Dementia in Alzheimer's Disease - Treatment

To date, the FDA has approved four acetylcholinesterase inhibitors—tacrine, donepezil, rivastigmine, and galantamine—for mild to moderate Alzheimer's disease, and the NMDA glutamate receptor antagonist memantine for severe dementia.

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Takrin

Tacrine (9-amino-1,2,3,4-tetrahydroacridine) was the first cholinesterase inhibitor approved for use in Alzheimer's disease. It is a centrally acting, noncompetitive, reversible inhibitor of acetylcholinesterase. Although the drug was synthesized in 1945, its ability to inhibit acetylcholinesterase was not recognized until 1953. Tacrine slows the progression of symptoms in some patients with Alzheimer's disease, 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 daily dosing and frequent monitoring of serum drug levels, as well as the risk of hepatotoxicity and gastrointestinal side effects.

Pharmacokinetics

Tacrine is well absorbed from the intestine, but its bioavailability may decrease by 30-40% when taken with food. The concentration of the drug in plasma reaches a peak 1-2 hours after oral administration. Steady-state concentrations are reached 24-36 hours after the start of regular administration. The volume of distribution of tacrine is 300 L/kg, and the half-life is from 2 to 3 hours. The drug is metabolized in the liver by CYP1A2 HCYP2D6 isoenzymes. It undergoes hydroxylation and conjugation to form 1-hydroxytacrine. Since only a very small amount of tacrine is excreted by the kidneys, no dose adjustment is 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 relationship between the plasma concentration of tacrine and the ingested dose of the drug is nonlinear. Plasma tacrine concentrations are twice as high in women as in men, possibly due to lower CYP1A2 activity. Since components of tobacco smoke induce CYP1A2, the serum tacrine level in smokers is one-third lower than in non-smokers. Tacrine clearance is not affected by age.

Clinical trials

Of note is the significant variability in the methodological soundness of the various clinical trials evaluating the efficacy of tacrine in Alzheimer's disease. The first studies showed promising results, but they were not controlled. The results of subsequent studies in the 1980s were mixed, due to methodological flaws, including inadequate doses or insufficient duration of treatment. Only after two well-designed 12- and 30-week studies demonstrated the efficacy of tacrine was the drug approved for use.

Problems associated with the use of the drug

To achieve a therapeutic effect, the daily dose of tacrine should be at least 80 mg and usually more than 120 mg. The minimum titration period required to reach a dose of 120 mg/day should be at least 12 weeks. If gastrointestinal side effects or increased transaminase activity occur, the titration period may be extended. Tacrine should be discontinued if liver transaminase activity exceeds the upper limit of normal by 5 times. However, the drug may be resumed after normalization of transaminase levels, since in this case a significant number of patients may achieve a dose higher than the initial dose with slower titration. No fatal outcomes due to hepatitis were noted during clinical trials. Tacrine should be used with caution in supraventricular cardiac arrhythmias and gastric ulcer, since the drug enhances parasympathetic activity.

Side effects

Most often, tacrine causes side effects from the gastrointestinal tract. These include dyspepsia, nausea, vomiting, diarrhea, anorexia, and 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 control group taking placebo, withdrawal from the study was significantly more often observed in the group receiving the test drug.

Drug interactions

When tacrine is combined with theophylline or cimetidine, the serum concentration of both drugs increases because they are metabolized by the enzyme CYP1A2. Tacrine inhibits the activity of butylcholinesterase, an enzyme that ensures the degradation of succinylcholine, due to which the effect of muscle relaxants can be prolonged.

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Dosage

Tacrine should be prescribed only after a thorough physical examination and determination of liver transaminase activity. Treatment is initiated at a dose of 10 mg 4 times a day, then increased every 6 weeks by 10 mg to a dose of 40 mg 4 times a day. Titration may be limited by gastrointestinal side effects, elevated transaminase levels, or other adverse events. Tolerability can be improved by taking the drug with food, but bioavailability is reduced by 30-40%. If transaminase levels increase, the dose should not be increased again and may require a dose reduction. If tacrine is discontinued for more than 4 weeks, treatment is resumed at a dose of 10 mg 4 times a day.

Liver monitoring and re-administration

If the patient tolerates tacrine well, without a significant increase in liver transaminase levels (alanine aminotransferase (ALT) levels do not exceed the upper limit of normal by more than 2 times), it is recommended to determine ALT activity once every 2 weeks for 16 weeks, then once a month for 2 months, and then once every 3 months. If the ALT level exceeds the upper limit of normal by 2-3 times, it is recommended to conduct this study weekly. If the ALT level exceeds the upper limit of normal by 3-5 times, then the tacrine dose should be reduced to 40 mg per day and enzyme activity should be monitored weekly. When the ALT level normalizes, dose titration can be resumed, while transaminase activity should be determined once every 2 weeks. If the ALT level exceeds the upper limit of normal by 5 times, the drug should be discontinued and continued monitoring for possible signs of toxic hepatitis. If jaundice (with total bilirubin levels usually exceeding 3 mg/dL) or hypersensitivity symptoms (e.g., fever) developed, tacrine treatment should be permanently discontinued without further reinitiation. In studies of the hepatotoxic effect of tacrine, 88% of patients were able to resume treatment with the drug, and in 72% of cases a higher dose than that at which the drug had to be discontinued was achieved.

When resuming tacrine, serum enzyme levels should be measured weekly. Once transaminase activity has returned to normal, tacrine is resumed at a dose of 10 mg 4 times daily. After 6 weeks, the dose may be increased if there are no serious side effects and transaminase levels do not exceed three or more times the upper limit of normal. Once transaminase levels have returned to normal, treatment may be resumed even if ALT levels were up to 10 times the upper limit of normal. However, in cases of hypersensitivity to tacrine, manifested by eosinophilia or granulomatous hepatitis, re-administration of the drug is not allowed.

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Therapeutic action of tacrine

Tacrine may prolong survival in patients with Alzheimer's disease and reduce the need for institutionalization. A two-year follow-up of 90% of 663 patients in a 30-week clinical trial of tacrine showed that those taking more than 80 mg of tacrine per day were less likely to die or be institutionalized than those taking lower doses of the drug (odds ratio > 2.7). Although the lack of a control group makes it difficult to generalize the results, the dose-response relationship makes them promising.

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Donenesil

Donepezil hydrochloride (2,3-dihydro-5,6-demethoxy-2[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-indene-1-monohydrochloride) is the second acetylcholinesterase inhibitor approved in the United States for use in Alzheimer's disease. Its advantages over tacrine include the ability to be administered once daily, the absence of significant hepatotoxicity, and the need for regular monitoring of serum enzyme activity. In addition, there is no need for lengthy dose titration, and treatment can be started immediately at a therapeutic dose. In vitro, donepezil is relatively selective in blocking acetylcholinesterase and has a lesser effect on butylcholinesterase.

Pharmacokinetics

When taken orally, the bioavailability of donepezil reaches 100%, and it is not affected by food intake. The concentration of the drug in plasma reaches a peak 3-4 hours after oral administration with a steady-state distribution volume of 12 L / kg. Donepezil is 96% bound to plasma proteins, mainly albumin (75%) and acidic alpha1-glycoprotein (21%). Steady-state plasma levels are achieved after 15 days, while a 4-7-fold increase in donepezil concentrations is possible. The half-elimination period is 70 hours. Donepezil is metabolized in the liver by CYP3D4 and CYP2D6 enzymes and undergoes glucuronidation. As a result, two active metabolites, two inactive metabolites and many small metabolites are formed - all of them are excreted in the urine. According to the manufacturer, in liver diseases (e.g., non-progressive alcoholic cirrhosis), the liver clearance of the drug is reduced by 20% compared to healthy individuals. In kidney diseases, the clearance of donepezil does not change.

Pharmacodynamics

Donepezil is a non-competitive, reversible inhibitor of acetylcholine hydrolysis. Thus, it mainly increases the synaptic concentration of this neurotransmitter in the brain. Donepezil is a more active inhibitor of acetylcholinesterase than tacrine and 1250 times more effective in blocking acetylcholinesterase than butylcholinesterase. There is a linear correlation between the oral dose (1-10 mg/day) and the plasma concentration of the drug.

Clinical trials

Efficacy in slowing the progression of AD symptoms has been demonstrated in several clinical trials. In a 12-week, double-blind, placebo-controlled study in patients with a probable diagnosis of Alzheimer's disease, donepezil 5 mg/day caused a significant improvement in the ADAS-Cog (Alzheimer's Disease Assessment Scale/Cognitive subscale) compared with placebo. No significant effect was observed with lower doses (1 mg and 3 mg per day). In another 12-week, double-blind, placebo-controlled study, donepezil 5 mg and 10 mg caused a significant improvement in the ADAS-Cog compared with placebo. The differences between the 5 mg and 10 mg groups were not statistically significant. At the follow-up examination after a 3-week washout period, no therapeutic effect of donepezil was detected. By the end of the 12th week, patients taking donepezil also showed statistically significant (when compared with the placebo group) improvement on the CIВIC-Plus scale, which allows assessing the physician's clinical impression based on the results of a conversation with the patient and his/her caregiver.

The efficacy of donepezil was also demonstrated in a 30-week study assessing patients' condition using the ADAS and CIВIC-Plus scales. The first 24 weeks of the study included active treatment and were organized according to the double-blind, placebo-controlled principle; the final 6 weeks were a washout period organized according to the blind, placebo-controlled principle. Patients were randomly assigned to three groups, one of which received donepezil at a dose of 5 mg/day, another - 10 mg/day (after a week of taking 5 mg/day), and the third - placebo. By the end of 24 weeks, statistically significant (compared to placebo) improvement was noted according to the ADAS-Cog and CIВIC-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 washout period, there were no significant differences in ADAS-Cog between patients taking donepezil and placebo. This indicated that donepezil does not affect the course of the disease. No direct comparative studies of tacrine and donepezil have been conducted, but the highest degree of improvement in ADAS-Cog with donepezil was lower than with tacrine.

Problems associated with the use of the drug

Donepezil does not have a hepatotoxic effect. Since donepezil enhances the activity of the parasympathetic system, caution should be exercised when prescribing the drug to patients with supraventricular cardiac arrhythmia, including sick sinus syndrome. Due to the parasympathomimetic effect, donepezil can cause gastrointestinal dysfunction and increase the acidity of gastric juice. During treatment with donepezil, patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) and having a history of peptic ulcer disease should be closely monitored due to 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 adverse effects of donepezil include diarrhea, nausea, insomnia, vomiting, cramps, fatigue, and anorexia (Table 9.6). They are usually mild and resolve with continued treatment. Adverse effects are more common in women and in the elderly. Nausea, diarrhea, and vomiting are the most common adverse effects of donepezil leading to treatment discontinuation. In one of the studies cited, patients taking 10 mg daily (after a week of taking 5 mg daily) were more likely to discontinue treatment than those taking 5 mg daily. In the open-label phase of the study, when the dose was increased to 10 mg daily after 6 weeks, these adverse effects were less common than with more rapid titration; their incidence was the same as in patients taking 5 mg daily.

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 protein binding. However, whether this phenomenon has clinical significance remains unclear. This question is very important, since many patients with Alzheimer's disease take several drugs simultaneously. Although the manufacturer reports that the binding of donepezil to albumin is not affected by furosemide, warfarin or digoxin, it remains unclear how the effect of donepezil changes in patients with nutritional deficiency or cachexia. The manufacturer also reports that donepezil does not have a significant pharmacokinetic effect on the action of warfarin, theophylline, cimetidine, digoxin, although no data are provided to confirm this. Due to the blockade of butylcholinesterase, the effect of succinylcholine may be enhanced. Drugs that inhibit CYP2D6 or CYP3A4 may inhibit the metabolism of donepezil, resulting in increased serum levels of both compounds. Conversely, inducers of CYP2D6 or CYP3A4 may increase the elimination of donepezil.

Dosage and administration

Donepezil is available as tablets containing 5 mg and 10 mg donepezil hydrochloride. It is recommended that treatment be initiated with a dose of 5 mg once daily. To minimize adverse effects that occur during peak drug concentrations, the drug is usually administered in the evening, with peak plasma concentrations occurring during sleep. The results of clinical trials do not allow a definitive answer to be given as to whether it is advisable to increase the donepezil dose from 5 to 10 mg per day. Although no statistically significant differences in the efficacy of these two doses were found, a trend towards a higher efficacy of the 10 mg/day dose compared with the 5 mg/day dose was noted. The patient and physician should jointly decide whether it is appropriate to increase the dose to 10 mg/day. The half-life is 70 hours, but this indicator was determined in young people, and similar studies have not been 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, it is preferable to use a dose of 5 mg/day in patients of this age category. Experience shows that an increase in the dose from 5 mg to 10 mg per day should be carried out no earlier than 4-6 weeks, carefully monitoring the therapeutic and possible side effects.

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Galantamine

A competitive reversible inhibitor of acetylcholinesterase that does not affect butyrylcholinesterase. In addition, due to the allosteric effect, it is able to increase the sensitivity of nicotinic cholinergic receptors. Multicenter trials conducted in the United States and Europe showed that the drug in doses of 16 mg / day and 24 mg / day improves ADAS scores reflecting the state of speech, memory, and motor functions. Side effects were noted 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.

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Rivastigmine

A "pseudo-irreversible" carbamate cholinesterase inhibitor with selective action in the hippocampus and cerebral cortex. In a 26-week, double-blind, placebo-controlled study, the drug was more effective than placebo, exerting 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 latter did not differ in effectiveness from placebo in one study. Treatment is usually started with a dose of 1.5 mg twice a day, then, taking into account the effect, it can be successively increased to 3 mg twice a day, 4.5 mg twice a day, 6 mg twice a day. The interval between dose increases should be at least 2-4 weeks. Side effects (including weight loss) occur in approximately half of patients taking high doses of the drug, and in 25% of cases require its discontinuation.

Memantine is an amantadine derivative, a low-affinity non-competitive NMDA receptor antagonist and a modulator of glutamatergic transmission. Double-blind, placebo-controlled studies have shown that in patients with Alzheimer's disease with moderate to severe dementia, memantine treatment slows down the progression of cognitive impairment, increases motivation, motor activity, and independence in everyday life, and reduces the burden on caregivers. The initial dose of memantine is 5 mg/day, which is increased to 10 mg/day after a week and to 20 mg/day after 2-3 weeks if the effect is insufficient. Subsequently, the dose can be increased to 30 mg/day if necessary.

Experimental Pharmacological Approaches to Treating Alzheimer's Disease

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Cholinesterase inhibitors

Physostigmine is a short-acting, reversible cholinesterase inhibitor that requires frequent dosing. Its use is limited by frequent peripheral cholinergic effects such as nausea and vomiting. A long-acting oral formulation of physostigmine has been developed and has been shown to be effective in phase III clinical trials, but is no longer used due to frequent side effects.

Eptastigmine is a long-acting form of physostigmine (heptylphysostigmine) that has shown some benefit in Alzheimer's disease, although the dose-response curve was inverted U-shaped. Due to frequent gastrointestinal side effects and a reported case of agranulocytosis, the drug is not recommended for use in Alzheimer's disease.

Metrifonate is an irreversible acetylcholinesterase inhibitor, similar in chemical structure to poison gases. Metrifonate blocks acetylcholinesterase to a much greater extent than butylcholinesterase. It is currently used to treat schistosomiasis. In vivo, the drug is converted to dichlorvos, a long-acting organic cholinesterase inhibitor. Animal studies and early clinical trials have shown promising results, but due to toxicity, the drug is currently not approved for use in Alzheimer's disease.

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Muscarinic receptor agonists

To date, five types of muscarinic receptors (M1–M5) have been identified that are involved in the control of cognitive and postural functions. These receptors are G-protein coupled and are found in the brain and autonomic nervous system. M1 receptors are most common in areas of the brain responsible for memory and learning and are not affected by the progression of Alzheimer's disease. M4 receptors are of particular interest because their density in the cerebral cortex increases in Alzheimer's disease. When administered systemically, muscarinic receptor agonists are unable to mimic normal pulse stimulation of receptors, which is likely the reason for their decreased sensitivity (desensitization). However, according to some data, tonic stimulation of receptors may be important in the processes of attention and maintenance of 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 in the late stage of the disease, when the number of presynaptic cholinergic neurons is significantly reduced, or in combination with cholinesterase inhibitors.

Milamelin. A non-specific partial agonist of muscarinic receptors that improves cognitive functions in a laboratory model. The drug is well tolerated by both healthy people and patients with Alzheimer's disease. Although the dose of milamelin required to stimulate the central cholinergic systems is lower than the dose that ensures activation of the peripheral cholinergic system, side effects such as nausea, vomiting, and painful abdominal cramps are possible when using the drug. A multicenter study of milamelin in Alzheimer's disease is currently underway.

Xanomeline. Partial agonist of M1 and M4 receptors. Studies have shown generally satisfactory tolerability of the drug, but in some cases the drug had to be discontinued due to side effects from the gastrointestinal tract and arterial hypotension. A phase III trial showed some positive effect of xanomeline on "non-cognitive" symptoms. A transdermal form of the drug has also been studied.

Nicotine

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

Pathomorphological studies and functional neuroimaging have revealed a decrease in the number of nicotinic receptors in patients with Alzheimer's disease. When nicotine is prescribed to patients with Alzheimer's disease, the number of intrusion errors decreases. When treated with nicotine, its side effect on affective status is 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 the decrease in the number and sensitivity of nicotinic receptors.

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

Other agents affecting glutamate transmission

As mentioned, increased glutamatergic transmission may promote apoptosis and cell death. For this reason, aniracetam and ampakines may be useful in Alzheimer's disease.

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 humans with experimentally induced cognitive impairment, aniracetam improved test performance. The ability of aniracetam to positively influence cognitive functions has also been shown in some clinical studies, but these results have not been confirmed by other authors. Confusion, fatigue, anxiety, restlessness, insomnia and some other side effects were noted when taking the drug, but they did not require discontinuation of the drug. The drug did not have a significant effect on liver function.

Ampakines. The decrease in the number of glutamate AMPA receptors found in the brain of patients with Alzheimer's disease may lead to disruption of calcium homeostasis and neuronal damage. Ampakines can increase the activity of AMPA receptors and facilitate learning and memory processes by enhancing long-term potentiation. Placebo-controlled phase II clinical trials of ampakines conducted in healthy adult men revealed the ability of the drugs to improve immediate recall. Currently, the safety and efficacy of ampakine CX-516 is being studied.

Oxidative stress reducing agents

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

Vitamin E and selegiline. Vitamin E and selegiline have antioxidant effects. A two-year, double-blind, placebo-controlled study showed that in patients with moderate to severe Alzheimer's disease (as measured by the Clinical Dementia Rating Scale), vitamin E (2000 IU/day) and selegiline (10 mg/day), alone and in combination, delayed some of the events that served as benchmarks for assessing efficacy: death, placement in a nursing home, and loss of self-care functions. However, no enhancement of the effect was observed with the combination of selegiline and vitamin E. Neither drug nor combination improved cognitive function compared with baseline or placebo.

Idebenone. Idebenone is chemically similar to ubiquinone, an intermediate product of oxidative phosphorylation. In a double-blind, placebo-controlled study, idebenone at doses up to 360 mg/day had a positive effect in patients with Alzheimer's disease. Patients taking idebenone showed more favorable ADAS scores (including the ADAS-Cog cognitive subscale) and a higher Clinical Global Impression score after 6 and 12 months of treatment than patients taking placebo. Phase III clinical trials of idebenone are currently underway in the United States.

Extracts of the plant Ginkgo biloba, possibly possessing antioxidant and anticholesterase activity, have been widely tested in Alzheimer's disease. Several studies have shown that they can have a moderate positive effect on some cognitive functions, but have relatively little effect on the general condition. Further studies of the effectiveness of these drugs are needed. Calcium channel blockers. Since the disturbance 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 conducted in Alzheimer's disease.

Nimodipine. Nimodipine has been reported to improve learning and memory in humans and laboratory animals, although these results have not been confirmed by other authors. It is possible that neurons are selectively sensitive to a given dose of nimodipine, depending on the optimal calcium level in the cells. Thus, in one study in patients with Alzheimer's disease, memory performance (but not other cognitive functions) improved when taking nimodipine at a relatively low dose (90 mg/day), while at a higher dose (180 mg/day) the effect of the drug was no different from the effect of placebo.

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, hippocampus, and cerebral cortex. This leads to an increase in the synthesis of acetylcholine due to increased production of acetylcholine transferase, an enzyme that ensures the synthesis of this neurotransmitter. The neuroprotective properties of NGF were revealed in primates in an experiment with neuronal damage. In one of the clinical studies, an increase in cerebral blood flow, improvement in verbal memory, and an increase in the density of nicotinic receptors were noted in 3 patients who received NGF intraventricularly. Apparently, NGF regulates the state of nicotinic receptors and is able to enhance glucose metabolism in the brain. However, since it is not able to penetrate the blood-brain barrier, its clinical use is limited. The use of substances that can penetrate the blood-brain barrier and potentiate the action of endogenous NGF may be effective in Alzheimer's disease and other neurodegenerative diseases.

Estrogens

Estrogens can prevent amyloid deposition in the brain and promote the survival and growth of cholinergic neurons. A small placebo-controlled study showed that taking 17-P-estradiol for 5 weeks improved attention and verbal memory. Epidemiological data indirectly confirm that estrogens can delay the onset of Alzheimer's disease. In a prospective study of a large group of women, 12.5% of whom took estrogens as replacement therapy after menopause, it was noted that women taking 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 in women who took estrogens as replacement therapy, even after accounting for ethnicity, education, and ALOE genotype. Additional confirmation of the positive effect of estrogens was obtained in a study of retired women: it was noted that women who took estrogens had a lower risk of developing Alzheimer's disease than those who did not receive hormone replacement therapy. The positive result depended on the duration of use and the dose of estrogen. In women with Alzheimer's disease, while taking estrogens, a decrease in the severity of slow-wave activity in the EEG and an increase in cerebral blood flow in the motor cortex and basal frontal cortex were noted according to SPECT data. In women with Alzheimer's disease, Mini-Mental State Examination (MMSE) scores increased at 3 and 6 weeks after starting estrogen. However, two recent double-blind, placebo-controlled trials failed to confirm that estrogen slows the progression of Alzheimer's disease.

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Combination treatment

Since the pathogenesis of Alzheimer's disease is apparently multifactorial, it seems logical to use a combination of several drugs for its treatment. It is possible that in the future, a combined (multimodal) approach will be used to treat Alzheimer's disease, similar to that currently used in the treatment of arterial hypertension, heart disease, cancer, and AIDS. A retrospective analysis of the results of a 30-week tacrine trial showed that a more significant improvement in functional and cognitive indicators was noted in women who simultaneously took estrogens. There is evidence of a positive effect of a combination of cholinesterase inhibitors and the glutamatergic drug memantine. However, only a prospective study of combinations of cholinesterase inhibitors with estrogens, memantine, or other drugs will allow us to establish their effectiveness and recommend them as standard therapy. A combination of two or more drugs does not always lead to an increased effect. For example, a trial of vitamin E and selegiline showed that each drug was superior to placebo on a number of “noncognitive” measures, but no additional benefit was observed when the drugs were combined. Combination therapy for Alzheimer’s disease involves not only combining several drugs, but also combining drug therapy with psychosocial interventions to correct the cognitive and behavioral disorders that occur in Alzheimer’s disease.

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