Anna Galkin

Inhibition of acetylcholinesterase by coumarins: The case of coumarin 106

In this contribution, from a coumarin library consisting of 29 compounds including natural and synthetic derivatives, an active acetylcholinesterase (AChE) inhibitor (coumarin 106) was found. This circumstance leaded us to continue with the pharmacological characterization of coumarin 106. The first study with the coumarin library was performed using a 96-microtiter well plate assay based on Ellmans reaction. Coumarins were assayed at 5 and 30 microM, and coumarin 106 was found the most active inhibitor at both concentrations. The follow-up analysis using kinetic studies demonstrated that coumarin 106 displays mixed-type AChE inhibition with a pIC(50)=4.97+/-0.09 and K(i)=2.36+/-0.17 microM. The ability of this molecule to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, while a secondary binding was demonstrated at the peripheral anionic site. Also, coumarin 106 was shown to inhibit butyrylcholinesterase (BChE) with slightly lower potency (pIC(50)=4.56+/-0.06), and found to be non-toxic in Caco-2 cells. The combination of these findings makes coumarin 106 an attractive molecule for further investigation. This is the first report where AChE inhibitory activity has been associated with coumarin 106, and proof has been given of its convenience as a lead molecule.

Effects of extracts of commonly consumed food supplements and food fractions on the permeability of drugs across Caco-2 cell monolayers.

AbstractPurpose. Extracts made from berries, herbs, and various plant materials, which might possess a range of activities, are used as health promoting products. Because little is known about their effects on the absorption of co-administered drugs, the effects of some food supplements, Finnish berries, and herbs were studied on the permeability of some commonly used drugs. Methods. The permeabilities of verapamil, metoprolol, ketoprofen, paracetamol, and furosemide were studied across Caco-2 cell monolayers with contemporaneously administered extracts from flax seed, purple loosestrife, and Scots pine bark; bilberries, cowberries, and raspberries; oregano, rosemary, and sage. Toxicological tests were conducted to determine cellular damage. Results. The effects of extracts on drug permeabilities were generally minor. Flax seed decreased the permeability of all drugs except verapamil. Purple loosestrife and pine decreased verapamil and metoprolol permeability. Changes caused by berries were mainly pH-related. Rosemary and oregano enhanced furosemide permeability. Conclusions. Ingestion of extracts of herbs and berries studied are not expected to markedly change the permeabilities of highly permeable drugs. Harmful effects at sites of or during absorption are unlikely. However, if high doses of extracts are administered with low permeable drugs in vitro,effects on drug permeabilities could not be excluded. Use of such extracts should therefore be evaluated during continuous medication.

Coumarins permeability in Caco-2 cell model

Objectives The presence of coumarins in human diet, their multiple pharma***ćological properties and occurrence in various herbal remedies represent significant reasons to explore their membrane permeability, as a first event contributing to coumarins oral bioavailability. Thus, we evaluated the permeability and cytotoxicity of 18 coumarins, with different substitution patterns involving OH, OCH3 and CH3 groups.

In-vitro mutagenic potential and effect on permeability of co-administered drugs across Caco-2 cell monolayers of Rubus idaeus and its fortified fractions

This study investigated the mutagenic, anti‐mutagenic and cytotoxic effects of acetone extract of raspberry, Rubus idaeus L. (v. Ottawa) Rosaceae, and the isolated and characterized ellagitannin and anthocyanin fractions thereof, suitable for food applications. The studied raspberry extract and fractions did not show any mutagenic effects determined in the miniaturized Ames test and were not cytotoxic to Caco‐2 cells at the used concentrations. However, the anti‐mutagenic properties were changed (i.e. decreased mutagenicity of 2‐nitrofluorene in strain TA98, and slightly increased mutagenicity of 2‐aminoanthracene in strain TA100) with metabolic activation. Further, their influence on the permeability of co‐administered common drugs (ketoprofen, paracetamol, metoprolol and verapamil) across Caco‐2 monolayers was evaluated. The apical‐to‐basolateral permeability of highly permeable verapamil was mostly affected (decreased) during co‐administration of the raspberry extract or the ellagitannin fraction. Ketoprofen permeability was decreased by the ellagitannin fraction. Consumption of food rich in phytochemicals, as demonstrated here with chemically characterized raspberry extract and fractions, with well‐absorbing drugs would seem to affect the permeability of some of these drugs depending on the components. Thus their effects on the absorption of drugs in‐vivo cannot be excluded.