In vitro effects of various cholinesterase inhibitors on acetyl- and butyrylcholinesterase of healthy volunteers

Thomsen, T.; Zendeh, B.; Fischer, J.P.; Kewitz, H.

doi:10.1016/0006-2952(91)90022-w

Cited by 75 publications

(35 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The esterase inhibitors iso-OMPA, BNPP, PMSF, and paraoxon (Thomsen et al, 1991;Madhu et al, 1997;Kraut et al, 2000) inhibited the conversion of dabigatran etexilate to BIBR 1087 SE and of BIBR 1087 SE to dabigatran. By contrast, the esterase inhibitor PCMB had no effect on the hydrolysis of dabigatran etexilate.…”

Section: Downloaded Frommentioning

confidence: 99%

The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans

Blech¹,

Ebner²,

et al. 2007

View full text Add to dashboard Cite

ABSTRACT:The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran ( Antithrombotic therapy plays an important role in the prevention and treatment of thromboembolic disorders. However, currently available agents are subject to certain limitations. Oral vitamin K antagonists, such as warfarin, have unpredictable pharmacokinetics and show numerous drug and food interactions (Ansell et al., 2004), whereas unfractionated and low molecular weight heparins and fondaparinux require parenteral administration. An orally active direct thrombin inhibitor would offer a number of potential advantages over these agents (Weitz and Bates, 2005).Dabigatran is a reversible, competitive, direct thrombin inhibitor that has been shown to be an effective antithrombotic agent in animal models (Stassen et al., 2001; Wienen et al., 2001a,b) and to be efficacious and safe in the prevention of deep vein thrombosis in patients undergoing elective total hip or knee replacement (Eriksson et al., 2005). Dabigatran etexilate is currently in Phase III development for primary prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery, acute VTE treatment, and VTE secondary prevention, as well as stroke prevention in patients with atrial fibrillation. Pharmacokinetic studies in healthy volunteers and orthopedic surgery patients showed that dose-dependent concentrations of dabigatran are achieved after p.o. administration of dabigatran etexilate, with peak concentrations reached after approximately 2 h and with a slight delay up to 6 h on the day of surgery (Eriksson et al., 2004(Eriksson et al., , 2005Stangier et al., 2005).This article describes a series of in vivo and in vitro studies performed to investigate the pharmacokinetics and metabolism of dabigatran in humans. ABBREVIATIONS: Dabigatran, -alanine, N-[[2-[[[4-[[[(hexyloxy) Materials and Methods Reference

show abstract

Section: Downloaded Frommentioning

confidence: 99%

The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans

Blech¹,

Ebner²,

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Galantamine has a 53-fold greater inhibitory activity in vitro for AChE than for butyrylcholinesterase (BChE) (IC 50 values were 0.35 and 18.6 ìmol/L, respectively) (56,58,59). In healthy volunteers, median maximal Red Blood Cell AChE inhibition by galantamine is about 40% at thirty minutes after a single oral dose (10 mg) (5).…”

Section: Ache Inhibitionmentioning

confidence: 99%

Galantamine — a Novel Cholinergic Drug with a Unique Dual Mode of Action for the Treatment of Patients with Alzheimer's Disease

2002

View full text Add to dashboard Cite

Galantamine hydrobromide is a tertiary alkaloid drug that has been developed and approved in a number of countries including the USA and several countries in Europe as a treatment for mild-to-moderate Alzheimer's disease (AD). Galantamine has a unique, dual mode of action. It is a reversible, competitive inhibitor of acetylcholinesterase (AChE), and is the only drug actively marketed for the treatment of AD with proven activity as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs). This latter activity is thought to be particularly important since decreases in the expression and activity of nAChRs make a large contribution to the reduction in central cholinergic neurotransmission in patients with AD. Galantamine exhibits favorable pharmacokinetic characteristics including predictable linear elimination kinetics at the recommended maintenance doses (16 and 24 mg/day), a relatively short half-life (approximately 7 h) and high bioavailability. It is extensively metabolized in numerous pathways, mainly in the liver via cytochrome P450 enzymes CYP2D6 and CYP3A4, and has a low potential for clinically significant drug-drug interactions. During four large randomized, double-blind, placebocontrolled trials of up to 6 months duration, galantamine 16 and 24 mg/day significantly benefited cognitive and global function, ability to perform activities of daily living (ADL) and behavior, relative to placebo and baseline, for up to 6 months. Caregiver burden (time spent by caregivers supervising patients or assisting them with ADL), and caregiver distress (related to patients' behavioral symptoms) were also reduced. Cognitive and functional abilities were preserved at or near baseline for at least 12 months in patients who re- 159CNS Drug Reviews Vol. 8, No.2, pp. 159-176 © 2002 Neva Press, Branford, Connecticut Address correspondence and reprint requests to: Sean Lilienfeld, MBBCh, FCP(SA), MMed(Neuro), Janssen Pharmaceutica Inc, Janssen Research Foundation, Div of Janssen Pharmaceutica Ltd, 1125 Trenton Harbourton Road, Titusville NJ 08560. Tel.: +1 (609) 730-3414; Fax: +1 (609) 730-2441; E-mail: slilien1@janus.jnj.com ceived galantamine 24 mg/day for 12 months in a long-term US study. These benefits were maximized by early and continued galantamine treatment and, again, were associated with significant reductions in caregiver burden. Trials of the efficacy of galantamine in dementia related to cerebrovascular disease have also yielded positive results. There are no safety concerns associated with the use of galantamine. The incidence of adverse events, particularly cholinergically mediated events affecting the gastrointestinal system, is generally low and can be minimized using the recommended slow dose-escalation scheme. Galantamine may, therefore, help to reduce the overall burden and cost involved in caring for dementia patients. Taking all evidence into account, galantamine has the potential to become a first-line therapy for dementia.

show abstract

“…However, Manumycins show much less inhibiton of BuChE than Tacrine, indicative of the better specificity of Manumycins toward AChE. Tacrine [16], the first approved drug for Alzheimer's disease, is able to significantly improve the cognitive function in Alzheimer's patients, but also causes hepatotoxic side effects due to inhibition of butyrylcholinesterase (BuChE) [17,18]. For this reason the search for selective inhibitors of AChE has attracted a lot of attention in recent years.…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain

Zheng¹,

Dong²,

Zhang³

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

A high throughput screening was carried out in order to search for inhibitors of acetylcholinesterase (AChE) from microorganism metabolites. An actinomycete strain was found to produce active compounds named N98-1272 A, B and C with IC 50 of 15.0, 11.5, 12.5 mM, respectively. Structural studies revealed that the three compounds are identical to the known antibiotics, Manumycin C, B and A. Kinetic analyses showed that N98-1272 C (Manumycin A) acted as a reversible noncompetitive inhibitor of acetylcholinesterase, with a Ki value of 7.2 mM. The cyclohexenone epoxide part of the structure plays a crucial role in the inhibitory activity against AChE. Compared with Tacrine, N98-1272 A, B, and C exhibit much better selectivity toward AChE over BuChE.

show abstract

In vitro effects of various cholinesterase inhibitors on acetyl- and butyrylcholinesterase of healthy volunteers

Cited by 75 publications

References 10 publications

The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans

The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans

Galantamine — a Novel Cholinergic Drug with a Unique Dual Mode of Action for the Treatment of Patients with Alzheimer's Disease

Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain

Contact Info

Product

Resources

About