Disease relevance of Tacrine

• The D2 RNA sequence is more tha 40% homologous to the small nucleolar RNA U3B from rat Novikoff hepatoma, and the implications of this evolutionary conservation are discussed [1].
• CONCLUSIONS--These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy [2].
• The Physicians' Health Study exemplifies the use of a prerandomization run-in period to exclude subjects who are nonadherent, while recent trials of tacrine for Alzheimer disease and carvedilol for congestive heart failure typify the use of run-in periods to exclude patients who do not tolerate or do not respond to the study drug [3].
• The aim of this study was to determine the cellular effects of tacrine that account for liver dysfunction [4].
• The model describes disease progression without treatment, the placebo effect, and the effect of tacrine as a function of daily dose [5].

Psychiatry related information on Tacrine

• Tacrine in Alzheimer's disease [6].
• Age, severity of dementia, and exposure to tacrine prior to randomization had no clear influence on the treatment effect [7].
• The results indicate tha the meningoencephalitis induced by SIV in monkeys is similar to the lesions of the central nervous system in patients with AIDS and that SIV infection in the macaque is a useful animal model to study the pathogenesis of human immunodeficiency virus--related subacute encephalitis or AIDS encephalopathy [8].
• A recent review suggests that tacrine is modestly effective in treating cognitive symptoms and that-neuroleptic drugs are modestly effective in treating agitation and aggression [9].
• The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6 [10].

High impact information on Tacrine

• It therefore seems likely tha differential alterations in the rate of histone synthesis do not occur to a significant degree as cells proceed through the cycle, but the association of newly synthesized histones with DNA takes place after the onset of DNA replication [11].
• Moreover, atypical BuChE demonstrated 1/200th the affinity for tacrine of normal BuChE or the related enzyme acetylcholinesterase (AChE) [12].
• Meta-analysis of tacrine for Alzheimer disease: the influence of industry sponsors [13].
• Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists' Collaboration [7].
• Among patients receiving 80 mg/d of tacrine, 51% achieved a four-point or greater improvement of the ADAS cognitive component after 12 weeks of treatment [14].

Chemical compound and disease context of Tacrine

• We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease [15].
• OBJECTIVE--To compare efficacy and safety of tacrine hydrochloride with placebo in patients with probable Alzheimer's disease [14].
• Fluvoxamine may modulate the hepatotoxicity of tacrine, depending on the relative contribution of tacrine and its reactive metabolites to this toxicity [16].
• Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer's disease [17].
• Finally it is apparent tha M can cause hypertension even in the absence of the AV3V area or during chronic renin angiotensin blockade, indicating multiple pathogenetic mechanisms in this experimental model [18].

Biological context of Tacrine

• In the absence of T cells, B cells were found to respond to the type 2 T-independent (TI-2) antigen, trinitrophenyl (TNP)-Ficoll, with a characteristic hierarchy of IgM and IgG subclass Ab production which directly correlated with 5' to 3' Igh-C gene order, i.e., IgM greater tha IgG3 greater than IgG1 greater than IgG2b greater than IgG2a [19].
• The active treatment was the maximum tolerated dose of tacrine up to 150 mg daily plus 10.8 g lecithin daily [20].
• RESULTS: In vitro, tacrine was taken up by rat liver mitochondria, decreased their membrane potential, and stimulated their respiration [4].
• In cells deesterified by alkali, CCRC-R1 labels the entire wall, suggesting that the RG-II epitope recognized by CCRC-R1 is masked by esterification in most of the wall and tha such RG-II esterification is absent near the plasma membrane [21].
• Binding of the Tet repressor to the operator blocked transcription only when the operator was inserted less tha 5 bp from the TATA box [22].

Anatomical context of Tacrine

• OBJECTIVE--To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease [2].
• Ex vivo, respiration was increased in rat mitochondria isolated 30 minutes after the administration of 2 mg of tacrine per kilogram [4].
• Lewy bodies and response to tacrine in Alzheimer's disease [23].
• Bombesin significantly increased the frquency of pacesetter potentials (PP) in tha antrum, duodenum, jejunum, and ileum [24].
• Heterologous hybridizations involving poly(A)+ RNA derived from tightly bound polysomes and cDNAfree indicated tha most of the overlapping sequences are not contributed by loosely bound (high-salt releasable) polysomes [25].

Associations of Tacrine with other chemical compounds

• Enhancement of plasticity under methylphenidate and tacrine was associated with an increase in corticomotoneuronal excitability of the prime mover of the practice, as measured by the motor evoked potential amplitude, but with a decrease under cabergoline [26].
• The aim of this study was to examine the influence of fluvoxamine administration on the disposition kinetics of single-dose tacrine administration [16].
• 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 [27].
• The "atypical" BuChE 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 [28].
• OBJECTIVE: To examine the effect of HRT with 2 mg estradiol valerate and 0.25 mg levonorgestrel once daily on the pharmacokinetics of tacrine [29].

Gene context of Tacrine

• Cabp4(-/-) retinas also had ectopic synapses originating from rod bipolar and horizontal cells tha HJt extended into the outer nuclear layer [30].
• Recent studies using human liver microsomes have suggested that a single liver enzyme, cytochrome P450 1A2 (CYP1A2), catalyzes the major route of metabolism and elimination of tacrine, and also catalyzes the pathway(s) involved in the generation of reactive metabolites capable of covalent protein binding and cytotoxicity [31].
• This indicates tha different molecular mechanisms might be operational for low and high salt responses of the GPD1 promoter [32].
• BuChE mutations that prevented tacrine interactions also hampered its ability to bind other drugs and inhibitors, which suggests a partial overlap of the binding sites [28].
• The histamine receptor H1 antagonist diphenhydramine, the antimalarial drug amodiaquine, the antifolate drug metoprine, and the anticholinesterase drug tacrine (an early drug for Alzheimer's disease) are surprisingly all potent HNMT inhibitors, having inhibition constants in the range of 10-100nM [33].

Analytical, diagnostic and therapeutic context of Tacrine

• A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group [15].
• RESULTS--Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%) [2].
• Tacrine is a cholinesterase inhibitor with activity in the central nervous system originally marketed for the reversal of competitive neuromuscular blockade [5].
• These results indicate that T4+ and T8+ T lymphocytes have receptors for different classes of MHC antigens and suggest tha cytotoxic T4+ subpopulations might be important in human transplantation and autoimmune disorders [34].
• These results suggest tha MSA paces MEC theta rhythm and that the presumed cholinergic projection which mediates this function travels in the dorsal fornix [35].

References