibitor of short action, requiring frequent administration. Its use is limited to frequent peripheral cholinergic effects, such as nausea and vomiting. A long-acting form of physostigmine for oral administration has been developed, the effectiveness of which has been shown in clinical trials of Phase III, but because of the frequent side effects it is not currently used.

Eptastigmine is a long-acting form of physostigmine (heptylphiostigmine), which had some positive effect in Alzheimer's disease, although the dose-response curve had an inverted U-shape. Due to the frequent side effects from the gastrointestinal tract, as well as the report of the case of agranulocytosis, the drug is not recommended for use in Alzheimer's disease.

Metrionate is an irreversible inhibitor of acetylcholinesterase, similar in chemical structure to poison gas. Metrionate blocks acetylcholinesterase to a much greater extent than butylcholinesterase. Currently, it is used to treat schistosomiasis. In vivo the drug is converted to dichlorvos - a long-acting inhibitor of organic cholinesterase. Studies in laboratory animals and early clinical trials have yielded promising results, but due to toxicity, the drug is currently not approved for use in Alzheimer's disease.

[28], [29]

Muscarinic receptor agonists

To date, five types of muscarinic receptors (M1-M5) have been identified, involved in the control of cognitive and postural functions. These receptors are conjugated with G-protein and are found in the brain and autonomic nervous system. M1 receptors are most common in those parts of the brain that are responsible for memory and learning, and are not affected in the progression of Alzheimer's disease. M4 receptors are of particular interest, since their density in the cerebral cortex in Alzheimer's disease increases. With systemic administration, muscarinic receptor agonists are not able to mimic normal pulse stimulation of the receptors, which is probably the reason for the decrease in their sensitivity (desensitization). However, according to some sources, tonic stimulation of receptors can be important in the processes of attention and wakefulness. Clinical studies of muscarinic receptor agonists have shown that they can have a positive effect. It is possible that these drugs may be more useful at a late stage of the disease, when the number of presynaptic cholinergic neurons is significantly reduced, or in combination with cholinesterase inhibitors.

Milamelin. Nonspecific partial agonist muscarinic receptors, improving cognitive function on the laboratory model. The drug is well tolerated by both healthy and sick Alzheimer's disease. Although the dose of milamelin needed to stimulate central cholinergic systems is lower than the dose providing activation of the peripheral cholinergic system, the side effects such as nausea, vomiting, and painful abdominal cramps are possible with the drug. A multicenter study of milamelin in Alzheimer's disease is currently under way.

Xanomelin. A partial agonist of the M1 and M4 receptors. Studies showed a generally satisfactory tolerability of the drug, but in a number of cases, due to side effects from the gastrointestinal tract and arterial hypotension, the drug had to be canceled. In the Phase III trial, a certain positive effect of xanomelin on "non-cognitive" symptoms was shown. The form for transdermal administration of the preparation was also studied.

Nicotine

Nicotinic cholinergic receptors also play an important role in cognitive functions. Linking to presynaptic receptors, nicotine facilitates the release of acetylcholine and other neurotransmitters involved in learning and memory processes. Based on this, it can be assumed that nicotinic receptor agonists can be effective in Alzheimer's disease.

With the help of pathomorphological studies and functional neuroimaging in patients with Alzheimer's disease, the number of nicotinic receptors decreased. With the appointment of patients with Alzheimer's disease of nicotine, they reduce the number of intrusive errors. In the treatment of nicotine, its side effect on affective status was noted. Nicotine can be administered transdermally or intravenously. It can be assumed that as the disease progresses, the effectiveness of nicotine will decrease - in parallel with a decrease in the number and sensitivity of nicotinic receptors.

Mechanisms of neuronal death. Prospects for the treatment of Alzheimer's disease are associated with the development of drugs that can affect the mechanisms of damage and death of neurons.

Other means influencing glu-

As already mentioned, the enhancement of glutamatergic transmission can promote the development of apoptosis and cell death. Because of this, with Alzheimer's disease, aniracetam and ampakines may be useful.

Aniracetam is a pyrrolidine derivative that affects metabotropic and AMPA-sensitive glutamate receptors. Positive modulation of these receptors can facilitate cholinergic transmission. In laboratory animals and people with experimentally induced cognitive impairment, aniracetam improved the performance of the tests. The ability of aniracetam to positively influence cognitive function is also shown in some clinical studies, but these results have not been confirmed by other authors. When taking the drug, confusion, fatigue, anxiety, anxiety, insomnia and some other side effects were noted, but they did not require the drug to be discontinued. The drug had no significant effect on liver function.

Ampakines. Identified in the brain in patients with Alzheimer's disease, a decrease in the number of glugamate AMPA receptors can lead to a violation of calcium homeostasis and damage to neurons. Ampakines are able to increase the activity of AMPA receptors and facilitate learning and memory processes by enhancing long-term potentiation. Placebo-controlled clinical trials of Phase II ampakines, conducted with the participation of healthy adult men, revealed the ability of drugs to improve immediate reproduction. At present, the safety and efficacy of ampakin CX-516 continues to be studied.

Means that reduce oxidative stress

Free radical oxidation can cause damage to neurons in BA and other neurodegenerative diseases. Moreover, free radicals can mediate the toxic effect of beta-amyloid in Alzheimer's disease (Pike, Cotman, 1996). Accordingly, antioxidant drugs can be effective in asthma.

Vitamin E and selegiline. Vitamin E and selegiline have an antioxidant effect. In a two-year, double-blind, placebo-controlled study, it was shown that vitamin E (2000 IU / day) and selegelin (10 mg / day) in patients with moderate or severe Alzheimer's disease (according to the Clinical Dementia Rating Scale) individually and in combination, separate some events, the offensive of which served as a benchmark for assessing effectiveness: death, placement in a nursing facility, loss of self-service functions. There was no increase in the effect in combination with selegelin and vitamin E. None of the drugs, nor a combination of them, improved cognitive function compared to the baseline or indices in the placebo group.

Idebenon. Idebenone in chemical structure is close to ubiquinone - an intermediate product of oxidative phosphorylation. In a double-blind, placebo-controlled study, idebenone in doses up to 360 mg / day had a positive effect in patients with Alzheimer's disease. In patients taking idebenone, after 6 and 12 months of treatment, more favorable assessments were made on the ADAS scale (including the cognitive subscale ADAS-Cog), as well as a higher score on the scale of the overall clinical impression than in patients taking placebo. At present, clinical trials of idibenone III phase are under way in the United States.

Extracts of the plant Ginkgo biloba, possibly possessing antioxidant and anticholinesterase action, were widely tested in Alzheimer's disease. A number of studies have shown that they can have a moderate positive effect on some cognitive functions, but have relatively little effect on the general condition. More research is needed on the efficacy of these drugs. Calcium channel blockers. Since the violation of calcium homeostasis can be one of the mechanisms of damage and death of neurons, clinical trials of calcium channel blockers (calcium antagonists) have been carried out in Alzheimer's disease.

Nimodipine. According to some reports, nimodipine is able to improve learning and memory processes in humans and laboratory animals, although these results have not been confirmed by other authors. It is possible that there is selective sensitivity of neurons to a certain dose of nimodipine, depending on the optimal level of calcium in the cells. Thus, in one study in patients with Alzheimer's disease, memory parameters (but not other cognitive functions) improved with nimodipine at a relatively low dose (90 mg / day), whereas at a higher dose (180 mg / day) the effect of the drug was not differed from the placebo effect.

Nerve growth factor

Nerve growth factor (NGF) is a substance necessary for the survival, regeneration and functioning of cholinergic neurons. NGF is transported by neurons in a retrograde direction and binds to receptors in the anterior basal region of the brain, the hippocampus, and the cerebral cortex. This leads to an increase in the synthesis of acetylcholine by increasing the production of acetylcholine transferase, an enzyme that provides the synthesis of this neurotransmitter. Neuroprotective properties of NGF were revealed in primates in an experiment with neuronal damage. In one of the clinical studies, in 3 patients, who were injected with intravenous infusion, there was an increase in cerebral blood flow, improvement of verbal memory, and an increase in the density of nicotinic receptors. Apparently, NGF regulates the state of nicotinic receptors and is able to enhance glucose metabolism in the brain. But since it is not able to penetrate the blood-brain barrier, its clinical application is limited. The use of substances that can penetrate the blood-brain barrier and potentiate the action of endogenous NGF can be effective in Alzheimer's and other neurodegenerative diseases.

Estrogens

Estrogens can prevent the deposition of amyloid in the brain and contribute to the survival and growth of cholinergic neurons. In a small placebo-controlled study, 17-P-estradiol administration for 5 weeks results in improved attention and verbal memory. Epidemiological data indirectly confirm that estrogens can delay the onset of Alzheimer's disease. In a prospective observation of a large group of women, 12.5% of whom took estrogen as a replacement therapy after menopause, it was noted that women who took estrogens developed Alzheimer's disease at a later age than women who did not take hormones. The relative risk of developing Alzheimer's disease in women who did not take estrogens after menopause was three times higher than that of women taking estrogen as a replacement therapy, even after taking into account the ethnicity, education and genotype of ALOE. Additional confirmation of the positive effect of estrogens was obtained in the study of retired women-it was noted that women taking estrogens had a lower risk of developing Alzheimer's disease than pleasures who did not receive hormone replacement therapy. The positive result depended on the duration of administration and the dose of estrogen. In women with Alzheimer's disease, against the background of taking estrogens, a decrease in the expression of slow wave activity on the EEG, an increase in cerebral blood flow in the motor cortex and basal parts of the frontal cortex, according to SPECT. In women with Alzheimer's disease, an increase in the MMSE score (Mini-Mental State Examination) was noted 3 and 6 weeks after the onset of estrogen administration. However, two recent double-blind, placebo-controlled trials failed to confirm the ability of estrogens to slow the progression of Alzheimer's disease.

[30], [31], [32], [33]

Combined treatment

Since the pathogenesis of Alzheimer's disease appears to be multifactorial in nature, it seems logical to use a combination of several drugs for its treatment. It is possible that in the future in the treatment of Alzheimer's disease will use a combined (multimodal) approach, similar to what is currently used in the therapy of hypertension, heart disease, cancer, AIDS. A retrospective analysis of the results of a 30-week trial of tacrine showed that a greater improvement in functional and cognitive performance was noted in those women who simultaneously took estrogens. There is evidence of a positive effect of the combination of cholinesterase inhibitors and glutamatergic memantine. However, only a prospective study of combinations of cholinesterase inhibitors with estrogens, memantine or other drugs will establish their effectiveness and be recommended as a standard therapy. The combination of two or more drugs does not always lead to an increased effect. For example, in the test of vitamin E and selegiline, it was shown that each of the drugs exceeded the placebo in a number of evaluated "non-cognitive" indices, but with a combination of these drugs, no additional effect was noted. Combined therapy of Alzheimer's disease involves not only a combination of several medicines, but also a combination of drug therapy with an impact on psychosocial factors in order to correct cognitive and behavioral disorders that occur in Alzheimer's disease.

[34], [35], [36], [37], [38], [39], [40]