Paper(s) concerning Tacrine68 reference(s) found.
Dileep KV, Ihara K, Mishima-Tsumagari C, Kukimoto-Niino M, Yonemochi M, Hanada K, Shirouzu M, Zhang KYJ Ref: Int J Biol Macromol, 210:172, 2022 : PubMed ESTHER: Dileep_2022_Int.J.Biol.Macromol_210_172 PubMedSearch: Dileep 2022 Int.J.Biol.Macromol 210 172 PubMedID: 35526766 Inhibitor(s) related to this paper: Tacrine Abstract Alzheimer's disease (AD) is one of the most common, progressive neurodegenerative disorders affecting the aged populations. Though various disease pathologies have been suggested for AD, the impairment of the cholinergic system is one of the critical factors for the disease progression. Restoration of the cholinergic transmission through acetylcholinesterase (AChE) inhibitors is a promising disease modifying therapy. Being the first marketed drug for AD, tacrine reversibly inhibits AChE and thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. However, the atomic level of interactions of tacrine towards human AChE (hAChE) is unknown for years. Hence, in the current study, we report the X-ray structure of hAChE-tacrine complex at 2.85 A resolution. The conformational heterogeneity of tacrine within the electron density was addressed with the help of molecular mechanics assisted methods and the low-energy ligand configuration is reported, which provides a mechanistic explanation for the high binding affinity of tacrine towards AChE. Additionally, structural comparison of reported hAChE structures sheds light on the conformational selection and induced fit effects of various active site residues upon binding to different ligands and provides insight for future drug design campaigns against AD where AChE is a drug target. Title: Kinetic analysis of the toxicological effect of tacrine (Cognex) on human retinal acetylcholinesterase activity Alhomida AS, Al-Rajhi AA, Kamal MA, Al-Jafari AA Ref: Toxicology, 147:33, 2000 : PubMed ESTHER: Alhomida_2000_Toxicology_147_33 PubMedSearch: Alhomida 2000 Toxicology 147 33 PubMedID: 10837930 Inhibitor(s) related to this paper: Tacrine Abstract For the first time, kinetic parameters of the effect of tacrine, an anti-cholinesterase inhibitor of therapeutic potential in Alzheimer's disease has been studied on human retinal acetyl-cholinesterase (AChE). Tacrine inhibited the AChE activity in a concentration dependent manner, the IC(50) being about 45 nM. The Michaelis-Menten constant (K(m)) for the hydrolysis of acetylthiocholine iodide was found to be 0.120 mM and this value was increased by 4-52.8% in the presence of tacrine. V(max) was observed to be 2.23 micromol/h per mg protein for the control system, while it was decreased by 14.73-56.25% in the tacrine treated systems. Dixon as well as Lineweaver-Burk plots and their secondary replots indicated that the nature of the inhibition was of the mixed type, i. e. a combination of competitive and noncompetitive inhibition. The values of K(i) and K(I) were estimated to be as 37.76 and 64.36 nM, respectively. Title: Huprine X is a Novel High-Affinity Inhibitor of Acetylcholinesterase That Is of Interest for Treatment of Alzheimer's Disease Camps P, Cusack B, Mallender WD, Achab RE, Morral J, Munoz-Torrero D, Rosenberry TL Ref: Molecular Pharmacology, 57:409, 2000 : PubMed ESTHER: Camps_2000_Mol.Pharmacol_57_409 PubMedSearch: Camps 2000 Mol.Pharmacol 57 409 PubMedID: 10648652 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuprineX, Tacrine Abstract Inhibitors of the enzyme acetylcholinesterase (AChE) slow and sometimes reverse the cognitive decline experienced by individuals with Alzheimer's disease. Huperzine A, a natural product used in traditional Chinese herbal medicine, and tacrine (Cognex) are among the potent AChE inhibitors used in this treatment, but the search for more selective inhibitors continues. We report herein the synthesis and characterization of (-)-12-amino-3-chloro-9-ethyl-6,7, 10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride (huprine X), a hybrid that combines the carbobicyclic substructure of huperzine A with the 4-aminoquinoline substructure of tacrine. Huprine X inhibited human AChE with an inhibition constant K(I) of 26 pM, indicating that it binds to this enzyme with one of the highest affinities yet reported. Under equivalent assay conditions, this affinity was 180 times that of huperzine A, 1200 times that of tacrine, and 40 times that of E2020 (donepezil, Aricept), the most selective AChE inhibitor currently approved for therapeutic use. The association and dissociation rate constants for huprine X with AChE were determined, and the location of its binding site on the enzyme was probed in competition studies with the peripheral site inhibitor propidium and the acylation site inhibitor edrophonium. Huprine X showed no detectable affinity for the edrophonium-AChE complex. In contrast, huprine X did form a ternary complex with propidium and AChE, although its affinity for the free enzyme was found to be 17 times its affinity for the propidium-AChE complex. These data indicated that huprine X binds to the enzyme acylation site in the active site gorge but interferes slightly with the binding of peripheral site ligands. Title: Mass psychogenic illness attributed to toxic exposure at a high school Heuser G Ref: N Engl J Med, 342:1674; author reply 1675, 2000 : PubMed ESTHER: Heuser_2000_N.Engl.J.Med_342_1674; author reply 1675 PubMedSearch: Heuser 2000 N.Engl.J.Med 342 1674; author reply 1675 PubMedID: 10836879 Inhibitor(s) related to this paper: Tacrine Title: Combining tacrine with milameline reverses a scopolamine-induced impairment of continuous performance in rhesus monkeys Callahan MJ Ref: Psychopharmacology (Berl), 144:234, 1999 : PubMed ESTHER: Callahan_1999_Psychopharmacology.(Berl)_144_234 PubMedSearch: Callahan 1999 Psychopharmacology.(Berl) 144 234 PubMedID: 10435389 Inhibitor(s) related to this paper: Tacrine Abstract RATIONALE: Cholinomimetic therapy in Alzheimer's disease (AD) has been hampered by narrow efficacious dose ranges and dose-limiting side effects. These limitations highlight the need for an alternative therapeutic approach for the symptomatic treatment of AD. OBJECTIVES: To determine in rhesus monkeys if combined treatment with the acetylcholinesterase inhibitor tacrine (Cognex) and the muscarinic agonist milameline improve behavioral efficacy in a scopolamine-reversal task without potentiating adverse side effects. Title: In vivo PET study of cerebral [11C] methyl- tetrahydroaminoacridine distribution and kinetics in healthy human subjects Traykov L, Tavitian B, Jobert A, Boller F, Forette F, Crouzel C, Di Giamberardino L, Pappata S Ref: Eur Journal of Neurology, 6:273, 1999 : PubMed ESTHER: Traykov_1999_Eur.J.Neurol_6_273 PubMedSearch: Traykov 1999 Eur.J.Neurol 6 273 PubMedID: 10210906 Inhibitor(s) related to this paper: Tacrine, [11C]N-methyl-tacrine Abstract It is unclear whether the palliative effects of tetrahydroaminoacridine (THA) (tacrine, Cognex) on the clinical symptoms of patients affected by Alzheimer's disease (AD) are the result of its inhibitory activity on acetylcholinesterase or on other complex sites of action. In order to investigate the cerebral distribution and kinetics of THA in the human brain in vivo, we performed positron emission tomography (PET) imaging with [11C]N-methyl-tetrahydro-aminoacridine (MTHA) in healthy human volunteers. After intravenous injection, [11C]MTHA crossed the blood-brain barrier and reached its maximum uptake between 10 and 40 minutes, depending on the brain regions. Uptake was higher in the grey matter structures, and lower in the white matter. After this peak, the radioactivity remained quasi- constant until 60 minutes in all regions with a half-life varying from 2.44 hours in the thalamus to 3.42 hours in the cerebral cortex. The ratios of regional to whole cerebral cortex brain radioactivity calculated between 50 and 70 minutes after the tracer injection were 1.14 +/- 0.04, 1.07 +/- 0. 03 and 1.06 +/- 0.04 in the putamen, cerebellum and thalamus, respectively. Overall, these results show that: (1) [11C]MTHA crosses the blood-brain barrier easily and is highly concentrated in the brain; (2) the regional brain distribution of [11C]MTHA does not parallel that of in vivo acetylcholinesterase (AChE) concentrations; and (3) the cerebral kinetics of [11C]MTHA are consistent with known plasmatic pharmacokinetics of THA in AD patients. We conclude that PET imaging with [11C]MTHA is a useful method for assessing the cerebral distribution and kinetics of THA in vivo. Title: Syntheses of benzoquinolizidine and benzoindolizidine derivatives as anti-amnesic agents Zhao S, Totleben MJ, Freeman JP, Bacon CL, Fox GB, O'Driscoll E, Foley AG, Kelly J, Farrell U and Szmuszkovicz J <2 more author(s)> Zhao S, Totleben MJ, Freeman JP, Bacon CL, Fox GB, O'Driscoll E, Foley AG, Kelly J, Farrell U, Regan C, Mizsak SA, Szmuszkovicz J (- 2) Ref: Bioorganic & Medicinal Chemistry, 7:1637, 1999 : PubMed ESTHER: Zhao_1999_Bioorg.Med.Chem_7_1637 PubMedSearch: Zhao 1999 Bioorg.Med.Chem 7 1637 PubMedID: 10482456 Inhibitor(s) related to this paper: Tacrine Abstract Tacrine, one of the drugs available for Alzheimer's disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine have been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research was undertaken to produce an acetylcholinesterase inhibitor by employing 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) as templates. Thus, we aimed to achieve three goals relative to tacrine: eliminate the pyridine and quinoline moieties and render the molecule less flat. Overall, the compounds we prepared were poorer inhibitors of acetylcholinesterase compared to tacrine. The single exception was compound 6f which exhibited an effect comparable to that of tacrine, but only at a dose of the order of 10(-3) M. However, despite the poor acetylcholinesterase inhibition by 6b, this compound proved to be an effective anti-amnesic agent at 45 mg/kg dose. Title: Central cardiovascular effects of tacrine in the conscious dog: a role for catecholamines and vasopressin release Allal C, Lazartigues E, Tran MA, Brefel-Courbon C, Gharib C, Montastruc JL, Rascol O Ref: European Journal of Pharmacology, 348:191, 1998 : PubMed ESTHER: Allal_1998_Eur.J.Pharmacol_348_191 PubMedSearch: Allal 1998 Eur.J.Pharmacol 348 191 PubMedID: 9652334 Inhibitor(s) related to this paper: Tacrine Abstract Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels. Title: Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease Badia A, Banos JE, Camps P, Contreras J, Gorbig DM, Munoz-Torrero D, Simon M, Vivas NM Ref: Bioorganic & Medicinal Chemistry, 6:427, 1998 : PubMed ESTHER: Badia_1998_Bioorg.Med.Chem_6_427 PubMedSearch: Badia 1998 Bioorg.Med.Chem 6 427 PubMedID: 9597187 Inhibitor(s) related to this paper: HuperzineA, Tacrine Abstract Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine. Title: Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activities Cheng DH, Tang XC Ref: Pharmacol Biochem Behav, 60:377, 1998 : PubMed ESTHER: Cheng_1998_Pharmacol.Biochem.Behav_60_377 PubMedSearch: Cheng 1998 Pharmacol.Biochem.Behav 60 377 PubMedID: 9632220 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuperzineA, Tacrine Abstract Comparative effects of cholinesterase inhibitors (ChEI) huperzine A with E2020 and tacrine on the radial maze performance in ethylcholine mustard aziridinium ion (AF64A)-treated rat and inhibition of cholinesterase activity were studied. The intracerebroventricular (i.c.v.) injection of AF64A (3 nmol/side) caused significant impairment in the rat's ability to fulfill the partially baited maze paradigm. Oral huperzine A (0.5-0.8 mg/kg), E2020 (1.0-2.0 mg/kg), and tacrine (8.0 mg/kg) effectively reversed AF64A-induced working memory deficit. The doses that improved AF64A-induced memory deficit were correlated to about 25-30% (huperzine A) and less than 10% (E2020, tacrine) inhibition of acetylcholinesterase (AChE) activity in the cortex and hippocampus. Huperzine A, E2020 and tacrine all produced dose-dependent inhibition of brain AChE following i.c.v. and oral administration. Oral huperzine A exhibited higher efficacy on the inhibition of AChE in the cortex and hippocampus than those of E2020 and tacrine. Tacrine was more effective in inhibiting plasma butyrylcholinesterase (BCHE) than it was brain AChE. Conversely, the BCHE activity was less affected by huperzine A and E2020. The results showed that huperzine A had high bioavailability and more selective inhibition on AChE activity in cortex and hippocampus. Huperzine A fits more closely with the established criteria for an ideal AChE inhibitor to be used in clinical studies. Title: Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease Costagli C, Galli A Ref: Biochemical Pharmacology, 55:1733, 1998 : PubMed ESTHER: Costagli_1998_Biochem.Pharmacol_55_1733 PubMedSearch: Costagli 1998 Biochem.Pharmacol 55 1733 PubMedID: 9634011 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, BW284C51, Edrophonium, Heptylphysostigmine, HuperzineA, Neostigmine~Prostigmine, Physostigmine~Eserine, Tacrine Abstract The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BCHE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BCHE-associated AAA activity. Serotonin and related amines were very weak on BCHE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BCHE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimer's disease is unlikely to be related to the action of these drugs on ChE-associated AAA. Title: Responses induced by tacrine in neuronal and non-neuronal cell lines De Ferrari GV, Von Bernhardi R, Calderon FH, Luza SC, Inestrosa NC Ref: Journal of Neuroscience Research, 52:435, 1998 : PubMed ESTHER: De Ferrari_1998_J.Neurosci.Res_52_435 PubMedSearch: De Ferrari 1998 J.Neurosci.Res 52 435 PubMedID: 9589388 Inhibitor(s) related to this paper: Tacrine Abstract Alzheimer's disease (AD) is associated with a reduction in cholinergic activity as a result of specific neuronal loss. Current potential treatments for the disease include both cholinomimetic drugs and anticholinesterase inhibitors. One of the drugs approved by the FDA is tacrine (9-amine-1,2,3,4 tetrahydroacridine; THA), a strong acetylcholinesterase (AChE) inhibitor. We have studied the effects of tacrine on glial and neuronal cells in culture assessing cell survival and viability and morphology. Lactate dehydrogenase (LDH) activity and methylthiazol-diphenyl-tetrazolium (MTT) reduction were used as toxicity indicators. We found that tacrine toxicity on rat B12 glial cells and mouse Neuro 2A cells was strongly dependent on its concentration (up to 500 microM) and time of exposure. The toxic effect was not prevented by serum factors nor by bovine serum albumin. Fluorescein-conjugated phalloidin was used to examine the arrangement of actin filaments at substrate adhesion regions and cell-cell contacts. Primary events following exposure to tacrine included changes in cell morphology, disappearance of actin filament bundles, and disruption of focal adhesion contacts. At concentrations between 10 and 50 microM, tacrine induced neurite outgrowth in Neuro 2A cells, an effect that was not observed in B12 cells, suggesting that certain tacrine effects could be specific for neuronal cells. Although similar trends of response were observed for both cell types, some differences between undifferentiated and differentiated cells were apparent. Title: Invited review: Cholinesterase inhibitors for Alzheimer's disease therapy: from tacrine to future applications Giacobini E Ref: Neurochem Int, 32:413, 1998 : PubMed ESTHER: Giacobini_1998_Neurochem.Int_32_413 PubMedSearch: Giacobini 1998 Neurochem.Int 32 413 PubMedID: 9676739 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, ENA-713~Rivastigmine, Galanthamine, Heptylphysostigmine, Physostigmine~Eserine, Tacrine, Trichlorfon~Metrifonate Abstract This review starts with an historical background of the pharmacological development of tacrine almost fifty years ago (1949). Tacrine is the first drug to be tested, clinically, on a large scale and to be registered (1993) for treatment of Alzheimer's disease. For the first time, clinical results of four second generation cholinesterase inhibitors (ChEI) (donepezil, ENA 713, eptastigmine and metrifonate) are reviewed and compared with other ChEI such as tacrine, physostigmine and galanthamine. Data based on more than 6000 patients show that second generation drugs are well tolerated and show evidence of clinical efficacy. Differences are mainly due to frequency of side effects, number of drop outs and percentage of improved patients. These results also demonstrate the presence of clinical efficacy for all ChEI tested so far. Clinical mechanism of action, levels of efficacy and differences among various ChEI are discussed. Future potential indications are suggested. The present data indicate that optimization of effects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties. Title: Effect of subchronic treatment with metrifonate and tacrine on brain cholinergic function in aged F344 rats Giovannini MG, Scali C, Bartolini L, Schmidt B, Pepeu G Ref: European Journal of Pharmacology, 354:17, 1998 : PubMed ESTHER: Giovannini_1998_Eur.J.Pharmacol_354_17 PubMedSearch: Giovannini 1998 Eur.J.Pharmacol 354 17 PubMedID: 9726626 Inhibitor(s) related to this paper: Tacrine, Trichlorfon~Metrifonate Abstract The effects of 21-day treatment with the acetylcholinesterase inhibitors metrifonate (80 mg kg(-1) per os (p.o.)) and tacrine (3 mg kg(-1) p.o.), twice daily, on cortical and hippocampal cholinergic systems were investigated in aged rats (24-26 months). Extracellular acetylcholine levels were measured by transversal microdialysis in vivo; choline acetyltransferase and acetylcholinesterase activities were measured ex vivo by means of radiometric methods. Basal cortical and hippocampal extracellular acetylcholine levels, measured 18 h after the last metrifonate treatment, were about 15 and two folds higher, respectively, than in control and tacrine-treated rats. A challenge with metrifonate further increased cortical and hippocampal acetylcholine levels by about three and four times, respectively. Basal extracellular acetylcholine levels, measured 18 h after the last treatment with tacrine were not statistically different from those of the control rats. A challenge with tacrine increased cortical and hippocampal extracellular acetylcholine levels by about four and two times. A 75% inhibition of cholinesterase activity was found 18 h after the last metrifonate administration, while only a 15% inhibition was detectable 18 h after the last tacrine administration. The challenge with metrifonate or tacrine resulted in 90 and 80% cholinesterase inhibition, respectively. These results demonstrate that in aging rats a subchronic treatment with metrifonate results in a long-lasting, cholinesterase inhibition, and a persistent increase in acetylcholine extracellular levels which compensate for the age-associated cholinergic hypofunction. Metrifonate is therefore a potentially useful agent for the cholinergic deficit accompanying Alzheimer's disease. Title: Safety of tacrine: clinical trials, treatment IND, and postmarketing experience Gracon SI, Knapp MJ, Berghoff WG, Pierce M, DeJong R, Lobbestael SJ, Symons J, Dombey SL, Luscombe FA, Kraemer D Ref: Alzheimer Disease & Associated Disorders, 12:93, 1998 : PubMed ESTHER: Gracon_1998_Alzheimer.Dis.Assoc.Disord_12_93 PubMedSearch: Gracon 1998 Alzheimer.Dis.Assoc.Disord 12 93 PubMedID: 9651138 Inhibitor(s) related to this paper: Tacrine Abstract The safety of tacrine (Cognex), a centrally active, reversible acetylcholinesterase inhibitor approved in 1993 for the treatment of mild to moderate dementia of the Alzheimer type, was evaluated in 2,706 patients with Alzheimer disease (AD) in clinical trials and in 9861 patients with AD in a treatment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following marketing approval. The most common tacrine-associated adverse events were elevated liver transaminase levels [alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase] and peripheral cholinergic events involving primarily the digestive system (nausea, vomiting, diarrhea, dyspepsia, anorexia, and weight loss). Based on clinical trial experience, potentially clinically significant (>3 x upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatment. The elevations were almost always asymptomatic, rarely accompanied by significant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointestinal events were related to dose and generally of mild to moderate intensity. Tacrine-associated events, including ALT elevations, were reversible. Cholinergic events were manageable with dosage adjustment. Tacrine was not associated with permanent liver injury in clinical trials or a TIND setting. Title: Penetration of tacrine into cerebrospinal fluid in patients with Alzheimer's disease Grothe DR, Piscitelli SC, Dukoff R, Fullerton T, Sunderland T, Molchan SE Ref: J Clin Psychopharmacol, 18:78, 1998 : PubMed ESTHER: Grothe_1998_J.Clin.Psychopharmacol_18_78 PubMedSearch: Grothe 1998 J.Clin.Psychopharmacol 18 78 PubMedID: 9472847 Inhibitor(s) related to this paper: Tacrine Abstract Tacrine is widely used for the treatment of Alzheimer's disease, but data are limited regarding cerebrospinal fluid (CSF) concentrations at steady state. To evaluate CSF penetration, seven patients with Alzheimer's disease who were receiving tacrine at doses of 40 to 140 mg/day as a part of a double-blind trial were studied. After 6 weeks of tacrine therapy, concomitant plasma and CSF samples were collected 30 minutes after the morning dose of tacrine. Although this time point is before the peak oral absorption in most patients, the critical issue for this study is that the plasma and CSF samples were collected concomitantly so that a percentage of tacrine penetration could be derived. The morning dose of tacrine ranged from 10 to 40 mg, which was given in the fasting state. Mean (+/-SD) plasma levels of tacrine were 8.01+/-7.07 ng/mL, whereas mean (+/-SD) CSF levels of tacrine were 5.21+/-6.00 ng/mL. The mean (+/-SD) ratio of CSF to plasma tacrine concentration was 0.50+/-0.45, with wide interindividual variability. No relationship between dose and percentage of penetration was observed. Plasma concentrations ranged from 0.99 to 22.6 ng/mL and were unrelated to dose, suggesting erratic oral absorption and/or rapid metabolism. CSF concentrations ranged from not detectable to 15.92 ng/mL. The authors support that penetration of tacrine into CSF is highly variable in patients with Alzheimer's disease and that disparity in tacrine concentrations at the site of action may be one reason for conflicting results from studies of the efficacy of tacrine in Alzheimer's disease. Title: Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats Meyer EM, King MA, Meyers C Ref: Brain Research, 786:252, 1998 : PubMed ESTHER: Meyer_1998_Brain.Res_786_252 PubMedSearch: Meyer 1998 Brain.Res 786 252 PubMedID: 9555043 Inhibitor(s) related to this paper: Tacrine Abstract The nicotinic alpha7 agonist dimethoxybenzilidene anabaseine (DMXB) and cholinesterase inhibitor tetrahydroaminoacridine (THA) were investigated in a trans-synaptic model for neocortical atrophy and degeneration following nucleus basalis lesions. Bilateral lesions reduced parietal neuronal density in layers II-V 8 months later. DMXB administered i.p. daily to rats for 3 months attenuated this loss in layers II-V at a 1 mg/kg i.p. dose. A lower, 0.2 mg/kg i.p. dose, was neuroprotective in layer IV only. THA (1 mg/kg i.p.) also protected against neocortical Nissl-staining deficits. Title: Functional and subcellular organelle changes in isolated rat and human hepatocytes induced by tetrahydroaminoacridine Monteith DK, Theiss JC, Haskins JR, de la Iglesia FA Ref: Archives of Toxicology, 72:147, 1998 : PubMed ESTHER: Monteith_1998_Arch.Toxicol_72_147 PubMedSearch: Monteith 1998 Arch.Toxicol 72 147 PubMedID: 9520138 Inhibitor(s) related to this paper: Tacrine Abstract Tacrine (tetrahydroaminoacridine) is a reversible cholinesterase inhibitor used for the treatment of Alzheimer's disease. This drug causes an elevation of serum aminotransferases in a limited population of patients. Several in vivo studies failed to elucidate the mechanism for the enzyme elevation but previous in vitro studies have indicated defects in mitochondrial function. In this study, electron microscopic, histochemical, and confocal microscopy techniques were used with primary hepatocyte cultures from humans and rats to examine the sequence of early cellular changes after tacrine exposure. Changes included ribosome alterations as early as 1-2 h following tacrine exposure at concentrations ranging between 0.1 and 1.0 mM. Mitochondrial membrane potential was also altered as indicated by decreased rhodamine 123 uptake with time. Cellular lysosome content increased as indicated by increased staining of fluorescein isothiocyanate (FITC)-conjugated dextran. The results of acid phosphatase histochemistry correlated with the FITC-dextran findings. Additionally, tacrine-related degranulation and vesiculation of the endoplasmic reticulum paralleled the ribosomal and mitochondrial changes. These subcellular changes were reproducible in rat and human hepatocytes, showing for the first time that human hepatocytes can be altered by tacrine. The molecular mechanism of the organelle changes is unknown at this time. Also, the relationship between these subcellular changes in isolated hepatocytes and the transaminase elevation noted in human populations treated with tacrine needs to be clarified. Title: Effects of AF102B and tacrine on delayed match-to-sample in monkeys O'Neill J, Fitten LJ, Siembieda D, Halgren E, Kim E, Fisher A, Perryman K Ref: Prog Neuropsychopharmacol Biological Psychiatry, 22:665, 1998 : PubMed ESTHER: O'Neill_1998_Prog.Neuropsychopharmacol.Biol.Psychiatry_22_665 PubMedSearch: O'Neill 1998 Prog.Neuropsychopharmacol.Biol.Psychiatry 22 665 PubMedID: 9682279 Inhibitor(s) related to this paper: Tacrine Abstract 1. Object working memory, a function which declines in aging and dementia, was tested in young and aged pretrained monkeys using a delayed match-to-sample task. 2. During drug treatment, monkeys were given the m 1 muscarinic agonist AF102B (0.1-2.1 mg/kg i.m.), the cholinesterase inhibitor tacrine (0.5-2.0 mg/kg p.o.), or vehicle controls in a repeated measures design to assess putative cognitive enhancement. 3. Both agents improved task performance in both young and aged monkeys, AF102B yielding equivalent or greater, and less variable, improvement than tacrine. 4. AF102B may represent a low-toxicity alternative to tacrine for the treatment of age-related memory disorders. Title: Shuttle-box avoidance learning in mice: improvement by combined glucose and tacrine Pavone F, Capone F, Battaglia M, Sansone M Ref: Neurobiol Learn Mem, 69:204, 1998 : PubMed ESTHER: Pavone_1998_Neurobiol.Learn.Mem_69_204 PubMedSearch: Pavone 1998 Neurobiol.Learn.Mem 69 204 PubMedID: 9619996 Inhibitor(s) related to this paper: Tacrine Abstract Glucose and the acetylcholinesterase inhibitor tacrine were tested, alone and in combination, in mice of the CD-1 strain subjected to five daily shuttle-box training sessions. Pretraining intraperitoneal administration of glucose alone (50-400 mg/kg) had no significant effect, while tacrine alone (0.5-3 mg/kg) improved avoidance acquisition at the dose of 2 mg/kg only. Significant avoidance learning improvements were instead produced by 50 or 100 mg/kg glucose combined with 0.5 or 1 mg/kg tacrine. The effects on shuttle-box avoidance acquisition produced by glucose combined with a cholinomimetic agent support the hypothesis that cholinergic mechanisms may be involved in the action of glucose on learning and memory. However, the main finding of the present study is related to the enhancement by glucose of the learning improving action of a drug clinically used as cognitive enhancer. Title: Tetrahydroaminoacridine improves the recency effect in Alzheimer's disease Riekkinen M, Soininen H, Riekkinen P, Sr., Kuikka J, Laakso M, Helkala EL, Partanen J, Riekkinen P, Jr. Ref: Neuroscience, 83:471, 1998 : PubMed ESTHER: Riekkinen_1998_Neurosci_83_471 PubMedSearch: Riekkinen 1998 Neurosci 83 471 PubMedID: 9460755 Inhibitor(s) related to this paper: Tacrine Abstract We investigated the effects of a single administration of tetrahydroaminoacridine (25 and 50 mg, orally), a cholinesterase inhibitor, on memory function in Alzheimer's disease patients. The recall of memory items from the end of the word list (recency effect) was improved in a subgroup of Alzheimer's disease patients (responders 10 out of 28) by tetrahydroaminoacridine 50 mg. However, tetrahydroaminoacridine 50 mg had no effect on the recall of those words from the beginning or middle of the list. Tetrahydroaminoacridine did not markedly improve non-verbal delayed matching to sample or paired associates learning in any of the Alzheimer's disease patients. The "responders" performed better than the "non-responders" in tests measuring memory and frontal functions. The responders had less severe hippocampal atrophy and less prefrontal blood flow defect, and had a lower frequency of the apolipoprotein E4 allele than the "non-responders". These results suggest that acute tetrahydroaminoacridine treatment may stimulate the recency effect, and that a severe dysfunction of hippocampus and prefrontal regions blocks this effect of tetrahydroaminoacridine on short-term memory performance. Title: Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation Riekkinen P, Jr., Ikonen S, Riekkinen M Ref: Neuroreport, 9:1633, 1998 : PubMed ESTHER: Riekkinen_1998_Neuroreport_9_1633 PubMedSearch: Riekkinen 1998 Neuroreport 9 1633 PubMedID: 9631478 Inhibitor(s) related to this paper: Tacrine Abstract The present study examines the efficacy of single and combined treatments with an antiocholinesterase, tetrahydroaminoacridine (THA, i.p.), and a glycine-B site partial agonist, D-cycloserine (DCS, i.p.) to alleviate water maze (WM) spatial navigation defect induced by medial septal (MS) lesion. THA 3 and DCS at 3 or 10 mg/kg improved acquisition of the WM test, but only DCS improved spatial bias. These drugs had no effect on consolidation. A combination of THA 3 and DCS 10 mg/kg enhanced WM acquisition more effectively than either of the treatments on their own. This suggests that combined modulation of acetylcholine and NMDA mechanisms may have greater therapeutic effect to stimulate cognitive dysfunctions. Title: Tacrine and donepezil attenuate the neurotoxic effect of A beta(25-35) in rat PC12 cells Svensson AL, Nordberg A Ref: Neuroreport, 9:1519, 1998 : PubMed ESTHER: Svensson_1998_Neuroreport_9_1519 PubMedSearch: Svensson 1998 Neuroreport 9 1519 PubMedID: 9631459 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Tacrine Abstract The effect of the cholinesterase inhibitors tacrine and donepezil on A beta(25-35)-induced toxicity was investigated in rat pheochromocytoma PC12 cells by measuring the mitochondrial activity. Tacrine and donepezil was found in clinical relevant concentrations (10(-7)-10(-6) M) to attenuate A beta(25-35)-induced toxicity in PC12 cells. The neuroprotective effect of tacrine was blocked in the presence of the nicotinic antagonists mecamylamine (10(-5) M) and tubocurarine (10(-5) M), suggesting an interaction via nicotinic receptors. This study demonstrates that tacrine and donepezil can exert neuroprotective properties which might be of importance and contribute to the clinical efficacy of cholinesterase inhibitors in the treatment of Alzheimer's disease. Title: Capillary zone electrophoretic determination of some drugs against Alzheimer's disease Vargas MG, Havel J, Patocka J Ref: Journal of Chromatography A, 802:121, 1998 : PubMed ESTHER: Vargas_1998_J.Chromatogr.A_802_121 PubMedSearch: Vargas 1998 J.Chromatogr.A 802 121 PubMedID: 9588015 Inhibitor(s) related to this paper: 7-Methoxytacrine, Tacrine Abstract A new capillary zone electrophoresis (CZE) method for the determination of tacrine (THA), 7-methoxytacrine (7-MTHA) and their basic metabolites (THAm, 7-MTHAm) in pharmaceutical and biological samples (urine and serum) was developed. Separation of all compounds by CZE was carried out using a 46.6 cm untreated fused-silica capillary applying 20 kV separation voltage using 50 mM phosphate buffer of pH 2.8 for THA and THAm and of pH 7.8 for 7-MTHA and 7-MTHAm as background electrolyte (BGE). Detection was carried out at 240 nm (THA and THAm) and 248 nm (7-MTHA and 7-MTHAm). THA and THAm were separated in less than 4 min while 7-MTHA and 7-MTHAm were separated in less than 7 min. The detection limits (SIN = 3) obtained were 3 ppb for THA and 4 ppb for 7-MTHA in aqueous solutions; 50 ppb for THA and 47 ppb for 7-MTHA for the determination in urine (diluted 1:10); 52 ppb for THA and 56 ppb for 7-MTHA, in deproteinized serum samples. The methods are suitable for therapeutic drug monitoring of the drugs. Title: Reversal of scopolamine-induced deficits in radial maze performance by (-)-huperzine A: comparison with E2020 and tacrine Wang T, Tang XC Ref: European Journal of Pharmacology, 349:137, 1998 : PubMed ESTHER: Wang_1998_Eur.J.Pharmacol_349_137 PubMedSearch: Wang 1998 Eur.J.Pharmacol 349 137 PubMedID: 9671090 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuperzineA, Tacrine Abstract The effects of (-)-huperzine A ((5R,9R,11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5, 9-methanocycloocta[b]pyridin-2(1H)-one), and of the hydrochloride salt of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine) and tacrine (9-amino-1,2,3,4-tetrahydroacridine), on the scopolamine-induced memory deficits in rats were compared in a radial maze, using a 4-out-of-8 baiting procedure. Scopolamine (0.15 mg/kg, i.p.) caused significant impairment in the rats' ability to fulfil the radial maze task. (-)-Huperzine A (0.2-0.4 mg/kg, p.o.; 0.1-0.4 mg/kg, i.p.) had greater efficacy than E2020 (0.6-0.9 mg/kg, p.o.; 0.3-0.6 mg/kg, i.p.) and tacrine (1.5-2.5 mg/kg, p.o.; 0.3-0.6 mg/kg, i.p.) on the improvement of scopolamine-induced working and reference memory errors, respectively. There appeared to be an inverse bell-shape dose-dependent effect for all three compounds tested. The compared data demonstrate that (-)-huperzine A is the most potent and orally active acetylcholinesterase inhibitor of the three, and fits more closely the established criterions for an ideal acetylcholinesterase inhibitor to be used in clinical studies. Title: Sensitivity of bovine retinal acetylcholinesterase (E.C. 3.1.1.7) toward tacrine: kinetic characterization Al-Jafari AA, Kamal MA, Alhomida AS Ref: J Biochem Mol Toxicol, 12:245, 1998 : PubMed ESTHER: al-Jafari_1998_J.Biochem.Mol.Toxicol_12_245 PubMedSearch: al-Jafari 1998 J.Biochem.Mol.Toxicol 12 245 PubMedID: 9580877 Inhibitor(s) related to this paper: Tacrine Abstract This work addresses the kinetic analysis of the interaction of tacrine with bovine retina acetylcholinesterase (A ChE, E.C. 3.1.1.7). It was found that the tacrine effect was reversible in nature. Tacrine inhibited bovine retinal AChE activity in a concentration-dependent manner; IC50 was fo to be 8.07 nM. The Michaelis-Menten constant (Ka) for the hydrolysis of acetylthiocholine iodide (ASCh) by AChE was 0.061 mM in the control system, and this value was increased by 54-67% in the tacrine-treated systems. The Vmax was 0.701 mumole/min per milligram protein for the control system, but it was decreased by 26-69% in the tacrine-treated systems. The Lineweaver-Burk plot, Dixon plot, and their secondary replots indicated that the nature of the inhibition was of the partial mixed type, that is, a mixture of competitive and noncompetitive inhibition. The values of Ki and Kt were estimated to be as 4.475 and 8.517 nM, respectively. Title: Effects of 9-amino-1,2,3,4-tetrahydroacridine (THA) on ATP diphosphohydrolase (EC 3.6.1.5) and 5'-nucleotidase (EC 3.1.3.5) from rat brain synaptosomes Bonan CD, Battastini AM, Schetinger MR, Moreira CM, Frassetto SS, Dias RD, Sarkis JJ Ref: General Pharmacology, 28:761, 1997 : PubMed ESTHER: Bonan_1997_Gen.Pharmacol_28_761 PubMedSearch: Bonan 1997 Gen.Pharmacol 28 761 PubMedID: 9184816 Inhibitor(s) related to this paper: Tacrine Abstract 1. 9-Amino-1,2,3,4-tetrahydroacridine (THA), an acetylcholinesterase inhibitor, significantly inhibited in vitro the ATP diphosphohydrolase activity of synaptosomes from the cerebral cortex and hippocampus of adult rats. 2. THA did not inhibit in vitro the 5'-nucleotidase activity of synaptosomes from cerebral cortex and hippocampus of rats. 3. THA exerted an uncompetitive inhibition on ATP diphosphohydrolase activity. This mechanism of inhibition was the same in the 2 different synaptosomal fractions (cerebral cortex and hippocampus) studied. 4. THA, proposed as a drug for the treatment of Alzheimer's disease, can alter in vitro ATP degradation in synaptosomes from the central nervous system. Title: Motor dysfunction produced by tacrine administration in rats Carriero DL, Outslay G, Mayorga AJ, Aberman J, Gianutsos G, Salamone JD Ref: Pharmacol Biochem Behav, 58:851, 1997 : PubMed ESTHER: Carriero_1997_Pharmacol.Biochem.Behav_58_851 PubMedSearch: Carriero 1997 Pharmacol.Biochem.Behav 58 851 PubMedID: 9408186 Inhibitor(s) related to this paper: Tacrine Abstract In the present study, three experiments were conducted to provide a characterization of some of the motor effects of the anticholinesterase tacrine (1.25-5.0 mg/kg I.P.) in rats. In the first experiment, tacrine was found to produce tremulous jaw movements in the dose range of 1.25-5.0 mg/kg. The second experiment examined the effects of tacrine on locomotion, and it was demonstrated that tacrine produced a dose-related suppression of open-field motor activity. In the third experiment, the effects of tacrine were assessed using operant conditioning procedures. Behavioral output during lever pressing on a fixed ratio 5 schedule was recorded by a computerized system that measured response initiation time (time from offset of one response to onset of the next) and duration for each lever press. Tacrine administration substantially depressed lever pressing response rate. This deficit was largely due to a substantial increase in the average response initiation time. Analysis of the distribution of response initiation times indicated that tacrine-treated rats made relatively few responses with fast initiation times (e.g., 0-125 ms), and also that tacrine led to a dramatic increase in the number of pauses in responding (i.e., response initiation times greater than 2.5 s). Tacrine-treated rats showed a slight increase in the average initiation time for fast responses (i.e., a slight decrease in the local rate of responding), and also showed a substantial increase in the average length of pauses greater than 2.5 s. Analysis of response durations indicated that there was an overall increase in average response duration among animals that received the higher doses of tacrine. Although tacrine-induced decreases in the local rate of responding and increases in response duration contribute to the overall deficit, the major reason why tacrine-treated animals responded less was because they took much longer breaks in responding. It is possible that the tacrine-induced increases in pausing reflect a drug-induced akinesia. Thus, the present experiments indicate that tacrine impairs several aspects of motor function in the dose range tested. In view of the fact that tremor and motor slowing are classic symptoms of Parkinsonism, the present results in rats are consistent with the human literature indicating that tacrine (Cognex) can produce Parkinsonian side effects. Studies of the motor dysfunctions produced by tacrine in rats could be useful for investigating the motor side effects of tacrine in humans. Title: Tremulous jaw movements induced by the acetylcholinesterase inhibitor tacrine: effects of antiparkinsonian drugs Cousins MS, Carriero DL, Salamone JD Ref: European Journal of Pharmacology, 322:137, 1997 : PubMed ESTHER: Cousins_1997_Eur.J.Pharmacol_322_137 PubMedSearch: Cousins 1997 Eur.J.Pharmacol 322 137 PubMedID: 9098680 Inhibitor(s) related to this paper: Tacrine Abstract Several experiments were conducted to study the effects of established or potential antiparkinsonian drugs on the tremulous jaw movements induced by the anticholinesterase tacrine (9-amino-1,2,3,4-tetrahydroaminoacridine hydrochloride). In the first group of four experiments, separate groups of animals that received 2.5 or 5.0 mg/kg tacrine showed a dose-dependent decrease in tremulous jaw movements following co-administration of the non-selective dopamine receptor agonist apomorphine, the full dopamine D2 receptor agonist bromocriptine, and the full dopamine D1 receptor agonist APB (R(+)-6-bromo-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine). Co-administration of the partial dopamine D1 receptor agonist SKF 38393 (R(+)-2,3,4,5-tetrahydro-7,8-dihydroxy-l phenyl-1 H-benzazepine: 7.5-30.0 mg/kg) did not reduce tremulous jaw movements produced by 2.5 or 5.0 mg/kg tacrine. In animals treated with 2.5 mg/kg tacrine, co-administration of SKF 38393 resulted in a dose-related trend towards a potentiation of tremulous jaw movements. In the second group of experiments, all rats received 2.5 mg/kg tacrine. The dopamine precursor L-DOPA (L-3,4-dihydroxyphenylalanine), the dopamine and norepinephrine releasing agent amantadine, and the muscarinic receptor antagonist benztropine all reduced tremulous jaw movements induced by 2.5 mg/kg tacrine. Across all experiments, it was noted that apomorphine, bromocriptine and benztropine were more potent than amantadine and L-DOPA. These results are broadly consistent with the therapeutic doses of these agents noted in the clinical literature. The results of these experiments indicate that tremulous jaw movements in rats may be a useful model for evaluating potential antiparkinsonian agents. Title: [Advantages in long-term treatment with Cognex in Alzheimer disease] Gracon S, Smith F, Shokry A Ref: Schweiz Rundsch Med Prax, 86:1350, 1997 : PubMed ESTHER: Gracon_1997_Schweiz.Rundsch.Med.Prax_86_1350 PubMedSearch: Gracon 1997 Schweiz.Rundsch.Med.Prax 86 1350 PubMedID: 9381027 Inhibitor(s) related to this paper: Tacrine Abstract Early diagnosis and treatment of AD is critical to maximize benefits for the patient and the caregiver. It is important to intervene early in the illness, before the quality of life of the patient and the caregiver has deteriorated to the point where treatment only prolongs an already difficult situation. If treatment begins early enough in the disease course, loss of functional independence may be delayed, just as nursing home placement was delayed in this study. In this way, quality of life is improved for both the patient and the caregiver. Title: The effect of several putative cognition enhancers on a water maze acquisition deficit produced by pCPA + scopolamine combination treatment Harder JA, Kelly ME Ref: Pharmacol Biochem Behav, 56:657, 1997 : PubMed ESTHER: Harder_1997_Pharmacol.Biochem.Behav_56_657 PubMedSearch: Harder 1997 Pharmacol.Biochem.Behav 56 657 PubMedID: 9130291 Inhibitor(s) related to this paper: Tacrine Abstract A combined treatment of a 3-day regimen of pCPA and low-dose scopolamine produced a significant deficit in the acquisition of a water maze task, which has been suggested as a model for the cognitive deficits of Alzheimer's disease. The putative cognition enhancers oxotremorine, captopril, ondansetron, and tacrine were used in attempts to alleviate the water maze impairment. The effects of oxotremorine were difficult to determine due to nonspecific motor effects causing alterations in swimming speed. No evidence for cognition-enhancing properties of captopril was found. Ondansetron showed a cognition-enhancing effect on one of 4 days, but only at a relatively high dose (1 mg/kg i.p.). Tacrine, however, alleviated the pCPA + scopolamine-induced cognitive deficit. This study may thus provide evidence for the usefulness of tacrine in treating spatial deficits in dementia. Title: The effects of chronic tacrine therapy on d-tubocurarine blockade in the soleus and tibialis muscles of the rat Ibebunjo C, Donati F, Fox GS, Eshelby D, Tchervenkov JI Ref: Anesthesia & Analgesia, 85:431, 1997 : PubMed ESTHER: Ibebunjo_1997_Anesth.Analg_85_431 PubMedSearch: Ibebunjo 1997 Anesth.Analg 85 431 PubMedID: 9249126 Inhibitor(s) related to this paper: Tacrine Abstract Tacrine (THA) is an anticholinesterase drug used to manage Alzheimer's dementia, but it is not clear how its chronic use might affect response to nondepolarizing muscle relaxants. We determined the magnitude and time course of the effects of chronic oral THA and of intravenous (IV) THA on d-tubocurarine (dTC) blockade at the soleus and tibialis muscles. Six groups of adult rats were given 10 mg/kg THA twice daily by gavage for 1, 2, 4, or 8 wk (chronic THA groups), or 1 mL of saline twice daily by gavage for 1-8 wk (control), or IV THA approximately 20 min before (acute), and the cumulative dose-response curves of dTC at the tibialis and soleus muscles were determined during indirect train-of-four stimulation in the anesthetized, mechanically ventilated rat. The 50% effective dose (ED50) and 95% effective dose (ED95) of dTC in control rats were (mean +/- SD) 30 +/- 10 and 61 +/- 18 microg/kg in the tibialis and 32 +/- 8 and 75 +/- 19 microg/kg in the soleus; respectively. IV THA increased the ED95 of dTC 2.5- to 3-fold (P < 0.05) but did not alter the ED50. Chronic THA increased both the ED50 and ED95 of dTC 1.5- to 2-fold (P > or = 0.05), and this effect tended to decrease with duration of THA therapy. We conclude that chronic THA therapy in rats causes resistance to dTC, with a tendency for the resistance to decrease with time, probably because of down-regulation of postsynaptic acetylcholine receptors. The same may apply to Alzheimer's patients taking THA chronically. Title: Combined cholinergic and 5-HT2 receptor activation suppresses thalamocortical oscillations in aged rats Jakala P, Riekkinen P, Jr. Ref: Pharmacol Biochem Behav, 56:713, 1997 : PubMed ESTHER: Jakala_1997_Pharmacol.Biochem.Behav_56_713 PubMedSearch: Jakala 1997 Pharmacol.Biochem.Behav 56 713 PubMedID: 9130298 Inhibitor(s) related to this paper: Physostigmine~Eserine, Tacrine Abstract The present study investigated whether combined stimulation of the cholinergic system and 5-hydroxytryptamine (5-HT) subtype 2 receptors can suppress neocortical high-voltage spindles (HVSs) reflecting thalamocortical oscillations in aged rats. Cholinesterase inhibitors-tetrahydro-aminoacridine (THA: 1.0 and 3.0 mg/kg i.p.) and physostigmine (0.36 mg/kg i.p.)- and a 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.3 and 1.0 mg/kg SC)-suppressed HVSs in aged rats. A combination of subthreshold doses of THA (0.3 mg/kg i.p.) and DOI (0.1 mg/kg s.c.) suppressed HVSs more effectively than either drug alone. Furthermore, a 5-HT2 receptor antagonist, ketanserin (5.0 and 20.0 mg/kg s.c.), reduced the efficacy of THA (1.0 and 3.0 mg/kg i.p.) and physostigmine (0.12 and 0.36 mg/kg i.p.) in decreasing HVSs. THA and ketanserin slightly decreased, physostigmine tended to increase, and DOI significantly increased behavioral activity of the rats, demonstrating that the effects of the drugs on behavioral activity may be separated from their effects on generation of thalamocortical oscillations. The results suggest that activation of the cholinergic system and 5-HT2 receptors has additive effects in the suppression of thalamocortical oscillations in aged rats. Title: Effects of NIK-247 on cholinesterase and scopolamine-induced amnesia [published erratum appears in Methods Find Exp Clin Pharmacol 1997 Jun;19(5):364] Kojima J, Nakajima K, Ochiai M, Nakayama K Ref: Methods Find Exp Clin Pharmacol, 19:245, 1997 : PubMed ESTHER: Kojima_1997_Methods.Find.Exp.Clin.Pharmacol_19_245 PubMedSearch: Kojima 1997 Methods.Find.Exp.Clin.Pharmacol 19 245 PubMedID: 9228650 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, NIK-247, Tacrine Abstract 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 (BCHE) 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. Title: Effects of cholinesterase inhibitors on the secretion of beta-amyloid precursor protein in cell cultures Lahiri DK, Farlow MR, Nurnberger JI, Jr., Greig NH Ref: Annals of the New York Academy of Sciences, 826:416, 1997 : PubMed ESTHER: Lahiri_1997_Ann.N.Y.Acad.Sci_826_416 PubMedSearch: Lahiri 1997 Ann.N.Y.Acad.Sci 826 416 PubMedID: 9329715 Inhibitor(s) related to this paper: Physostigmine~Eserine, Tacrine, Trichlorfon~Metrifonate Abstract One of the main characteristics of Alzheimer's disease (AD) is the cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). The majority of beta APP is processed by either a secretory of lysosomal/endosomal pathway. Carboxyl-truncated soluble derivatives of beta APP (sAPP) are generated by the proteolytic processing of full-length beta APP by either alpha- or beta-secretase enzyme. Our objective is to determine whether the processing of beta APP can be regulated by cholinesterase inhibitors, some of which were shown to produce a moderate improvement in memory and cognitive functions in patients with Alzheimer's disease. Here we have analyzed the levels of sAPP derivatives in cultured cells treated with different drugs by immunoblotting samples of conditioned media. The immunoreactive protein bands were developed by probing with the monoclonal antibody 22C11. Treating neuroblastoma, pheochromocytoma and fibroblast cells with high dose of either 3,4-diaminopyridine, metrifonate, or physostigmine did not inhibit the secretion of sAPP. Treating glioblastoma with either 3,4-diaminopyridine or metrifonate showed an increase in secretion of sAPP. However, treatment of cells with tacrine reduced release of sAPP in conditioned media of cell lines studied. The difference in action of metrifonate, physostigmine, and tacrine on beta APP is independent of their anticholinesterase activities. Our results suggests that noncatalytic functions of cholinesterase inhibitors can be utilized to alter the metabolism of beta APP, which might in turn affect the process of deposition of A beta, a key component of the cerebrovascular amyloid detected in AD. Title: Alzheimer's disease: an overview for the pharmacist McGuffey EC Ref: J Am Pharm Assoc, 3:347, 1997 : PubMed ESTHER: McGuffey_1997_J.Am.Pharm.Assoc_3_347 PubMedSearch: McGuffey 1997 J.Am.Pharm.Assoc 3 347 PubMedID: 9170813 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Tacrine Abstract Alzheimer's disease (AD) occurs more frequently in women, with an incidence greater than expected from longevity alone--a finding possibly related to reduced estrogen levels. The epidemiology, societal costs, clinical presentation, pathophysiology, etiology, and treatment of AD are reviewed. At present, only two drugs, tacrine and donepezil, are approved for treatment of AD. These drugs enhance central cholinergic activity by inhibiting cholinesterase. The goal of current drug development research is to halt progress of AD, and efforts are underway to discover ways to restore neuronal activity via neurotrophins and to prevent neuronal loss. Pharmacists are well positioned to assist AD patients (in the early stages) and caregivers by encouraging early intervention and by presenting realistic expectations about the disease and its treatment. A number of easily accessible resources for health care providers and consumers are presented. Title: Prevention of amitriptyline-induced avoidance impairment by tacrine in mice Pavone F, Battaglia M, Sansone M Ref: Behavioural Brain Research, 89:229, 1997 : PubMed ESTHER: Pavone_1997_Behav.Brain.Res_89_229 PubMedSearch: Pavone 1997 Behav.Brain.Res 89 229 PubMedID: 9475630 Inhibitor(s) related to this paper: Amitriptyline, Tacrine Abstract The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes. Title: Effect of tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain injury Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG Ref: Journal of Neurotrauma, 14:897, 1997 : PubMed ESTHER: Pike_1997_J.Neurotrauma_14_897 PubMedSearch: Pike 1997 J.Neurotrauma 14 897 PubMedID: 9475371 Inhibitor(s) related to this paper: Tacrine Abstract An emerging literature exists in support of deficits in cholinergic neurotransmission days to weeks following experimental traumatic brain injury (TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to improve cognitive outcome following TBI in rats. We examined the effects of repeated postinjury administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA), on cognitive performance following experimental TBI. Rats were either injured at a moderate level of central fluid percussion TBI (2.1+/-0.1 atm) or were surgically prepared but not delivered a fluid pulse (sham injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0 mg/kg THA (TBI: n = 8, 8, 10, and 7, respectively, and Sham: n = 5, 7, 8, 7, respectively). Cognitive performance was assessed on Days 11-15 after injury in a Morris water maze (MWM). Analysis of maze latencies over days indicated that chronic administration of THA produced a dose-related impairment in MWM performance in both the injured and sham groups, with the 9.0 mg/kg dose producing the largest deficit. The 1.0 and 3.0 mg/kg doses of THA impaired MWM performance without affecting swimming speeds. Thus, the results of this investigation do not support the use of THA as a cholinomimetic therapeutic for the treatment of cognitive deficits following TBI. Title: Studies on a new series of THA analogues: effects of the aromatic residues that line the gorge of AChE Pomponi M, Marta M, Colella A, Sacchi S, Patamia M, Gatta F, Capone F, Oliverio A, Pavone F Ref: FEBS Letters, 409:155, 1997 : PubMed ESTHER: Pomponi_1997_FEBS.Lett_409_155 PubMedSearch: Pomponi 1997 FEBS.Lett 409 155 PubMedID: 9202137 Inhibitor(s) related to this paper: Bucricaine, Tacrine Abstract A series of N-monoalkylsubstituted 1,2,3,4-tetrahydro-9-aminoacridines have been prepared after modelling simulation of the AChE-inhibitor complex. Molecular modelling has predicted a number of hydrophobic residues to be involved in the catalytic mechanism of this interaction between the binding sites of AChE and this series of aminoacridines. In these compounds the acridine moiety becomes sandwiched between the rings of PHE330 and TRP84. In particular, the alkyl chain shows the important role of aromatic groups as binding sites. Their in vitro inhibitory properties (enzyme from Electrophorus electricus) confirm the aromatic groups as a general and significant characteristic of the mechanism of AChE inhibition. Title: Metabolic disposition of the cognition activator tacrine in rats, dogs, and humans. Species comparisons Pool WF, Reily MD, Bjorge SM, Woolf TF Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, 25:590, 1997 : PubMed ESTHER: Pool_1997_Drug.Metab.Dispos_25_590 PubMedSearch: Pool 1997 Drug.Metab.Dispos 25 590 PubMedID: 9152598 Inhibitor(s) related to this paper: Tacrine Abstract The metabolic fate of tacrine [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA)] was examined in rats, dogs, and humans. After administration of single oral doses of [14C]THA to rats, dogs, and humans, drug-derived material was well absorbed, with urinary excretion being the predominant route of radiolabel elimination. Metabolic profiling of plasma and urine from rats, dogs, and humans showed THA to be extensively metabolized with marked species differences in quantitative amounts of metabolites observed. Plasma profiles were similar to respective urinary profiles in all three species. Present in profiles of urine from rats were 1-hydroxy (OH)-THA (major), 2-OH-THA, and 4-OHA-THA, and unchanged THA. Also observed were trace amounts of more polar metabolites, presumably arising from sequential metabolism. Metabolic profiling of dog urine also showed 1-OH-THA to be the major metabolite, with trace amounts of the 2-OHA-THA and 4-OH-THA regioisomers and THA excreted. In dog urine, more of the radioactivity was associated with polar metabolites, including 1,3-dihydroxy-THA and a dihydrodiol metabolite. Human urinary metabolic profiles were more similar to that in dogs than in rats, with no single metabolite constituting > 10% of urinary radioactivity. Present in human urine were phenol glucuronide metabolites, of which 7-OH-THA was identified as an aglycone. Relevance of the marked quantitative differences in THA metabolism between rats, dogs, and humans to species differences in THA hepatotoxic potential remains to be established. Title: Frontal dysfunction blocks the therapeutic effect of THA on attention in Alzheimer's disease Riekkinen P, Jr., Riekkinen M, Soininen H, Kuikka J, Laakso M, Riekkinen P, Sr. Ref: Neuroreport, 8:1845, 1997 : PubMed ESTHER: Riekkinen_1997_Neuroreport_8_1845 PubMedSearch: Riekkinen 1997 Neuroreport 8 1845 PubMedID: 9223063 Inhibitor(s) related to this paper: Tacrine Abstract We evaluated the effect of a single dose of a cholinesterase inhibitor, tetrahydroaminoacridine (THA; 25 and 50 mg, orally), on attention in patients with Alzheimer's disease (AD). THA 50 mg improved performance in attentional measures (Trail Making Test, Big/Little Circle, Simple and Choice Reaction Time) in nine of 28 patients with AD. We analysed retention of 99mTc-labelled ethylene dicysteinate (ECD) in the cortical areas using single photon emission computed tomography. Those patients who benefited from THA treatment had bilaterally higher frontal and prefrontal ECD retention values. We suggest that THA may improve attention in patients with AD, but a severe frontal dysfunction may block the therapeutic effect of THA. Title: Enhanced performance of spatial and visual recognition memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys Rupniak NM, Tye SJ, Field MJ Ref: Psychopharmacology, 131:406, 1997 : PubMed ESTHER: Rupniak_1997_Psychopharmacology_131_406 PubMedSearch: Rupniak 1997 Psychopharmacology 131 406 PubMedID: 9226744 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Tacrine Abstract Hepatotoxicity limits the clinical utility of the cholinesterase inhibitor tacrine as a palliative therapy for Alzheimer's disease. The present studies examined the effects of E2020, a selective acetylcholinesterase inhibitor not associated with liver toxicity in man, on cognitive performance in rhesus monkeys using tasks employed previously to evaluate tacrine and other cholinomimetic agents. The ability of E2020 to prevent the induction of a cognitive impairment by the muscarinic receptor antagonist scopolamine was assessed using an automated spatial delayed response task. Coadministration of E2020 (0.5-1.75 mg/kg) caused a dose-dependent reversal of the scopolamine (0.03 mg/kg) induced impairment observed after retention intervals of 10 and 20 s. At the highest dose of E2020 examined (1.75 mg/kg), choice accuracy approached normal control levels. In this dose range, E2020 was well tolerated, but at the higher dose of 2 mg/kg, cholinergic side-effects were apparent. The effect of E2020 on choice accuracy in a visual recognition task was also assessed as this task does not require the use of scopolamine to disrupt performance and beneficial effects of cholinomimetics can therefore be detected at lower doses than in the spatial memory paradigm. In this task, administration of E2020 increased choice accuracy from 59 +/- 1% correct to up to 71 +/- 2% at doses of 0.03 and 0.05 mg/kg. No observable adverse effects were induced by E2020 in this dose range. The ability of E2020 to improve performance in these cognitive tasks resembles the profile of other cholinesterase inhibitors, including tacrine, that also improve cognitive function in Alzheimer's disease patients. Because of its more favourable clinical safety profile, E2020 may provide a significantly improved palliative therapy for dementia. Title: Pharmacological basis of drug therapy of Alzheimer's disease Sharma A, Parikh V, Singh M Ref: Indian J Exp Biol, 35:1146, 1997 : PubMed ESTHER: Sharma_1997_Indian.J.Exp.Biol_35_1146 PubMedSearch: Sharma 1997 Indian.J.Exp.Biol 35 1146 PubMedID: 9567741 Inhibitor(s) related to this paper: Galanthamine, Tacrine Abstract Alzheimer's disease is a progressive neurodegenerative disorder primarily manifesting as a loss of memory. Senile plaques and neurofibrillary tangles are the major histopathological alteration in the brain of Alzheimer's disease patients. A considerable deficiency of cholinergic neurons is a consistent finding in Alzheimer's disease. Therefore, many therapeutic strategies to augment cerebral concentration of acetylcholine such as cholinergic precursors, cholinergic receptor agonists, cholinesterase inhibitors and acetylcholine release modulators have been evaluated in Alzheimer's disease. Although cholinesterase inhibitors such as tacrine and galanthamine offer modest clinical benefits, other cholinergic agents have proved to be of limited therapeutic value. Efforts to enhance monoaminergic neurotransmission have also been largely disappointing. Therefore, emphasis is not being put on the use of combination of two class of drugs. Moreover, use of therapeutic agents based on the putative pathogenic etiology of the disease such as excitotoxicity, amyloidosis, aluminium accumulation, inflammatory mechanisms and free radical production is being evaluated. Desferrioxamine, non-steroidal anti-inflammatory drugs, prednisone, dapsone, vitamin E and idebenone are some such agents that are currently under investigation for the preventive or palliative effect in Alzheimer's disease. Neurotrophic factors such as nerve growth factor, brain derived neurotrophic factor and epidermal growth factor have shown promising results in animal studies. However, novel methods for delivering these molecules into the brain required to be developed before launching their clinical trials in man. Title: Functional activation of cerebral blood flow abolished by scopolamine is reversed by cognitive enhancers associated with cholinesterase inhibition: a positron emission tomography study in unanesthetized monkeys Tsukada H, Kakiuchi T, Ando I, Ouchi Y Ref: Journal of Pharmacology & Experimental Therapeutics, 281:1408, 1997 : PubMed ESTHER: Tsukada_1997_J.Pharmacol.Exp.Ther_281_1408 PubMedSearch: Tsukada 1997 J.Pharmacol.Exp.Ther 281 1408 PubMedID: 9190877 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Physostigmine~Eserine, Tacrine Abstract The effects of somatosensory stimulation on the regional cerebral blood flow (rCBF) response were studied in unanesthetized monkeys before and after treatment with scopolamine and three cognitive enhancers (physostigmine, E2020 and tacrine) that inhibit cholinesterase, using 15O-labeled water and high-resolution positron emission tomography. Under control conditions, somatosensory stimulation induced a significant increase in the rCBF response in the contralateral somatosensory cortex of monkey brain. Intravenous administration of scopolamine (50 microg/kg) resulted in abolishment of the rCBF response to stimulation. The rCBF response abolished by pretreatment with scopolamine was recovered by administration of physostigmine (1 or 10 microg/kg), E2020 (10 or 100 microg/kg) or tacrine (100 or 1000 microg/kg), in a dose-dependent manner. The effect of E2020 (100 microg/kg) on the rCBF response lasted for >4 hr, whereas the effects of physostigmine and tacrine were of shorter duration. These findings suggest that these compounds reversed the scopolamine-abolished rCBF response to somatosensory stimulation via enhancement of cholinergic neurotransmission, which was mainly induced by cholinesterase inhibition. Title: The effect of cytochromes P4501A induction and inhibition on the disposition of the cognition activator tacrine in rat hepatic preparations Bezek S, Kukan M, Pool WF, Woolf TF Ref: Xenobiotica, 26:935, 1996 : PubMed ESTHER: Bezek_1996_Xenobiotica_26_935 PubMedSearch: Bezek 1996 Xenobiotica 26 935 PubMedID: 8893040 Inhibitor(s) related to this paper: Tacrine Abstract 1. The disposition of tacrine 1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA, Cognex), was studied using livers obtained from control, phenobarbital (PB), isosafrole (ISO), and 3-methycholanthrene (3-MC) treated rats. 2. Pretreatment of rats with PB, ISO, and 3-MC reduced AUC(10-120 min) of THA in liver perfusates by 28, 32, and 86% respectively. 3. Elimination of [14C]-THA-derived radioactivity into bile was 7.6 +/- 1.2%, 11.7 +/- 2.9%, 14.8 +/- 2.0%, and 46.3 +/- 9.7% (mean +/- SD) of the infusion dose for control PB, ISO, and 3-MC pretreated isolated perfused rat livers, respectively. 4. In perfusion experiments using 3-MC pretreated livers, a marked increase in irreversible protein binding of 3-, 7-, and 8-fold was observed to microsomal, cytosolic and total liver proteins, respectively, compared to control. Only a slight effect was observed on protein binding in perfusion experiments using PB and ISO pretreated animals. 5. Co-incubations of [14C]-THA with the metabolic inhibitors enoxacin, ethimizol, and furafylline in hepatocyte preparations obtained from 3-MC pretreated rats markedly inhibited THA-derived irreversible protein binding. Furafylline, a specific inhibitor of cytochrome P4501A2, had the greatest inhibitory effect (approximately 70%). 6. These results are consistent with a major role of cytochrome P4501A in the metabolism and irreversible protein binding of THA in rat liver and demonstrate the utility of isolated liver perfusion and hepatocyte models for examining the effect of metabolic modulators. Title: Huperzine A, a novel promising acetylcholinesterase inhibitor Cheng DH, Ren H, Tang XC Ref: Neuroreport, 8:97, 1996 : PubMed ESTHER: Cheng_1996_Neuroreport_8_97 PubMedSearch: Cheng 1996 Neuroreport 8 97 PubMedID: 9051760 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuperzineA, Tacrine Abstract The effects of huperzine A on memory impairments induced by scopolamine were evaluated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine. Scopolamine (0.2 mg kg-1) significantly impaired spatial memory in rats. Huperzine A (0.1-0.4 mg kg-1, p.o.), E2020 (0.5-1.0 mg kg-1, p.o.) and tacrine (1.0-2.0 mg kg-1, p.o.) could reverse these scopolamine-induced memory deficits. The ratios of huperzine A, E2020 and tacrine for butyrylcholinesterase:acetylcholinesterase determined by a colourimetric method were 884.57, 489.05, and 0.80, respectively. The results demonstrated that huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, suggesting it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease. Title: Inhibition of tacrine oral clearance by cimetidine Forgue ST, Reece PA, Sedman AJ, deVries TM Ref: Clinical Pharmacology & Therapeutics, 59:444, 1996 : PubMed ESTHER: Forgue_1996_Clin.Pharmacol.Ther_59_444 PubMedSearch: Forgue 1996 Clin.Pharmacol.Ther 59 444 PubMedID: 8612390 Inhibitor(s) related to this paper: Tacrine Abstract Plasma tacrine, 1-hydroxytacrine, 2-hydroxytacrine, and 4-hydroxytacrine concentrations were measured in 12 healthy elderly subjects in this nonblinded two-period study to assess the effect of multiple doses of cimetidine on single-dose tacrine pharmacokinetics. Subjects received 40 mg tacrine (Cognex) alone and during multiple-dose cimetidine (300 mg four times a day) administration. Overall, tacrine and cimetidine were well tolerated by healthy elderly subjects. After coadministration of cimetidine with tacrine, plasma tacrine concentrations were approximately one-third higher than values after administration of tacrine alone; metabolite concentrations were also higher. Mean tacrine oral clearance was reduced by 30%; however, mean absorption rate and elimination half-life values were not affected by cimetidine. It was concluded that cimetidine inhibits first-pass hepatic extraction of tacrine by cytochrome P450 enzymes but has little effect on systemic drug clearance. Clinical considerations may dictate a reduction in tacrine dosage when tacrine is coadministered with cimetidine. Title: An enriched-population, double-blind, placebo-controlled, crossover study of tacrine and lecithin in Alzheimer's disease. The Tacrine 970-6 Study Group Foster NL, Petersen RC, Gracon SI, Lewis K Ref: Dementia, 7:260, 1996 : PubMed ESTHER: Foster_1996_Dementia_7_260 PubMedSearch: Foster 1996 Dementia 7 260 PubMedID: 8872417 Inhibitor(s) related to this paper: Tacrine Abstract We studied the effects of 40 and 80 mg/day of tacrine on patients with probable Alzheimer's disease (AD) in an 8-week, randomized, double-blind, placebo-controlled crossover trial with an enriched-population design. In the initial dose titration phase, an intent-to-treat analysis showed significantly more improvement with 80 mg/day of tacrine than placebo. In the subsequent crossover trial that included only 'responders', no significant improvement was observed with tacrine, whether or not it was given with lecithin. We found that individualized dose titration and enrichment strategies were not helpful and had the effect of reducing the power of the study. In the dose titration phase of this study we found that more impaired subjects were as likely to improve as those who were less impaired, suggesting that tacrine should be further investigated in more severely demented AD patients. Title: Allosteric regulation of the binding of [3H]acetylcholine to m2 muscarinic receptors Gnagey AL, Ellis J Ref: Biochemical Pharmacology, 52:1767, 1996 : PubMed ESTHER: Gnagey_1996_Biochem.Pharmacol_52_1767 PubMedSearch: Gnagey 1996 Biochem.Pharmacol 52 1767 PubMedID: 8986140 Inhibitor(s) related to this paper: Gallamine~Flaxedil, Physostigmine~Eserine, Tacrine Abstract Muscarinic receptors of the m2 subtype expressed in Chinese hamster ovary cells were labeled with [methyl-3H]acetylcholine([3H]ACh), and the rate of dissociation in the presence and absence of several compounds known to exert allosteric effects on labeled antagonist binding was observed. At 25 degrees C, [3H]ACh bound to the receptors with a Kd of 1.2 nM and dissociated with a half-time of 1.6 min. This binding was sensitive to appropriate concentrations of guanine nucleotide and the muscarinic antagonist N-methylscopolamine (NMS). Gallamine, tetrahydroaminoacridine, physostigmine, obidoxime, and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8) all inhibited the binding of [3H]ACh and all slowed the rate of dissociation of [3H]ACh in a concentration-dependent manner. However, the nature of some of the allosteric effects differed from previous studies that used other labeled ligands. In particular, TMB-8, which is very effective in slowing the dissociation of the antagonist [3H]NMS, had much weaker effects on the dissociation of [3H]ACh. Furthermore, TMB-8 was able to partially reverse the stronger effects of gallamine on the dissociation of [3H]ACh, consistent with the possibility that TMB-8 and gallamine share a common site on the receptor. In summary, the binding of ACh to muscarinic receptors is subject to allosteric regulation, and assays using [3H]ACh may be especially useful in the evaluation of potential allosteric regulators of muscarinic systems. Title: Effects of tacrine (THA) on spatial reference memory and cholinergic enzymes in specific rat brain regions Jackson JJ, Soliman MR Ref: Life Sciences, 58:47, 1996 : PubMed ESTHER: Jackson_1996_Life.Sci_58_47 PubMedSearch: Jackson 1996 Life.Sci 58 47 PubMedID: 8628110 Inhibitor(s) related to this paper: Tacrine Abstract Cognitive function of rats treated with saline (control), THA (8 mg/kg, i.p.), scopolamine (5 mg/kg, i.p.), or a combination of THA (8 mg/kg) and scopolamine (5 mg/kg) was tested in the Morris water maze. The latency to find the platform in the water maze was used to evaluate performance. THA did not significantly alter the latency period as compared to control rats. Scopolamine resulted in a highly significant (p<0.01) increase in latency period (183% increase) as compared to saline treated controls. However, when THA was concurrently administered with scopolamine, it was able to completely reverse the performance decrement induced by scopolamine. Immediately following spatial reference memory testing, animals were sacrificed by decapitation one hour post injection. Brains were immediately removed and the cortex, hippocampus, hypothalamus, and pituitary were dissected and their choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity were determined spectrophotometrically. THA administration resulted in a significant increase in ChAT activity in the cortex (23% increase). However, when THA was concurrently administered with scopolamine, a significant increase in ChAT activity was observed in cortex (77% increase), hippocampus (32% increase), hypothalamus (97% increase), and pituitary (92.5% increase). THA administration resulted in a significant decrease in AChE activity (p<0.001) in cortex (62% decrease), hippocampus (78% decrease), and hypothalamus (90% decrease). When tacrine was administered with scopolamine, a significant increase was found in the cortex (197% increase) and the hippocampus (207% increase). In conclusion, the increase in ChAT activity produced by tacrine may in part explain its ability to reverse the scopolamine induced decrease in spatial reference memory and may play a role in its beneficial effect in improving cognitive ability. Title: Overlapping drug interaction sites of human butyrylcholinesterase dissected by site-directed mutagenesis Loewenstein-Lichtenstein Y, Glick D, Gluzman N, Sternfeld M, Zakut H, Soreq H Ref: Molecular Pharmacology, 50:1423, 1996 : PubMed ESTHER: Loewenstein-Lichtenstein_1996_Mol.Pharmacol_50_1423 PubMedSearch: Loewenstein-Lichtenstein 1996 Mol.Pharmacol 50 1423 PubMedID: 8967962 Gene_locus related to this paper: human-BCHE Inhibitor(s) related to this paper: BW284C51, Cocaine, Dibucaine, Solanine, Succinylcholine~Suxamethonium, Tacrine Abstract Butyrylcholinesterase [BCHE (acylcholine acyl hydrolase); EC 3.1.1.8] limits the access of drugs, including tacrine, to other proteins. The "atypical" BCHE variant, in which Asp70 at the rim of the active site gorge is substituted by glycine, displayed a more drastically weakened interaction with tacrine than with cocaine, dibucaine, succinylcholine, BW284c51 [1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide], or alpha-solanine. To delineate the protein domains that are responsible for this phenomenon, we mutated residues within the rim of the active site gorge, the region parallel to the peripheral site in the homologous enzyme acetylcholinesterase [AChE (acetylcholine acetyl hydrolase); EC 3.1.1.7], the oxyanion hole, and the choline-binding site. When expressed in microinjected Xenopus laevis oocytes, all mutant DNAs yielded comparable amounts of immunoreactive protein products. Most mutants retained catalytic activity close to that of wild-type BCHE and were capable of binding ligands. However, certain modifications in and around the oxyanion hole caused a dramatic loss in activity. The affinities for tacrine were reduced more dramatically than for all other ligands, including cocaine, in both oxyanion hole and choline-binding site mutants. Modified ligand affinities further demonstrated a peripheral site in residues homologous with those of AChE. BCHE mutations that prevented tacrine interactions also hampered its ability to bind other drugs and inhibitors, which suggests a partial overlap of the binding sites. This predicts that in addition to their genetic predisposition to adverse responses to tacrine, homozygous carriers of "atypical" BCHE will be overly sensitive to additional anticholinesterases and especially so when exposed to several anticholinesterases in combination. Title: [Pharma-clinics. Drug of the month. Tacrine (Cognex)] Scheen AJ Ref: Rev Med Liege, 51:379, 1996 : PubMed ESTHER: Scheen_1996_Rev.Med.Liege_51_379 PubMedSearch: Scheen 1996 Rev.Med.Liege 51 379 PubMedID: 8992561 Inhibitor(s) related to this paper: Tacrine Title: [Alzheimer disease cannot be treated with Cognex] Shafazand M Ref: Lakartidningen, 93:1406, 1996 : PubMed ESTHER: Shafazand_1996_Lakartidningen_93_1406 PubMedSearch: Shafazand 1996 Lakartidningen 93 1406 PubMedID: 8667714 Inhibitor(s) related to this paper: Tacrine Title: Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase Pacheco G, Palacios-Esquivel R, Moss DE Ref: Journal of Pharmacology & Experimental Therapeutics, 274:767, 1995 : PubMed ESTHER: Pacheco_1995_J.Pharmacol.Exp.Ther_274_767 PubMedSearch: Pacheco 1995 J.Pharmacol.Exp.Ther 274 767 PubMedID: 7636741 Inhibitor(s) related to this paper: Physostigmine~Eserine, MSF, Tacrine, Trichlorfon~Metrifonate Abstract One consistent finding in senile dementia of the Alzheimer's type is that the brain has reduced ability to synthesize acetylcholine. This has been related, in part, to memory dysfunctions. Although a cholinergic deficit is not singularly responsible for symptoms of dementia, treatment strategies have been designed to facilitate cholinergic activity by inhibiting acetylcholinesterase (AChE). To minimize toxicity, however, a cholinesterase inhibitor selective for only AChE would be an ideal treatment. The purpose of this study was to determine the selectivity of physostigmine, metrifonate, methanesulfonyl fluoride and tetrahydroaminoacridine (tacrine) toward AChE as compared with butyrylcholinesterase (BChE) in human cortex. The results show that methanesulfonyl fluoride is selective as an inhibitor of AChE as compared with BChE. Physostigmine inhibited AChE more than BChE. Metrifonate was found to inhibit BChE more than AChE. Tetrahydroaminoacridine inhibited both enzymes in a complex way. Title: Discovery of a novel tetrahydroacridine acetylcholinesterase inhibitor through an indexed combinatorial library Pirrung MC, Chau JH, Chen J Ref: Chemistry & Biology, 2:621, 1995 : PubMed ESTHER: Pirrung_1995_Chem.Biol_2_621 PubMedSearch: Pirrung 1995 Chem.Biol 2 621 PubMedID: 9383467 Inhibitor(s) related to this paper: 7-Nitrotacrine, Tacrine Abstract BACKGROUND: Methods for the rapid and efficient preparation of drug candidates through combinatorial chemistry are of increasing interest. We have previously reported an indexed combinatorial library method that allows both the preparation and testing of compounds in solution. We set out to apply this method to develop more effective analogs of the known, marketed drug tacrine, an acetylcholinesterase inhibitor. RESULTS: A one-step condensation of cyclohexanones with cyanoanilines to generate tetrahydroacridine pools was developed. The resulting library of (formally) 72 tetrahydroacridines was screened against acetylcholinesterase, and a compound 10-fold more potent than tacrine, 7-nitrotacrine, was discovered. Its increased potency could be readily explained by examining the known structure of the complex of acetylcholinesterase with tetrahydroacridine. CONCLUSIONS: In this work, we have provided a relatively rare example of carbon-carbon bond formation in a pool synthesis and have discovered a potentially useful acetylcholinesterase inhibitor. Title: [New therapeutic prospects in Alzheimer disease] Rouhart F Ref: Rev Med Interne, 16:860, 1995 : PubMed ESTHER: Rouhart_1995_Rev.Med.Interne_16_860 PubMedSearch: Rouhart 1995 Rev.Med.Interne 16 860 PubMedID: 8570945 Inhibitor(s) related to this paper: Tacrine Abstract The approval for marketing of tacrine (Cognex), an acetylcholinesterase inhibitor, allowed physicians and the general people to attract attention to a degenerative disease, which prevalence dramatically increases every year. This drug is hopeful. Meanwhile, we must keep in mind that it has only a symptomatic effect. Its hepatotoxicity requires regular biological tests. Many medications are actually in earlier stages of development along with various etiological approaches. Title: MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice Murai S, Saito H, Abe E, Masuda Y, Odashima J, Itoh T Ref: Journal of Neural Transmission General Section, 98:1, 1994 : PubMed ESTHER: Murai_1994_J.Neur.Transm_98_1 PubMedSearch: Murai 1994 J.Neur.Transm 98 1 PubMedID: 7710736 Inhibitor(s) related to this paper: Tacrine Abstract The effects of acute and chronic administration of MKC-231, a new choline uptake enhancer, and two other nootropic agents, linopiridine (Dup 996) and tetrahydroaminoacridine (THA) on working memory deficits and decreased hippocampal acetylcholine (ACh) content were studied in a delayed non-matching to sample task, using a T-maze, in ethylcholine aziridinium ion (AF64A)-treated mice. Treatment with AF64A (3.5 nmol, i.c.v.) produced memory deficits and decreased hippocampal ACh content. In acute behavioral experiments, MKC-231 and THA had no significant effect on AF64A-induced memory deficits at any doses tested (0.3, 1.0 and 3.0 mg/kg), whereas Dup 996, at a dose of 1.0 mg/kg, significantly improved memory deficits. In chronic experiments, MKC-231 improved memory deficit at all doses tested (0.3, 1.0, or 3.0 mg/kg p.o., once daily for 11 days) and Dup 996 did so only at a dose of 3.0 mg/kg, whereas THA did not improve memory deficit at any doses tested. In acute neurochemical experiments, MKC-231 and THA did not reverse the AF64A-induced hippocampal ACh depletion. Dup 996, however, further decreased hippocampal ACh content compared to that in the AF64A-treated group. In chronic experiments, MKC-231 significantly reversed hippocampal ACh depletion at doses of 0.3 and 1.0 mg/kg, whereas neither Dup 996 nor THA reversed hippocampal ACh depletion at any doses tested. These results indicate that MKC-231 improved the AF64A-induced working memory deficit and hippocampal ACh depletion, probably by recovering reduced high-affinity choline uptake and ACh release. Title: The next generation of cholinesterase inhibitors Adem A Ref: Acta Neurologica Scandinavica Supplementum, 149:10, 1993 : PubMed ESTHER: Adem_1993_Acta.Neurol.Scand.Suppl_149_10 PubMedSearch: Adem 1993 Acta.Neurol.Scand.Suppl 149 10 PubMedID: 8128831 Inhibitor(s) related to this paper: Tacrine Abstract Clinical trials with tacrine (THA) have resulted in elevations of liver enzymes in Alzheimer patients that showed improvement. In an effort to minimize these side effects several THA analogues were synthesized. These analogues were compared to THA in biochemical as well as behavioural studies. The biochemical effects of these drugs on plasma cholinesterase activity and cholinergic receptors as well as the effect of these drugs on spatial learning in adult rats were examined. It is possible that some of these analogues with more potent cholinergic effect than THA might be the next generation of cholinesterase inhibitors which can be useful in the treatment of Alzheimer's disease. Title: Changes of rat blood and tissue cholinesterases following administration of tacrine derivatives in vivo Bajgar J, Skopec F Ref: Sbornik Vedeckych Praci Lekarske Fakulty Karlovy Univerzity, 36:73, 1993 : PubMed ESTHER: Bajgar_1993_Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove_36_73 PubMedSearch: Bajgar 1993 Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove 36 73 PubMedID: 8165433 Inhibitor(s) related to this paper: Soman, Tacrine Abstract Acetylcholinesterase (blood, hippocampus, frontal cortex, basal ganglia, septum and diaphragm) or butyrylcholinesterase (liver) activities following i.m. administration of tacrine (9-amino-1,2,3,4-tetrahydroacridine), its 7-methoxy- and 7-hydroxy derivatives to rats in dose of 1.2 x LD50 were detected. The most marked inhibition of the enzymes studied following tacrine administration was demonstrated in the frontal cortex, diaphragm, liver and blood. Inhibition of acetylcholinesterase in the frontal cortex and blood only was observed following administration of tacrine derivatives. The results indicate that inhibition of cholinesterases could be important but not unique part explaining the action of these drugs in general. Title: Cholinesterase inhibitor effects on extracellular acetylcholine in rat cortex Messamore E, Warpman U, Ogane N, Giacobini E Ref: Neuropharmacology, 32:745, 1993 : PubMed ESTHER: Messamore_1993_Neuropharmacol_32_745 PubMedSearch: Messamore 1993 Neuropharmacol 32 745 PubMedID: 8413838 Inhibitor(s) related to this paper: Heptylphysostigmine, Physostigmine~Eserine, Tacrine Abstract A microdialysis technique was used to sample acetylcholine (ACh) from the cerebral cortex of conscious rats. We thus investigated the effects of systemically administered cholinesterase inhibitors (ChEI) such as physostigmine (300 micrograms/kg), heptylphysostigmine (5 mg/kg) and tetrahydroaminoacridine (tacrine, 5 mg/kg) on extracellular ACh levels. Baseline quantities of extracellular ACh could be detected, even in the absence of ChEI. Acetylcholine levels increased to 1100% over baseline within 30 min of physostigmine administration and returned to control levels after 1.25 hr. Heptylphysostigmine elicited a maximal increase of 1000% within 1.5 hr, and the effect persisted up to 9.5 hr. A 500% increase was observed 1.5 hr after tacrine administration, and ACh returned to control levels after 4 hr. Although the ACh effects observed in this study correlated with previously determined levels of acetylcholinesterase (AChE) inhibition, we conclude that measures of cortical AChE activity alone are not sufficient to predict extracellular ACh levels following systemic ChEI administration. Title: Three distinct domains in the cholinesterase molecule confer selectivity for acetyl- and butyrylcholinesterase inhibitors Radic Z, Pickering NA, Vellom DC, Camp S, Taylor P Ref: Biochemistry, 32:12074, 1993 : PubMed ESTHER: Radic_1993_Biochemistry_32_12074 PubMedSearch: Radic 1993 Biochemistry 32 12074 PubMedID: 8218285 Inhibitor(s) related to this paper: 9-Aminoacridine, Acridine, Chlorpromazine, Edrophonium, Ethopropazine, N-Methyl-acridinium, Promazine, Promethazine, Tacrine Abstract By examining inhibitor interactions with single and multiple site-specific mutants of mouse acetylcholinesterase, we have identified three distinct domains in the cholinesterase structure that are responsible for conferring selectivity for acetyl- and butyrylcholinesterase inhibitors. The first domain is the most obvious; it defines the constraints on the acyl pocket dimensions where the side chains of F295 and F297 primarily outline this region in acetylcholinesterase. Replacement of these phenylalanine side chains with the aliphatic residues found in butyrylcholinesterase allows for the catalysis of larger substrates and accommodates butyrylcholinesterase-selective alkyl phosphates such as isoOMPA. Also, elements of substrate activation characteristic of butyrylcholinesterase are evident in the F297I mutant. Substitution of tyrosines for F295 and F297 further alters the catalytic constants. The second domain is found near the lip of the active center gorge defined by two tyrosines, Y72 and Y124, and by W286; this region appears to be critical for the selectivity of bisquaternary inhibitors, such as BW284C51. The third domain defines the site of choline binding. Herein, in addition to conserved E202 and W86, a critical tyrosine, Y337, found only in the acetylcholinesterases is responsible for sterically occluding the binding site for substituted tricyclic inhibitors such as ethopropazine. Analysis of a series of substituted acridines and phenothiazines defines the groups on the ligand and amino acid side chains in this site governing binding selectivity. Each of the three domains is defined by a cluster of aromatic residues. The two domains stabilizing the quaternary ammonium moieties each contain a negative charge, which contributes to the stabilization energy of the respective complexes. Title: In vitro protection of acetylcholinesterase and butyrylcholinesterase by tetrahydroaminoacridine. Comparison with physostigmine Galli A, Mori F, Gori I, Lucherini M Ref: Biochemical Pharmacology, 43:2427, 1992 : PubMed ESTHER: Galli_1992_Biochem.Pharmacol_43_2427 PubMedSearch: Galli 1992 Biochem.Pharmacol 43 2427 PubMedID: 1610407 Inhibitor(s) related to this paper: DFP, Neostigmine~Prostigmine, Physostigmine~Eserine, Tacrine Abstract The protective action of 1,2,3,4-tetrahydro-9-aminoacridine (THA) against the long-lasting inactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BCHE) brought about by diisopropylfluorophosphate (DFP) and physostigmine, as well as by neostigmine in the case of AChE only, was evaluated by a dilution technique using Electrophorus electricus AChE and horse serum BCHE as target enzymes. In parallel experiments, the ability of physostigmine itself to protect these enzymes from DFP was evaluated and compared with that of THA. THA pretreatment was seen to prevent in a dose-dependent manner the inhibition of both AChE and BCHE. However, it was appreciably more potent towards AChE than towards BCHE. THA mean EC50 values for protecting AChE against 10, 40 and 100 microM DFP were 0.04, 0.16 and 0.45 microM, respectively; against 1 microM physostigmine the value was 1.8 microM and against 1.2 microM neostigmine it was 3.0 microM. The THA mean EC50 value for protecting BCHE against 3 microM physostigmine was 0.55 microM and the values for protecting against 3, 10 and 40 microM DFP were 1.5, 3 and greater than 10 microM, respectively. The protective action of THA was time independent: recovery of the maximal enzymic activity was immediate upon dilution. Unlike THA, the protective action of physostigmine developed progressively after dilution and was maximal within 3-4 (AChE) or 6-8 hr (BCHE). Under our experimental conditions, 0.3 microM physostigmine protected approximately 70% of AChE from 40 microM DFP and 5 microM physostigmine protected 9 and 47% of BCHE from 40 and 3 microM DFP, respectively. The results of this work suggest that THA exerts its protective action by shielding the active site of AChE and BCHE from the attack of the inactivating agents on account of its higher enzymic affinity, whereas the protective action of physostigmine against DFP takes advantage also of the carbamylation of the enzyme. These results are in line with the hypothesis that protection of AChE is the primary mechanism responsible for the antidotal action of THA against organophosphorus poisoning. Title: Preferential inhibition of acetylcholinesterase molecular forms in rat brain Ogane N, Giacobini E, Messamore E Ref: Neurochemical Research, 17:489, 1992 : PubMed ESTHER: Ogane_1992_Neurochem.Res_17_489 PubMedSearch: Ogane 1992 Neurochem.Res 17 489 PubMedID: 1528356 Inhibitor(s) related to this paper: BW284C51, Echothiophate, Heptylphysostigmine, Physostigmine~Eserine, Tacrine, Trichlorfon~Metrifonate Abstract The effect of eight different acetylcholinesterase inhibitors (AChEIs) on the activity of acetylcholinesterase (AChE) molecular forms was investigated. Aqueous-soluble and detergent-soluble AChE molecular forms were separated from rat brain homogenate by sucrose density sedimentation. The bulk of soluble AChE corresponds to globular tetrameric (G4), and monomeric (G1) forms. Heptylphysostigmine (HEP) and diisopropylfluorophosphate were more selective for the G1 than for the G4 form in aqueous-soluble extract. Neostigmine showed slightly more selectivity for the G1 form both in aqueous- and detergent-soluble extracts. Other drugs such as physostigmine, echothiophate, BW284C51, tetrahydroaminoacridine, and metrifonate inhibited both aqueous- and detergent-soluble AChE molecular forms with similar potency. Inhibition of aqueous-soluble AChE by HEP was highly competitive with Triton X-100 in a gradient, indicating that HEP may bind to a detergent-sensitive non-catalytic site of AChE. These results suggest a differential sensitivity among AChE molecular forms to inhibition by drugs through an allosteric mechanism. The application of these properties in developing AChEIs for treatment of Alzheimer disease is considered. Title: Effects of tacrine, velnacrine (HP029), suronacrine (HP128), and 3,4-diaminopyridine on skeletal neuromuscular transmission in vitro Braga MF, Harvey AL, Rowan EG Ref: British Journal of Pharmacology, 102:909, 1991 : PubMed ESTHER: Braga_1991_Br.J.Pharmacol_102_909 PubMedSearch: Braga 1991 Br.J.Pharmacol 102 909 PubMedID: 1649660 Inhibitor(s) related to this paper: Suronacrine, Tacrine, Velnacrine Abstract 1. The effects of tacrine (9-amino-1,2,3,4-tetrahydroacridine), velnacrine (HP029, 9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate), suronacrine (HP128, 9-benzylamino-1,2,3,4-tetrahydroacridin-1-ol maleate), and 3,4-diaminopyridine on neuromuscular transmission were compared on isolated nerve-muscle preparations. 2. Tacrine, HP029, and 3,4-diaminopyridine augmented responses of chick biventer cervicis preparations to nerve stimulation, with tacrine and HP029 increasing responses to exogenously applied acetylcholine. HP128 blocked responses to nerve stimulation and to carbachol, but increased responses to acetylcholine. 3. In mouse diaphragm preparations that were partially paralysed by tubocurarine or low calcium solutions, tacrine, HP029, and 3,4-diaminopyridine reversed the twitch block. HP128 deepened the block. 4. In mouse triangularis sterni preparations, tacrine and HP029 prolonged the decay phase of endplate potentials and miniature endplate potentials, but had no effect on quantal content at 36 degrees C; above 10 microM, they reduced endplate potential amplitude. 3,4-Diaminopyridine increased quantal content without affecting the time course of the endplate potentials. HP128 (1-10 microM) had no effect on amplitude or time course of endplate potentials, but reduced their amplitude at higher concentrations. 5. Extracellular recording of nerve terminal currents from triangularis sterni preparations revealed that 3,4-diaminopyridine and HP128 had a selective blocking action on the waveform associated with K+ currents, tacrine reduced and prolonged the K(+)-related waveform, and HP029 had nonselective blocking actions only seen at high concentrations. 6. Tacrine and HP029 behave predominantly as anticholinesterase agents, while HP128 has weaker anticholinesterase actions that are masked by cholinoceptor blockade. Tacrine and HP128, but not HP029, have some blocking actions on K+ currents of mouse motor nerve terminals. Title: Reversibility of the inhibition of acetylcholinesterase by tacrine Dawson RM Ref: Neuroscience Letters, 118:85, 1990 : PubMed ESTHER: Dawson_1990_Neurosci.Lett_118_85 PubMedSearch: Dawson 1990 Neurosci.Lett 118 85 PubMedID: 2259472 Inhibitor(s) related to this paper: Tacrine Abstract Inhibition of bovine erythrocyte acetylcholinesterase (AChE) by 1,2,3,4-tetrahydro-9-acridinamine (tacrine) was independent of time of incubation and was partially reversed by dilution and by increased substrate concentration. It was fully reversed by dialysis. Similar results were obtained with AChE from other sources. The results are consistent with some reports in the literature, but not with others; none of these reports examined all four criteria of reversibility. The results do not explain the prolonged inhibition of AChE in vivo or the ability of tacrine to protect animals against the lethal effects of organophosphate anticholinesterases. Title: The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro Hunter AJ, Murray TK, Jones JA, Cross AJ, Green AR Ref: British Journal of Pharmacology, 98:79, 1989 : PubMed ESTHER: Hunter_1989_Br.J.Pharmacol_98_79 PubMedSearch: Hunter 1989 Br.J.Pharmacol 98 79 PubMedID: 2804555 Inhibitor(s) related to this paper: Tacrine Abstract 1. The effect of tetrahydroaminoacridine (THA) on cholinergically mediated behaviour in the rat and mouse has been investigated. In addition the actions of this compound on cholinesterase activity and on muscarinic and nicotinic receptors has also been examined. 2. Administration of THA (5-20 mg kg-1, i.p.) produced a dose-dependent increase in tremor, hypothermia and salivation in both rats and mice. A similar profile of activity was seen following physostigmine (0.1-0.6 mg kg-1) administration. 3. THA was approximately fifty fold less potent than physostigmine in inducing behavioural change but its effects persisted for over twice as long as those of physostigmine. For example THA-induced hypothermia was still present at 4 h in the mouse and 8 h in the rat. 4. In vitro THA was a potent non-competitive inhibitor of rat brain cholinesterase (IC50: 57 +/- 6 nM) and bovine erythrocyte acetylcholinesterase (IC50: 50 +/- 10 nM) but was a more potent inhibitor of horse serum butyrylcholinesterase (IC50: 7.2 +/- 1.4 nM). 5. Radioligand binding studies indicated that THA binds non-selectively but with moderate potency to both M1 (Ki: 600 nM) and M2 (Ki: 880 nM) muscarinic receptors. THA also interacted with the allosteric site present on cardiac M2 receptors. 6. It is concluded that THA is a reversible non-competitive inhibitor of cholinesterase with a long half life (compared with physostigmine). It also may antagonize muscarinic receptors at high doses. The long half life may account for its reported efficacy in the treatment of Alzheimer's disease. Title: The mechanism of tetrahydroaminoacridine-evoked release of endogenous 5-hydroxytryptamine and dopamine from rat brain tissue prisms Robinson TN, De Souza RJ, Cross AJ, Green AR Ref: British Journal of Pharmacology, 98:1127, 1989 : PubMed ESTHER: Robinson_1989_Br.J.Pharmacol_98_1127 PubMedSearch: Robinson 1989 Br.J.Pharmacol 98 1127 PubMedID: 2611486 Inhibitor(s) related to this paper: Tacrine Abstract 1 Tetrahydroaminoacridine (THA) is an acetylcholinesterase (AChE) inhibitor which may have a greater therapeutic effect in Alzheimer-type dementia (ATD) than other cholinergic agents. This suggests possible non-cholinergic properties. We have therefore studied the effects of THA on the release of endogenous 5-hydroxytryptamine (5-HT) from rat cortical prisms and dopamine from striatal prisms. 2 In the presence of K+ (1 mM), THA stimulated release of both 5-HT and dopamine. THA (100 microM)-evoked monoamine release was comparable, but not additive with the release produced by K+ (35 mM). The effect was not maximal at 1 mM THA. THA-evoked release of 5-HT was independent of the presence of Ca2+ in the external medium. 3 Drugs acting on the cholinergic system, nicotine, mecamylamine, atropine, oxotremorine, physostigmine and neostigmine (all 10 microM) had no effect on 5-HT and dopamine-release. 4-Aminopyridine (4-AP), a potent acetylcholine-releasing agent, had no effect on 5-HT release and was approximately 100 fold less active than THA on dopamine release. 4 Both THA and reserpine enhanced the release of 5-HT in the presence of the monoamine oxidase inhibitor, pargyline. Reserpine- but not THA-evoked release was abolished in the absence of pargyline. Reserpine (5 mg kg-1, i.p.) markedly depleted brain monoamine concentrations 3 h after injection, while THA (15 mg kg-1, i.p.) had no effect. 5 Chloroamphetamine and fenfluramine both released 5-HT in a Ca2(+)-independent manner and with a similar potency to THA, while (+)-amphetamine released dopamine with a similar potency to THA. The effects of the amphetamines were not maximal at 1 mM. However, unlike THA, chloroamphetamine-evoked release of 5-HT was additive with release evoked by K+ (35 mM). 6 Clomipramine (IC50 = 0.036 microM) and THA (IC50 = 19.9 microM) all inhibited the uptake of [3H]-5-HT into a P2 membrane preparation. However, none of these compounds inhibited [3H]-5-HT uptake into tissue prisms during the release experiments in which the reuptake inhibitor fluoxetine (5 microM) was present. 7 We conclude that THA does not release endogenous 5-HT through a cholinergic, reserpine- or amphetamine-like mechanism or through inhibition of reuptake. The possibility exists that the release may occur via blockade of 4-AP-insensitive K+ channels. Title: Inhibitory effect of 1,2,3,4-tetrahydro-9-aminoacridine on the depolarization-induced release of GABA from cerebral cortex de Belleroche J, Gardiner IM Ref: British Journal of Pharmacology, 94:1017, 1988 : PubMed ESTHER: de Belleroche_1988_Br.J.Pharmacol_94_1017 PubMedSearch: de Belleroche 1988 Br.J.Pharmacol 94 1017 PubMedID: 3207970 Inhibitor(s) related to this paper: Tacrine Abstract 1,2,3,4-Tetrahydro-9-aminoacridine (THA) has an inhibitory effect on the activity of acetylcholinesterase which has led to its use in the treatment of Alzheimer's disease. Other actions of THA include the inhibition of voltage-dependent ion channels. In this paper we describe the effect of THA on the depolarization-induced release of [14C]-gamma-aminobutyric acid (GABA) from tissue slices of rat cerebral cortex. THA produced a dose-dependent inhibition of the 30 mM K+-evoked release of [14C]-GABA with an IC50 of 56 microM. The maximal response was an 84% inhibition of the evoked response. THA (up to a concentration of 1 mM) had no effect on the basal release of GABA. A similar inhibitory effect on the K+-evoked release of [14C]-GABA was seen with 4-aminopyridine (4-AP) but no inhibition was obtained with tetraethylammonium up to a concentration of 20 mM. The maximal inhibitory effect of 4-AP (39%) occurred at 1 mM (IC50 of 112 microM) and this response was much smaller in magnitude than that obtained with THA. | ||||||||
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