amiridine and Alzheimer-Disease

This is a review of the data available in the literature and the authors' own findings on pathogenetical rationale for the use and clinical study of current treatments for Alzheimer's disease (AD) (synonym: Alzheimer-type dementia). In the past decade many attempts have been made at targeting different links of the pathogenesis of a neurodegenerative process that underlie AD. Several areas of pathogenetical therapy for AD have been developed on the basis of experimental studies and pilot clinical tests. The most developed areas are as follows: various compensatory (replacement) treatments aimed at overcoming neurotransmitter deficit in different neuronal systems that are damaged in AD to a greater or lesser extent; neuroprotective therapy promoting increased viability (survival) of neurons and their plasticity, and vasoactive therapy. Rather new directions of AD pathogenetic therapy, such as antiinflammatory and hormonal therapy along with antiamyloid therapeutic strategies are still under study.

Topics: Aged; Alzheimer Disease; Amino Acids; Aminoquinolines; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Dopamine Agents; Estrogens; Ginkgo biloba; Humans; Indans; Memantine; Monoamine Oxidase Inhibitors; Multicenter Studies as Topic; Neuronal Plasticity; Neuroprotective Agents; Neurotransmitter Agents; Nicergoline; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Piracetam; Pyrithioxin; Rivastigmine; Selegiline; Tacrine; Time Factors

16 patients with dementia of Alzheimer's type (DAT) were examined. Functional activity of lymphocytes was determined according to proliferating activity of T-lymphocytes, production of Interleukin-1 (IL-1) and estimation of subpopulations of T-leukocytes (T-helpers, T-suppressors). The patients were observed both before and 1-2.5 months after amiridin therapy. Considerable reduction of both IL-1 production and proliferating activity of T-lymphocytes was observed after the treatment in 8 patients of 11. Their cognitive functioning after the therapy was either improved or stable by the moment of repeated observation. It is quite important that initial functional activity of lymphocytes was considerably higher in this group of patients as compared with the age-matched controls. Change for the worse in cognitive functions by the moment of the second examination was accompanied in 5 patients with an increase in IL-1 production as compared to the initial level. It is proposed that high level of IL-1 production by blood lymphocytes may be used as a criterion in selection of DAT patients for amiridin therapy.

Topics: Alzheimer Disease; Aminoquinolines; Cell Movement; Cholinesterase Inhibitors; Humans; Interleukin-1; Neuroprotective Agents; T-Lymphocytes; Treatment Outcome

The efficacy of neuromidin (ipidacrinum), a nonselective inhibitor of acetylcholinesterase and butyrilcholinesterase was studied in patients with mixed vascular and Alzheimer's dementia of mild and moderate severity. Thirty patients of the main group received neyromidin in dosage 80 mg/day during 3 months; 10 patients of the comparison group matched by age, sex and severity of cognitive disorders did not receive the drug. The positive effect was seen in 53,3% of patients of the main group. The worsening was observed in 40% of patients of the comparison group. The positive effect of the drug on spatial and neurodynamic functions was revealed. No serious side-effects of the treatment were found.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aminoquinolines; Cholinesterase Inhibitors; Dementia, Vascular; Female; Humans; Male; Middle Aged; Treatment Outcome

The paper presents a study concerning an influence of cerebrolysin on the efficiency of subsequent therapy with amiridin in patients with mild and moderate dementia of Altzheimer's type (DAT). A study included 2 groups of patients similar in terms of clinical and demographic parameters. The patients of group 1 (23 cases) were treated by amiridin in daily dose of 80 mg during 10 weeks. In group 2 (26 patients) a session of 20 intravenous infusions of cerebrolysin (30 ml in 150 ml of physiologic solution during 4 weeks) preceded the same therapy with amiridin. The neuropsychological assessment was made according to Luria's method with a quantitative estimation of the regulatory and operational components of mental activity. Comparison of the results of neuropsychologic examination both before and after the therapy showed a more pronounced improvement in the states of all regulatory and separate operational components of mental activity in combined therapy with cerebrolysin and amiridin versus monotherapy with amiridin. In patients of group 2 with disturbances of higher mental functions the pathological symptomatology connected with anterior frontal and deep structures of brain was significantly decreased as compared with the patients from group 1.

Topics: Aged; Alzheimer Disease; Amino Acids; Aminoquinolines; Cholinesterase Inhibitors; Cognition Disorders; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Male; Neuroprotective Agents; Neuropsychological Tests; Nootropic Agents; Severity of Illness Index; Treatment Outcome

As many as 88 patients with Alzheimer's type senile dementia were followed up. Of these, 28 patients suffered from marked and 60 from unpronounced dementia. 74 patients received amiridine and 14 made up a control group. Amiridine was administered per os in the daily doses 20, 40 and 60 mg. The treatment lasted up to 14 months. The follow-up studies included clinical observations and testing according to a specially devised scale. A double blind study was carried out together with examinations of the drug withdrawal effect and comparisons of the main and control groups. All the tests demonstrated amiridine to have a well-defined therapeutic effect in 30-46% of the patients. Cognitive functions and the general mental status of the patients continued improving or got stabilized for a long time (up to 14 months). The speech improved for a shorter period of time. Amiridine was found to produce a beneficial effect both at the initial and marked stages of the disease. The most significant results were attained in the patients with unmarked dementia. The treatment efficacy correlated well with the dose of amiridine.

Topics: Administration, Oral; Aged; Alzheimer Disease; Aminoquinolines; Cholinesterase Inhibitors; Cognition; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Placebos; Psychotropic Drugs

Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis-

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Antioxidants; Butyrylcholinesterase; Cholinesterase Inhibitors; GPI-Linked Proteins; Humans; Kinetics; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Structure-Activity Relationship

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Animals; Antioxidants; Benzothiazoles; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Horses; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Oxidative Stress; Piperazine; Structure-Activity Relationship; Sulfonic Acids

We studied the effects of anti-Alzheimer drugs (tacrine, amiridine, and memantine) on phosphorylation of tubulin and microtubule-associated proteins isolated from rat brain, evaluated the capacity of these proteins to polymerize into microtubules after addition of study pharmacological agents, and analyzed the structure of generated microtubules. It was shown that test substances impair assembly of microtubules to a different extent. Dose-dependent effects of these agents on phosphorylation of tubulin and microtubule-associated proteins were observed. Triazolam (not approved for clinical use as anti-Alzheimer drug) in the same concentrations was used as the reference substance in the same tests. It was observed that this substance even in minimal concentration induced the most pronounced changes in microtubule structure. A direct correlation between the capacity of the test substances to modulate tubulin phosphorylation and to impair microtubule structure was found: the more the substance inhibited tubulin phosphorylation, the more it disordered microtubule structure.

Topics: Alzheimer Disease; Aminoquinolines; Animals; Brain; Memantine; Microtubule-Associated Proteins; Microtubules; Nootropic Agents; Phosphorylation; Rats; Rats, Wistar; Tacrine

In in vitro experiments, amiridine in concentration of 100, 200, and 300 microM restored disturbed structure of microtubules assembled from tubulin and microtubule-associated proteins isolated from the brain of patients with Alzheimer disease. Tacrine in a concentration of 100, 250, and 500 microM inhibited phosphorylation of tubulin and microtubule-associated proteins isolated from the brain of patients with Alzheimer disease, while memantine and amiridine in the specified concentrations had no effect on phosphorylation.

Topics: Alzheimer Disease; Aminoquinolines; Brain; Dopamine Agents; GABA Modulators; Humans; Memantine; Microtubule-Associated Proteins; Microtubules; Nootropic Agents; Phosphorylation; Tacrine; Triazolam

Acetylcholinesterase (AChE) activity and parameters of the system of regulation of lipid peroxidation (LPO) were estimated in blood of patients with Alzheimer's disease (AD) during therapy with amiridine and gliatiline. It was found that the therapy was accompanied by inhibition of AChE activity. A significant correlation was observed between clinical efficiency and changes of AChE activity. AD was characterised by essential changes in LPO parameters: the level of the primary products of oxidation was increased three times with a sharp increase (seven times) of total unsaturation of lipids. A significant correlation was found between AChE activity and the level of the primary products of oxidation in blood erythrocytes of AD patients before and after therapy with amiridine and gliatiline.

Topics: Aged; Alzheimer Disease; Aminoquinolines; Cholinesterase Inhibitors; Cognition Disorders; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Severity of Illness Index

This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Animals; Benzazepines; Brain; Butyrylcholinesterase; Carbamates; Cholinesterase Inhibitors; Donepezil; In Vitro Techniques; Indans; Inhibitory Concentration 50; Male; Phenylcarbamates; Physostigmine; Piperidines; Rats; Rivastigmine; Tacrine; Time Factors

The effects of NIK-247 on cholinesterase, scopolamine-induced amnesia and spontaneous movement were examined and compared with those of the well-known cholinesterase inhibitors tacrine and E-2020. NIK-247, tacrine and E-2020 all strongly inhibited acetylcholinesterase (AChE) in human red blood cells (IC50s = 1.0 x 10(-6), 2.9 x 10(-7) and 3.7 x 10(-8) M, respectively). In addition, NIK-247 and tacrine, but not E-2020, strongly inhibited butyrylcholinestrase (BuChE) in human serum. All three drugs produced mixed inhibition of AChE activity. Moreover, the inhibitory effect of NIK-247 on AChE was reversible. All compounds at 0.1-1 mg/kg p.o. significantly improved the amnesia induced by scopolamine (0.5 mg/kg s.c.) in rats performing a passive avoidance task. The three compounds at 1 and 3 mg/kg p.o. did not significantly decrease spontaneous movement by rats. These findings suggest that NIK-247 at a low dose (0.1-1 mg/kg p.o.) improves scopolamine-induced amnesia but does not affect spontaneous movement. The findings suggest that NIK-247 may be a useful drug for the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Amnesia; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Male; Motor Activity; Piperidines; Psychotropic Drugs; Rats; Rats, Wistar; Scopolamine; Tacrine

Impoverished grasp of the abstract and the essential notions (IG) and delusion of stealing (DS) were investigated in Alzheimer's senile dementia (ASD) and multi-infarction dementia (MID). IG severity was evaluated in impairment of memory and disorientation in 67 ASD and 70 MID patients. DS was studied in 24 ASD and 56 MID patients. It was found that in similar impairment of memory and disorientation, IG was more distinct in ASD, especially at early stages of the disease. DS occurred more frequently in ASD than in MID. In MID the IG and DS symptoms were more common and severe in patients over 80. No age-specific relations were recorded in ASD. The findings suggest involvement of cerebral senile-atrophic processes in IG and DS genesis in MID patients.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aminoquinolines; Cholinesterase Inhibitors; Delusions; Dementia, Multi-Infarct; Diagnosis, Differential; Female; Humans; Male; Memory Disorders; Middle Aged; Orientation; Psychotropic Drugs

The study of the drugs effective in the treatment of cognitive deficits and memory loss associated with senile dementia of the Alzheimer's type--tacrine and amiridin, acetylcholinesterase inhibitor physostigmine and nootrop piracetam on uptake of 3H-serotonin (3H-5-HT), 3H-adrenaline (3H-AD), 3H-noradrenaline (3H-HA), 2H-dopamine (3H-DA), 3H-gamma-aminobutyric acid (3H-GABA), 3H-glutamic acid (3H-GLU), 3H-aspartic acid (3H-ASP) and 3H-glycine (3H-GLI) showed that tacrine and amiridin (5 x 10(-5) M) statistically significantly (P less than 0.05) inhibited the uptake of 3H-DA and 3H-5-HT. Physostigmine at concentration 5 x 10(-4) M statistically significantly (P less than 0.05) inhibited uptake of 3H-5-HT only. Piracetam at concentration range 1-5 x 10(-3) M had no effect on uptake of all investigated neurotransmitters. The above finding suggest that the uptake of neurotransmitter in nerve terminals is not the main target of amiridin and tacrine.

Topics: Alzheimer Disease; Aminoquinolines; Animals; Cholinesterase Inhibitors; Dopamine; Epinephrine; gamma-Aminobutyric Acid; Neurotransmitter Agents; Norepinephrine; Physostigmine; Piracetam; Psychotropic Drugs; Rats; Serotonin; Synaptosomes; Tacrine

In vitro comparative studies of effects of amiridin (9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopentane (b) choline monohydrate hydrochloride) and tacrine physostigmine and piracetam on monoamine oxidase A (MAO-A) and B (MAO-B) activity in the rat brain were carried out. Piracetam (1 x 10(-4)-1 x 10(-3) M) dose-dependently increased MAO-A and MAO-B activity. At all concentrations used (1 x 10(-7)-5 x 10(-4) M) physostigmine had no effect on MAO-A and MAO-B activity. Amiridin was found to inhibit MAO-B activity at 5 x 10(-4) M concentration only. Tacrine inhibited MAO-A activity at 5 x 10(-4) M concentration. The therapeutical effects of amiridin and tacrine in treatment of Alzheimer disease were not related to their action on MAO-A and -B activity.

Topics: Alzheimer Disease; Aminoquinolines; Animals; Brain; Cholinesterase Inhibitors; In Vitro Techniques; Male; Monoamine Oxidase; Piracetam; Psychotropic Drugs; Rats; Tacrine

The model of amnestic syndrome obtained by treatment with scopolamine during 20 days in rats was used to study anti-amnesic activity of amiridin in comparison with that of tacrine, physostigmine and piracetam. Multiple injection of Sc resulted in significant deterioration of rats, performance in passive avoidance test. Behavioral disorders were accompanied by such changes in lipid composition of brain synaptosomes which indicated a decreased membrane fluidity. Amiridin and tacrine as well as piracetam showed anti-amnesic action which in the course of treatment correlated with their normalizing effect on lipid content of synaptosomes. The diverse effect of amiridin and tacrine with respect to physostigmine implies that the former drugs can't be attributed to anticholinesterase preparations which are traditionally used in the treatment of Alzheimer disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Amnesia; Animals; Cerebral Cortex; Cholinesterase Inhibitors; In Vitro Techniques; Lipids; Male; Physostigmine; Piracetam; Psychotropic Drugs; Rats; Scopolamine; Synaptosomes; Syndrome; Tacrine

The effects of amiridin (9-amino-2,3,5,6,7,8-hexahydro-IH-cyclopenta(b) quinoline) and tacrine (1,2,3,4-tetrahydro-9-aminoacridine) on Schaffer collaterals--CAI field potentials were compared in rat hippocampal slice preparations. Similar dose-dependent increase in pop-spike amplitude was observed during slice perfusion with low concentrations of amiridin (5-50 microM) or tacrine (0.5-10 microM). This facilitation was not always fully reversible. The effect was accompanied by slight decrease in pop-EPSP amplitude suggesting membrane depolarization as a possible mechanism of pop-spike facilitation. Further increase in drug concentrations led to the depression and full blockade of pop-spike, that was associated with significant decrease in the pop-EPSP and fiber potential amplitudes. In contrast structurally related 4-aminopyridine evoked dose-dependent increase in both pop-EPSP and pop-spike amplitudes with all the concentrations tested (0.05-1000 microM), this facilitation was transformed into epileptiform response with 4-aminopyridine concentration about 500 microM. Possible mechanisms of drug actions on hippocampal neuron reactivity are discussed. It is suggested that amiridin might turn to be as effective as tacrine in symptomatic treatment of Alzheimer disease.

Topics: 4-Aminopyridine; Alzheimer Disease; Aminoacridines; Aminoquinolines; Animals; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Hippocampus; In Vitro Techniques; Neurons; Rats; Rats, Inbred Strains; Tacrine