Biomedical subjects

Christopher Grantham

Publications and source records attributed to Christopher Grantham.

2 recordsLinked to original sources

PubMed2005

Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits.

Galantamine is a rather weak acetylcholinesterase (AChE) inhibitor, currently approved for the symptomatic treatment of Alzheimer's disease, with possible additional allosteric potentiating effects at the nicotinic ACh receptor (nAChR). Earlier data from in vitro biochemical tests suggest that donepezil is 40- to 500-fold more potent than galantamine in inhibiting AChE. In this study, both brain levels and Ki values for AChE inhibition for donepezil and galantamine in rat, mouse, and rabbit after subcutaneous application were determined. Clearance of galantamine from the brain is in general faster that donepezil and is faster in rabbits compared to rats and mice. The brain-to-plasma ratio for galantamine and donepezil, respectively, ranges from 1.2 to 1.5 in the rabbit, 3.3 to 5.2 in the mouse, and 6.6 to 13 in the rat. Galantamine doses between 1.5 and 5 mg/kg are appropriate to reach brain levels within the documented optimal allosteric potentiating ligand dose-response. Ki values of brain AChE inhibition for galantamine and donepezil, respectively, are 7.1 and 2.3 microg/g in rats, 8.3 and 0.65 microg/g for mice, and 19.1 and 1.3 microg/g in rabbits. The data also suggest that for a similar degree of brain AChE inhibition, 3-15 times higher galantamine than donepezil doses are needed.

Acetylcholinesterase↗

PubMed2005

Identifying modulators of hERG channel activity using the PatchXpress planar patch clamp.

The authors used the PatchXpress 7000A system to measure compound activity at the hERG channel using procedures that mimicked the "gold-standard" conventional whole-cell patch clamp. A set of 70 compounds, including hERG antagonists with potencies spanning 3 orders of magnitude, were tested on hERG302-HEK cells using protocols aimed at either identifying compound activity at a single concentration or obtaining compound potency from a cumulative concentration dependence paradigm. After exposure to compounds and subsequent washout of the wells to determine reversibility of the block, blockade by a reference compound served as a quality control. Electrical parameters and voltage dependence were similar to those obtained using a conventional whole-cell patch clamp. Rank order of compound potency was also comparable to that determined by conventional methods. One exception was flunarizine, a particularly lipophilic compound. The PatchXpress accurately identified the activity of 29 moderately potent antagonists, which only weakly displace radiolabeled astemizole and are false negatives in the binding assay. Finally, no false hits were observed from a collection of relatively inactive compounds. High-quality data acquisition by PatchXpress should help accelerate secondary screening for ion channel modulators and the drug discovery process.

Cell Line↗