Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002395 (Alzheimer's disease)
 110,584 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously used in Alzheimer disease Tacrine (THA): tetrahydroaminoacridine has shown a rise of hepatic transaminase enzyme activity (TEA) in 18% of patients for Summers and 19% for Ames. Although studies using THA from USA or Canada have noticed a rise of TEA in 30% of the patients, after a treatment course with French THA we also have noted a rise of TEA in 12% of the Alzheimer patients. However, these secondary effects yielded to the end of treatment. These studies have been done with THA from different origins and different associations. Summers, the Canadian group and the French one have used THA in association with lecithin, when american group study has been made with no additional product. Therefore we have initiated a trial with oral THA in AIDS patients. 52 patients with HIV infection (26 in the IVC1 group and 26 in IVC2 group) have been treated with the same THA as the one used for Alzheimer french group. The common dosage was 150 to 200 mg (3 to 4 of 50 mg dosing capsules per day). The THA has been synthetized such as having an over 99% pureness product. After a period of 260 months/patient no elevation of TEA has been noted in any patients of our group. These results observed in HIV advanced patients with this THA are discordant with the one observed in Alzheimer's study. The dosage used in AIDS is twice higher than the one used for Alzheimer which gives us credit to the lack of hepatic toxicity in HIV advanced patient after 7 months of treatment.
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PMID:[Comparison of tacrine hepatotoxicity in patients with Alzheimer disease or AIDS]. 129 25

The interaction of pharmacological agents potentially useful in Alzheimer's disease, 9-amino-1,2,3,4-tetrahydroacridine (THA or tacrine) and its major metabolite velnacrine (or HP-029), along with related compounds with cytoskeletal proteins in human erythrocyte membrane was investigated using electron paramagnetic resonance spin labeling techniques. The results suggest that: (1) the position of the positive charge of tacrine may be important in the mechanism of its interaction with the membrane cytoskeleton; (2) like tacrine, velnacrine also strengthens cytoskeletal protein-protein interactions in erythrocyte membranes, but appears to be only about half as potent as tacrine. These results are discussed with relevance to therapeutic use of these agents in Alzheimer's disease.
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PMID:Membrane-altering effects of velnacrine and N-methylacridinium: relevance to tacrine and Alzheimer's disease. 131 41

Oral pretreatment of mice with aldosterone or corticosterone blocked the memory-enhancing effects of piracetam, pramiracetam, aniracetam and oxiracetam in a dose-related manner, without, however, impairing the animals' learning performance. The improvement of memory induced by physostigmine, arecoline, and tacrine (THA) was similarly inhibited. The fact that elevated steroid levels suppress the memory-enhancing effects of entirely different substances could indicate that these substances have a common site of action. In the light of new observations showing increased cortisol concentrations in Alzheimer patients, this steroid dependency of the effects of memory enhancers might explain why only a limited number of these patients respond to therapy with nootropics or cholinomimetics.
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PMID:Elevated corticosteroid levels block the memory-improving effects of nootropics and cholinomimetics. 141 Jan 29

Tetrahydroaminoacridine (THA) and metrifonate are cholinesterase inhibitors used in the treatment of Alzheimer's disease. In experimental animals they inhibit acetylcholinesterase activity and have been reported to increase levels of brain acetylcholine. This paper presents results from studies of their effect at two dose levels on the dynamics of acetylcholine in mouse brain. Metrifonate at two doses (10 and 30 mg/kg intraperitoneally), known to cause cholinesterase inhibition, had no effect on levels of acetylcholine or choline or on the rate of synthesis of acetylcholine. THA (3 mg/kg intraperitoneally) had no effect on levels of acetylcholine and choline but had a shortlasting decreasing effect on the synthesis rate of acetylcholine. THA (10 mg/kg intraperitoneally) increased levels of acetylcholine and choline and markedly decreased the synthesis rate of acetylcholine. At this dose, the animals showed severe cholinergic effects, e.g. tremor and salivation. It is suggested that a moderate cholinesterase inhibition in brain facilitates cholinergic nerve transmission which is obtained at a broader dose range for metrifonate than for THA.
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PMID:Metrifonate and tacrine: a comparative study on their effect on acetylcholine dynamics in mouse brain. 143 50

Tetrahydroacridine (THA), or Cognex, is currently awaiting FDA approval for the treatment of Alzheimer's disease. In addition to reports indicating that THA improves the symptoms of patients with Alzheimer's disease, we have found that THA possesses potent antiplatelet activity. THA produced dose-dependent inhibition of human platelet aggregation induced by collagen, ADP, A23187, and phorbol ester. THA, when added to activated platelets, dispersed the platelet aggregates. We have also examined the effects of THA on intracellular Ca++ mobilization, ATP release, and production of cyclic AMP.
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PMID:The inhibitory effect of 9-amino-1,2,3,4-tetrahydroacridine (THA) on platelet function. 144 87

Alterations in calcium transport appear to be functionally significant. Treatment with drugs that promote calcium uptake partially reverse some of the age-related deficits in calcium-dependent processes. Thus, the relevance of decreased calcium coupled receptor binding is supported by the ability of 3,4-diaminopyridine to promote acetylcholine release by forebrain slices from aged mice. This drug also reduces the age-related depression in synaptosomal calcium uptake in aged rats and mice. 3,4-Diaminopyridine also reverses the age-related deficit in calcium transport, the age-related deficits in the tight rope test, and 8 arm maze performance. 3,4-Diaminopyridine is also effective in nonexcitable tissues, such as cultured skin fibroblasts; it increases the decreased cytosolic-free calcium. Depressed cell spreading of fibroblasts can be reversed by treatment of cells with the calcium ionophore A23187 which promotes calcium influx. 4-Aminopyridine, a similarly related compound, partially reverses short-term memory deficits in patients with Alzheimer's disease. Tetrahydroaminoacridine, an aminopyridine analog with anticholinesterase properties, produces clinical improvement in behavioral deficits due to Alzheimer's disease. Only recently has the aging brain become a subject of intense study. Evidently, the neurobiology of aging needs to develop its own theories to account for the unique aspects of brain aging as well as integrate them with the peripheral changes. An exciting but unexplored area of research in the aging brain concerns the coupling between calcium and the final end product, the induction of genes. Still unknown are the molecular events that set these processes in motion. In addition, whether conditions such as dietary restriction that increase longevity in certain rodents also retard age-related changes in calcium remains to be determined.
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PMID:Changes in calcium's role as a messenger during aging in neuronal and nonneuronal cells. 148 59

Unilateral lesions of rat entorhinal cortex produce a transitory performance deficit on spatial learning tasks, such as reinforced alternation in a T-maze. Tetrahydroaminoacridine (THA), a cholinesterase inhibitor, was administered to determine its effects on behavioral recovery using a reinforced alternation task in a T-maze. Rate of recovery after unilateral entorhinal lesion was not affected by a low dose of THA (0.05 mg/kg), while a higher dose (5.0 mg/kg) impaired recovery. Behavioral recovery was subsequently evaluated in the same rats following lesions to the contralateral entorhinal cortex. Serial bilateral lesions of the entorhinal cortex are known to produce a prolonged performance deficit on the alternation task. The 0.05 mg/kg THA group exhibited an intermediate rate of recovery, between the undamaged control group and bilateral lesion-saline injected groups. The group receiving 5.0 mg/kg of THA after bilateral lesion did not differ from the bilateral lesion-saline group. The failure of THA to significantly improve functional recovery in rats with lesions of the entorhinal cortex indicates that the compound may have limited applicability in treating human neurodegenerative disorders such as Alzheimer's disease.
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PMID:Effects of tetrahydroaminoacridine (THA) on functional recovery after sequential lesion of the entorhinal cortex. 174 69

THA (Tacrine), a drug used in the experimental therapy of dementia of Alzheimer's disease type, and whose biochemical site of action is believed to be the neural cholinesterase, is shown, for the first time, to be an immunosuppressant in vitro on normal human peripheral blood lymphocytes in microgram quantities. THA down-regulates non-MHC restricted natural killer (NK) cell activity without affecting the general viability of cells. This down-regulation can be demonstrated at all effector and target (K562) concentrations, in purified resting NK cells as well as in lymphokine (interleukin 2) activated killer cells in 3- or 16-h NK assays and in all the blood samples tested. Kinetic analysis shows that the Vmax (maximal cytotoxic potential) and Km of NK cell-mediated cytolysis are also attenuated. Single cell assays using agarose matrix reveal that THA moderately interferes with tumor target binding/recognition events and strongly abrogates the delivery of lethal hit, thus lowering the frequency of active killer cells among THA-treated lymphocytes. THA down-regulates NK cells upon direct interaction and does not require the help of non-NK cells. The THA sensitive site(s) on NK cells does not appear to be perturbed significantly either by their proliferative status or by membrane modulations that may be normally induced by interleukin 2. The in vitro immunomodulatory pharmacological properties of THA reveal that the biological site of action of THA extends to non-neural cells also. Such non-neural models may be helpful in exploring the pathophysiological neuroimmunomodulatory properties of THA at cellular and molecular levels.
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PMID:Immunomodulation by 9-amino-1,2,3,4-tetrahydroacridine (THA): 1. Down-regulation of natural cell-mediated cytotoxicity in vitro. 176 1

Tacrine (THA) is a potent cholinesterase inhibitor being studied for the treatment of Alzheimer's disease. The metabolism and excretion of THA were studied in rats following a single oral dose of 20 mg/kg of THA. The results show THA was extensively metabolized in rats after oral administration. Three major urinary metabolites were isolated by HPLC on a semi-prep analytical phenyl column, and subsequent purification of the individual fractions on a semi-prep analytical cyano column. The major metabolic pathways involve the hydroxylation of the saturated ring at positions 1, 2, and 4. The structures of the metabolites 9-amino-1,2,3,4-tetrahydroacridin-1-ol (1-OH-THA), 9-amino-1,2,3,4-tetrahydroacridin-2-ol (2-OH-THA), and 9-amino-1,2,3,4-tetrahydroacridin-4-ol (4-OH-THA) were determined by electron impact mass spectrometry and/or 1H-NMR, and compared with synthetic references. The urinary excretion of THA and metabolites was quantitated by HPLC with UV detection. About 60% of the oral dose was eliminated as total THA, 1-OH-THA, 2-OH-THA, and 4-OH-THA over a 48-hr collection interval; and the non-conjugated THA and hydroxylated metabolites accounted for 45% of the dose.
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PMID:Identification of the urinary metabolites of tacrine in the rat. 198 36

Tetrahydroaminoacridine (THA), an acetylcholinesterase inhibitor that is reported to have significant effects on cognition and memory in Alzheimer's disease patients, binds to rat brain membranes in a saturable and reversible manner. Computer analysis of the binding data revealed high- and low-affinity sites with Kd values of 97.8 nM and 4.65 microM and Bmax values of 4.13 and 114 pmol/mg protein. Autoradiographic studies show that these binding sites are not co-localized with acetylcholinesterase activity. The binding of [3H]THA to membranes does not appear to be related to receptors for several neurotransmitters/neuromodulators, including acetylcholine and other acetylcholinesterase inhibitors. Amiridin, a closely related acetylcholinesterase inhibitor, was able to block specific [3H]THA binding (IC50 = 1.05 microM). While the function of THA mediated by these sites is unknown, they may be responsible in part for the distinct clinical effects of tetrahydroaminoacridine compared to other acetylcholinesterase inhibitors.
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PMID:High-affinity [3H]THA (tetrahydroaminoacridine) binding sites in rat brain. 202 67


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