ALZHEIMER S DISEASE WHAT IS NEW IN THE PHARMACOTHERAPY?

34, 47, 2011, 4?. 1, 2.-. 2 1, 2,. ALZHEIMER S DISEASE WHAT IS NEW IN THE PHARMACOTHERAPY? P. Gateva 1, 2, S.-G. Panagis Moshonas 2 1 Pharmacology and Toxicology Department, Medical University Sofia 2 Medical Faculty, Sofia University Kl. Ohridski : : : Summary: Key words: Address for correspondence: ( ) - -..,. - - Memantin -. - -,., Memantine, - -,,,. 2, 1431, -mail: pandreeva_gateva@yahoo.com Alzheimer s disease is the most prevalent cause for dementia worldwide. The treatment of this disease is an important and unresolved problem up to now. The modern treatment is based on proved pathogenetic mechanisms and thus favorably influences symptoms. Acetylcholinesterase in mild and moderate cases and memantine in severe cases are used. Important investigational candidate drugs for treatment of Alzheimer s disease are also discussed in the paper. Alzheimer s disease, memantine, acetylcholinesterase inhibitors Pavlina Gateva, M. D., Pharmacology and Toxicology Department, Medical University, 2, Zdrave Str., Bg 1431 Sofia, -mail: pandreeva_gateva@yahoo.com 1. ALZHEIMER, - 1906. - Alois Alzheimer [4] -.,, - -.. -,. - - e,, 5-10 -,. -. 2006. 26.6., 2050. 85 [37]. -, 60-. -, 5-10%. - 50-, -. -, Plassman. [28] -

..-..... 35, -. - -, [2]., 90-100.,, 60-70.., -, -. - [10]: -,, - E -4-,, -,, -,,,., - [22]., - :, - ( )., -, - -. ( - tangles), 1907. Alois Alzheimer,, - - -. 15-20.. -, - [7], - -. Alois Alzheimer -,,,.,,, - -amyloid, A,,, [8]. -, - (APP, ). - - -, - A. - -, A. - A. - ( -1-2.), - A [35]. 21 (Down syndrome). 21-, [25]., 4 ( 4), - 30%, - [34]. 4 A,., SORL1, [32]. -, -. SORL1,, -, A. A. A - -. - -, -,, -,. -, -. - -, 1975. [36]. -. - A

36, 47, 2011, 4 -., -, -. -.., : - -,,,, -,,,. 2., -,, -. -, - (. 1). - N-methyl-D-aspartate (NMDA)., -,,. a), (Glu) -. 70% -. p,,, [23].. - -. - NMDA, -, - Ca 2+. NMDA - Ca 2+, Mg 2+. -, - Ca 2+. 1. NMDA- - Ca 2+., - [16]. Memantine (3,5-dimethyladamantan -1-amine) NMDA -., -, Axura, Akatinol, Namenda, Ebixa, Abixa, Memox., Memantine. (< 10% ), (~ 100%). 60-100 [24].?, - Memantine NMDA-?. 1..?

..-..... 37 Memantine NMDA - Mg 2+ - Ca 2+,. Memantine -, NMDA -. - NMDA - ( 10 77% NMDA -70 mv, NMDA +70mV) [18]. Memantine NMDA (off-rate or Koff; Koff = 0,2/sec) (IC50 = 3 μ ). -. Memantine. -,, - -,,,. Memantine D2 [20]. -, [31]. -,,,,. - -,,, -. - -., -,. ), Choline-leakage, - - (A ) (leakage, ), - - [7]. -, - - - PC12, -, - -. - - ( ) leakage. -, leakag -. - - - -. - 2 : - [27]. - -,. - - -, - (positive feedback),. - -. Galantamine: (C 17 H 21 NO 3 ), Galanthus nivalis, Lycoris radiata Galanthus woronowii. - ( ). galantamine : Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine. -, -. Galantamine., - 80 100%. 7 h ( 18% ). 75% -. - CYP2D6 CYP3A4 [15]. - Paroxetine ( CYP 2D6) Ketoconazole ( CYP 3A4) - 40% 30%. (95% -, 32% ) - ( 7%). Galantamine,, -

38, 47, 2011, 4 :, -. -, - leakage -. Galantamine -,,, - - [1]. Galantamine, -.., myasthenia gravis,,, -,. Galantamine, - - - -,,., -,,. Rivastigmine. -, -, - (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate. ( - ),, - -., [25]. Rivastigmine, 40%. 12 mg, -., 40% -. 1,5 h. - CYP450 [26]. - -. - -, -., - -. Donepezil. (RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy- 2,3-dihydroinden-1-one)., (100%) -. - 70 h, -. ( 96% - ) [33]. M mantine, -. Donepezil, -, Down CADASIL ( - - - ), bypass,,. - -,,,,, -,,. Tacrine. -, (1,2,3,4-tetrahydroacridin-9-amine) [21]. -. - -N-. ( 2,4-36%). (55%). -. CYP450 1- ( ),. 2-4. - -,. - -,,, -,,,,,,. -. -,,. 1.

..-..... 39 1 Donepezil,, Aldemiz, Alzepil, Aricept, Aripezile, Cognezyl, Dorizol, Dentap, Donecept, Donectil, Donesyn, Yasnal Galantamine, Galsia SR, Nivalin, Rivastigmine, Ridaxin, Ristidic, Rivastigmine Synthon 3.,,,, - Alzheimer,. Varenicline. - 4 2 - - 7 - (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino (2,3- h)(3) benzazepine). [17]., (< 20%), 24 (81-91% ). (< 10%),, [6]. -. Varenicline,,,,,. - Varenicline [14],. ST101. - - [11]. - -. Exenatide., -4, 2., 2,4. Exenatide -, Gila monster ( ). - -1., -,. [12].,, - [19].,,, -.., [30]. [13]. MAO-B. - -, Selegiline Rasagiline, - [38], - - locus ceruleus, -. -,,, II. Selegiline (2000 UI/ ), - > 400 UI/ - - [3].,. - -, Memantine.,, -, -,,,.

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