Preclinical Investigation of the Topical Administration of Phenserine: Transdermal Flux, Cholinesterase Inhibition, and Cognitive Efficacy

Abstract

Phenserine (PS) was designed as a selective acetylcholinesterase (AChE) inhibitor, with a tartrate form (PST) for oral administration in mild to moderate Alzheimer's disease (AD). Recent phase 3 trials of PST in Europe indicate that any clinically relevant activity of PST may be limited by its duration of action. Like many oral drugs, bioavailability and plasma concentrations of PST are regulated by hepatic and gastrointestinal first-pass effects. To minimize the kinetic limitations of first-pass metabolism, transdermal formulations of PS and PST (ointment/ patch) were developed and characterized in vitro and in vivo. Initial in vitro kinetic characterization of PS or PST formulations used a diffusion cell chamber and skin samples isolated from hairless mice. Liquid paraffin and fatty alcohol/propylene glycol (FAPG) were found to be suitable vehicles for ointment formulation. Addition of a penetration enhancer, 1-[2-(decylthio)ethyl]-azacyclopentane-2-one (HPE-101), improved stratum corneum permeability. Application of the optimal formulation of PS/HPE-101/FAPG to the shaved back of rats resulted in significantly lowered plasma and brain AChE activities and improved cognitive performance in animals with scopolamine-induced cognitive impairment. These results suggest that the transdermal application of AChE inhibitors may represent an effective therapeutic strategy for AD. Particular benefits over oral therapies might include avoiding first-pass metabolic effects and improved dosing compliance.

The alpha-synuclein 5′untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

“…In this scenario, SNCA 5′UTR inhibitors would be predicted to leave β - and γ -synuclein unchanged, and such an action could prove of value for a proposed drug as these proteins appear to compensate for diminished or absent SNCA expression in vivo (Dauer et al 2002). Although we characterized (−)-phenserine and Posiphen as SNCA 5′UTR directed leads, based on their known ability to lower translation of APP through related 5′UTR sequences (Shaw et al 2001; Lahiri et al 2007a, b; Utsuki et al 2007), we nevertheless co-screened for actions on APP translation to further define selectivity. From a clinical perspective, however, compounds that lack significant differential action between SNCA and APP could retain great value, as there remains significant overlap between PD and Alzheimer’s disease beyond DLB (Strobel 2009).…”

Development and Characterization of Plant Oil-Based Potent Anticholinesterase Microemulsion Containing Withania Somnifera Extract With Enhanced Transdermal Delivery of Phytoconstituents for the Treatment of Cognitive Disorders

“…These side effect can be overcome by the administration of drug through transdermal route. Transdermal drug delivery system has several advantages over conventional oral administration, including controlled drug delivery while maintaining steady drug concentration [8], bypasses the first pass metabolism [9]., useful for elderly patients who have difficulty in swallowing.…”

A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimer’s Disease

“…Delivering a drug through the skin directly into the bloodstream avoids first-pass effects, therefore reducing rates of nausea and vomiting. 9 10 Compared with oral formulations, transdermal patch formulations can reduce the maximum systemic drug concentration by decreasing the absorption rate, which decreases the necessary dosing frequency; this lower frequency leads to improved treatment compliance. Indeed, this administration route is particularly useful in patients with chronic neurological disorders because it can circumvent their unwillingness or inability to swallow; it also avoids the need for intramuscular injections or intravenous infusions.…”