Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease. 223 61

Loss of cholinergic function in the neocortex and hippocampus arising from death or atrophy of basal forebrain cholinergic neurons is a consistent feature of the Alzheimer brain at autopsy or biopsy. Replacement of lost cholinergic function, therefore, may be of therapeutic benefit to the Alzheimer's (AD) patients. This can be accomplished by enhancing endogenous levels of acetylcholine (ACh) through inhibition of its degradation by acetylcholinesterase on by directly mimicking its actions at postsynaptic muscarinic receptors. Initial efforts focused on inhibition of cholinesterase activity with tacrine (1,2,3,4-tetrahydroaminoacridine monochloride, CAS 1684-40-8, THA, Cognex). Tacrine is a mixed, reversible inhibitor of cholinesterase activity that binds near but not to the catalytically active serine in the active site of the enzyme. Through this action tacrine indirectly elevates ACh levels in the brains of animals and improves cognitive performance in rodents and monkeys. More importantly, tacrine has been shown to significantly improve several measures of cognitive performance in probable AD patients in well-controlled clinical trials, although not all patients respond to this agent. CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxyaldehyde-O-meth yl oxime, CAS 139886-04-7) is a non-subtype selective, partial muscarinic agonist that enhances cognitive performance and increases central cholinergic activity in rodents at doses below those required to increase peripheral cholinergic tone. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. Expected signs of mild to moderate peripheral cholinergic stimulation were noted at 0.5 to 1.0 mg doses (q 6 h).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cholinergic therapies for Alzheimer's disease. Palliative or disease altering? 776 38

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.
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PMID:[New therapeutic prospects in Alzheimer disease]. 857 Sep 45

Following the introduction of tacrine hydrochloride (Cognex) in the United States and several other countries, researchers are pursuing two broad therapeutic strategies for Alzheimer's disease (AD). The first involves identifying agents or combinations of agents whose actions can compensate for the considerable cerebral damage that has typically occurred by the time the diagnosis of AD is made. Such therapeutic approaches include the development of additional cholinesterase inhibitors, agents that work on the receptors of other systems damaged by the disease process, and anti-inflammatory and immunomodulatory agents. The second and ultimately more promising strategy involves the development of approaches to retard, halt, or even prevent disease progression. Such protective approaches, which depend on the development of more effective methods for predicting and diagnosing AD, include the administration of nerve growth factor and other neurotrophins and the use of pharmacologic or genetic interventions to limit amyloid deposition and the formation of neurofibrillary tangles.
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PMID:Treatment of Alzheimer's disease: future directions. 874 Oct

Tacrine [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA), Cognex] is a potent acetylcholinesterase inhibitor recently approved for treatment of mild-to-moderate Alzheimer's disease. The potential for THA and/or a metabolite of THA to accumulate in brain tissue was investigated by autoradiographic and metabolic profiling techniques in rats given single and multiple doses of [14C]THA. In addition, the brain-to-plasma distribution time course of orally administered 1-hydroxy-THA (1-OH-THA, 24 mg/kg), a primary rat metabolite with anticholinesterase activity, was also examined. Results from a 16 mg/kg single-dose study showed THA to cross the blood-brain barrier readily and concentrate in brain tissue, approximately 5-fold compared with plasma. The metabolite 1-OH-THA was found in much lower amounts relative to THA and when given separately at a similar dose the levels in brain tissue were comparable with plasma concentrations. After multiple-dose administration, THA concentrations in brain tissue were approximately 3-fold higher than those achieved after a single oral dose. However, concentration of 1-OH-THA metabolite increased only 50%. These data suggest a marked difference between the ability of THA and 1-OH-THA to accumulate in brain tissue and may reflect differences in lipophilicity as estimated by calculated log p values. The relevance of THA accumulation in brain tissue to delays observed in THA clinical management of Alzheimer's disease remains to be established.
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PMID:Distribution of tacrine and metabolites in rat brain and plasma after single- and multiple-dose regimens. Evidence for accumulation of tacrine in brain tissue. 878 77

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.
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PMID:Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. 965 Nov 38

Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer's disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short-term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron-dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9-aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1-hydroxy and 7-hydroxy tacrine metabolites, acridine hydrochloride and acridine 9-carboxylic acid, and the non-acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine-like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes.
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PMID:Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro. 998 75

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.
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PMID:In vivo PET study of cerebral [11C] methyl- tetrahydroaminoacridine distribution and kinetics in healthy human subjects. 1021 Sep 6

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.
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PMID:Huprine X is a novel high-affinity inhibitor of acetylcholinesterase that is of interest for treatment of Alzheimer's disease. 1064 52

A Treatment IND (TIND) is a mechanism available to the Food and Drug Administration (FDA) in the United States by which promising new drugs can be provided to patients with life-threatening illnesses. In many instances, the illness is life-threatening but of relatively low incidence, making the demand for the new treatment limited. However, if the disease is more prevalent and incidence is increasing, the demand for access to an experimental therapy may be substantially greater. Novel approaches and technologies would help manage recruitment of physicians, enrollment of patients and retrieval and timely analysis of data. Such was the case in the TIND for tacrine hydrochloride (Cognex), a cholinesterase inhibitor which was under development for the treatment of patients with Alzheimer's Disease (AD). There were an estimated 4 million prevalent cases of AD in the US for which no approved therapeutic option was available at the time this TIND was initiated. We anticipated that there could be a large demand by both physicians and patients to enroll in the TIND. Therefore, to meet this demand, various mechanisms were employed to allow rapid enrollment and drug shipments to the patient. In addition, physicians who participated in the TIND were able to use a telephone touch-tone data entry system for reporting data and ordering new supplies of tacrine for their patients. Serious adverse events were reported directly to trained operators and summarized on a weekly basis for reporting to the FDA. At the time the programme was terminated, nearly 2000 physicians had enrolled to participate in the TIND and nearly 10,000 patients had received tacrine under the programme. The methods employed in this study to collect clinic visit and safety data met both regulatory and good clinical practice guidelines. In summary, a large volume of data was handled rapidly and efficiently in this programme.
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PMID:Tacrine hydrochloride treatment IND: methods for rapid physician and patient enrollment and data retrieval. 1507 61


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