Alzheimer Disease: Bachurin SO

Bachurin SO. · Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Moscow region, Russia. · Med Res Rev. · Pubmed #12424753 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites.

Bachurin SO. · Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russia. · Vopr Med Khim. · Pubmed #11450439 No free full text.

Abstract: The analysis and justification of medicinal chemistry approaches for focused search of novel agents for Alzheimer's disease (AD) and related disorders treatment and prevention have been reviewed. The systematization of modern biochemical and structural date related to the action of physiologically active compounds on the nervous system apparatus engaged in the AD-like disorders pathogenesis was performed. The major attention was paid to the cholinomimetic, anti-amyloid and antimetabolic approaches, basing on the results published in scientific literature in 3-4 last years and results of preclinical and clinical trials, presented in the internet database in the fall of 2000.

Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, Anonymous00052. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX, USA. · Lancet. · Pubmed #18640457 No free full text.

Abstract: BACKGROUND: Although treatments for Alzheimer's disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimer's disease. METHODS: We enrolled 183 patients with mild-to-moderate Alzheimer's disease (mini-mental state examination [MMSE] scores 10-24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. FINDINGS: 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference -4.0 [95% CI -5.73 to -2.28]; p<0.0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference -1.9 [-2.92 to -0.85]; p=0.0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. INTERPRETATION: Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease.

Shevtsov PN, Shevtsova EF, Burbaeva GSh, Bachurin SO. · Laboratory of Neurochemistry, National Center for Mental Health, Russian Academy of Medical Sciences. · Bull Exp Biol Med. · Pubmed #16984114 No free full text.

Abstract: It is shown for the first time that microtubular proteins isolated from the brain of patients with Alzheimer's disease can in vitro polymerize into microtubules with abnormal structure.

Myagkova MA, Gavrilova SI, Lermontova NN, Kalyn YB, Selezneva ND, Zharikov GA, Kolykhalov IV, Abramenko TV, Serkova TP, Bachurin SO. · Department of Biochemical Assays, Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka. · Bull Exp Biol Med. · Pubmed #14534609 No free full text.

Abstract: We measured serum content of autoantibodies to beta-amyloid protein Abeta(1-42), its neurotoxic fragment Abeta(25-35), vasopressin, bradykinin, thrombin, antithrombin III, alpha(2)-macroglobulin, and angiotensin II in patients with various forms of Alzheimer's dementias, including presenile and senile dementias of the Alzheimer type. The ratio of antibradykinin and anti-Abeta(1-42) autoantibody contents differed by 39% in these patients. Our results can be used for the development of a new biochemical method for differential diagnostics of dementias of the Alzheimer type.

Lermontova NN, Mukhina TV, Van'kin GI, Serkova TP, Bachurin SO. · Laboratory of Neurochemistry, Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka. · Bull Exp Biol Med. · Pubmed #12717512 No free full text.

Abstract: Systemic oral administration of NT-0409, a new synthetic agonist of AMPA subtype glutamate receptor, to rats with chronic partial AF64A-induced deprivation of cholinergic functions improved their learning in a Morris water maze. NT-0409 is close to memantine by the effect on learning and, in contrast to cholinomimetic arisept, ensures longer retention of the developed habit.

Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO. · Department of Biological Research, Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow Region. · Bull Exp Biol Med. · Pubmed #11865327 No free full text.

Abstract: Dimebon, a Russian-made drug, inhibited toxic effects of beta -amyloid on cultured neurons. Excessive accumulation of beta-amyloid in the brain is characteristic of Alzheimer dementias. Antialzheimer preparations tacrine and dimebon improve survival of cerebellar granule cells during long-term incubation with Abeta25-35, the neurotoxic fragment of beta-amyloid. Both preparations can block potential-dependent Ca(2+) entry into neurons by about 20%, which is explained by their selective action on L-type Ca(2+) channels. It was assumed that the neuroprotective effect of dimebon and tacrine against Abeta25-35 partially depends on inhibition of potential-dependent Ca(2+) entry.

Myagkova MA, Gavrilova SI, Lermontova NN, Kalyn YB, Selezneva ND, Zharikov GA, Kolykhalov IV, Abramenko TV, Serkova TP, Bachurin SO. · Laboratory of Neurochemistry, Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow Region, Russia. · Bull Exp Biol Med. · Pubmed #11391392 No free full text.

Abstract: The content of autoantibodies to beta-amyloid protein Abeta(1-42), its neurotoxic fragment Abeta(25-35), and neurotransmitters were studied in the blood of patients with presenile Alzheimer's disease and senile dementia of the Alzheimer type. Significant differences in the relative content of autoantibodies to Abeta(1-42)and autoantibodies to biogenic amines were demonstrated. These results can be used for the development of a biochemical method for differential diagnosis of Alzheimer dementias.

Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO. · Laboratory of Neurochemistry, Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow Region. · Bull Exp Biol Med. · Pubmed #11022244 No free full text.

Abstract: Systemic administration of antihistamine drug dimebon improves active avoidance conditioning in rats with chronic partial deprivation of cerebral cholinergic functions caused by intracerebroventricular injections of AF64A. The effects of dimebon on learning are similar to those of tacrine used in the treatment of Alzheimer's disease.