Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case is reported of a patient who was given THA with suxamethonium and who demonstrated a prolonged apnoea. This patient was later shown to have a variant cholinesterase enzyme. The different techniques of THA and suxamethonium administration are discussed and it is suggested that an initial dose of suxamethonium should precede a THA-suxamethonium combination in order to try and avoid a prolonged apnoea.
 ...
PMID:Suxamethonium apnoea masked by tetrahydroaminacrine. 68 34

The present experiments were performed to investigate the potential role of central adrenergic neurons in regulating occurrence of yawning in rats. Intraperitoneal injection of tacrine (THA) or 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate HCl (NIK-247), cholinesterase inhibitors, induced yawning, which was markedly increased by pretreatment with the beta-adrenoceptor antagonist, pindolol. The yawning evoked by tacrine or NIK-247 given alone or in combination with pindolol was inhibited by pretreatment with scopolamine but not by mecamylamine or spiperone. Treatment with tacrine or NIK-247 increased acetylcholine content of the striatum, but this effect was not enhanced by pindolol, which per se did not affect basal acetylcholine content. Moreover, pretreatment with the central adrenaline synthesis inhibitors, (+-)-2,3-dichloro-alpha-methylbenzylamine HCl (LY-78335) and 2-cyclooctyl-2-hydroxyethylamine HCl (UK-1187A), increased tacrine-induced yawning. Subcutaneous injection of talipexole (B-HT 920), a dopamine D2 receptor agonist, evoked yawning, which was also increased by pindolol, LY-78335, and UK-1187A. These receptors antagonists and synthesis inhibitors per se did not cause yawning responses. The results suggest that the beta-adrenoceptor blockade and the inhibition of adrenaline synthesis facilitate the occurrence of yawning induced by cholinergic and dopaminergic agonists, and thus the central adrenergic neuronal systems may be implicated in the regulation of yawning responses.
 ...
PMID:Role of adrenergic neuronal activity in the yawning induced by tacrine and NIK-247 in rats. 136 95

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.
 ...
PMID:Metrifonate and tacrine: a comparative study on their effect on acetylcholine dynamics in mouse brain. 143 50

Basal and high K(+)-stimulated efflux of endogenous ACh from slices of brain was measured to evaluate the cholinomimetic effect of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b] quinoline monohydrate HCl (NIK-247) on the central nervous system. The drug NIK-247 dose-dependently accelerated the efflux of ACh from slices of striatum. The maximum increase produced by 1.0 x 10(-4) M of NIK-247 was 329% in basal and 1332% in 30 mM K(+)-stimulated efflux. This drug was nearly twice as potent as THA (9-amino-1,2,3,4-tetrahydroacridine HCl) but had the same potency as physostigmine, in enhancing basal efflux, although there was no significant difference between the efficacy of these drugs in enhancing the K(+)-stimulated efflux. Both basal and 50 mM K(+)-stimulated efflux of ACh were increased by NIK-247, not only from the striatum but also from slices of frontal cortex and hippocampus. The activity was more effective in the striatum than in other tissues, and more effective on K(+)-stimulated than on basal efflux, regardless of the region of the brain. These effects of NIK-247 may be a result mainly of its inhibition of cholinesterase and its other biological characteristics, such as K+ channel blockade, capable of modulating release of ACh, may not be of major importance.
 ...
PMID:Evaluation of a cholinomimetic drug, 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b] quinoline (NIK-247), as an enhancer of endogenous efflux of acetylcholine from brain slices. 154 4

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.
 ...
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.
 ...
PMID:Immunomodulation by 9-amino-1,2,3,4-tetrahydroacridine (THA): 1. Down-regulation of natural cell-mediated cytotoxicity in vitro. 176 1

An in vitro comparison demonstrated that the concentration of NIK-247 that inhibited cholinesterase (ChE) activities to half the normal level (ID50) was 1.3 x 10(-6) M. This value was higher than those for both physostigmine (PHY; 1.2 x 10(-7) M) and tetrahydroaminoacridine (THA; 3.6 x 10(-7) M), which are used as cholinesterase inhibitors in the treatment of cholinergic deficits. Neither NIK-247 nor THA affected the activity of choline acetyltransferase (ChAT). These inhibitions of ChE by NIK-247 and PHY lasted for 2 h, while that by THA lasted for over 4 h. In the effects of NIK-247 and PHY, the concentrations of intrastriatal acetylcholine (ACh) were changed in relation to the inhibition of the ChE activity. However, THA caused a transient increase in the ACh level lasting for only 2 h instead of inhibiting the enzyme activity for over 4 h. These findings suggest that NIK-247 is a drug with a similar profile in its effect on cholinergic neurons to PHY, the prototype drug among ChE inhibitors. The data indicate that NIK-247 may be useful as a drug for the treatment of central as well as peripheral deficits of the cholinergic mechanism.
 ...
PMID:Effect of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta-(b)-quinoline monohydrate hydrochloride (NIK-247) on cholinergic enzyme activity in rats. 194 90

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.
 ...
PMID:Identification of the urinary metabolites of tacrine in the rat. 198 36

Neurochemical studies of Alzheimer's disease (AD) suggest deficiencies in the cholinergic system. We evaluated the steady-state pharmacokinetics of tacrine (Cognex), an oral cholinesterase inhibitor, in 12 patients with AD. Patients sequentially received nine doses of 10 mg, 20 mg, and 30 mg of tacrine every 6 hours. Blood samples were collected until 24 hours after the final dose. Plasma tacrine concentrations were measured using a validated high-performance liquid chromatographic method. Mean maximum plasma concentrations (Cmax) were 5.1 ng/ml, 20.7 ng/ml, and 33.9 ng/ml following administration of 10 mg, 20 mg, and 30 mg doses, respectively. Corresponding mean values for steady-state area under the curve (AUC) were 19.7 ng/ml, 82.9 ng/ml, and 139 ng/ml.hr. Dose-normalized Cmax and AUC values after administration of the 20 mg and 30 mg doses of tacrine were comparable to each other but were significantly greater (p less than .05) than those after the 10 mg doses. The apparent elimination half-life was approximately 3.4 hours for all dosing regimens. Dose-dependent increases in Cmax and AUC values in patients with AD were similar to those previously reported in normal volunteers. The mechanism of the nonlinearity in tacrine pharmacokinetics is unknown.
 ...
PMID:Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease. 223 61

The effect of nicotine (1-10 microM) and tacrine (9-amino-1,2,3,4-tetrahydroacridine; THA) on stimulation evoked release of [3H]acetylcholine from the rat brain slice preparation preincubated with [3H]choline was investigated. In these preparations, nicotine enhanced while tacrine inhibited evoked [3H]acetylcholine release. These effects were blocked by (+)tubocurarine (1 microM) and atropine (0.1 microM) respectively. In the presence of idazoxan (0.3 microM) plus atropine (0.1 microM), nicotine (3 microM) continued to enhance evoked [3H]acetylcholine release while the inhibitory effect of tacrine (1 microM) on evoked [3H]acetylcholine release was reversed to an enhancement. Under these circumstances the effects of both nicotine and tacrine were blocked by (+)tubocurarine (1 microM). These findings demonstrate that tacrine can both inhibit or enhance [3H]acetylcholine release, most likely through its activity as a cholinesterase inhibitor. Under normal circumstances following tacrine the predominant effect of the elevated levels of acetylcholine will be activation of inhibitory presynaptic muscarine receptors on cholinergic nerves and an inhibition of evoked [3H]acetylcholine release. Under conditions where both presynaptic inhibitory muscarine and alpha 2-adrenoceptors are blocked, the elevated levels of acetylcholine produced by tacrine will lead to the activation of facilitatory presynaptic nicotine cholinoceptors on cholinergic nerves and an enhancement of evoked [3H]acetylcholine release.
 ...
PMID:Effect of nicotine and tacrine on acetylcholine release from rat cerebral cortical slices. 240 2


1 2 3 4 5 6 Next >>