Phenserine (also known as (-)-phenserine or (-)-eseroline phenylcarbamate) is a synthetic drug that has been investigated as a potential treatment for Alzheimer's disease (AD). The compound exhibits both neuroprotective and neurotrophic effects. The development of phenserine, initially patented by the National Institute on Aging (NIA), was suspended following phase III clinical trials conducted in 2006, shortly after licensing agreements were issued. Because the clinical trials were not completed, the FDA did not approve the drug. A retrospective meta-analysis of phenserine research suggested that its clinical invalidation arose from unresolved methodological issues that were not adequately addressed prior to progression into later-phase trials. Phenserine was initially developed as an acetylcholinesterase (AChE) inhibitor and demonstrated significant amelioration of several neuropathological features, alongside improvements in cognitive functions. Its therapeutic effects involve both cholinergic and non-cholinergic mechanisms. Clinically translatable doses of phenserine have demonstrated relatively high tolerability and rarely produce severe adverse effects. At supratherapeutic doses (approximately 20 mg/kg), a limited number of cholinergic adverse effects—such as nausea and tremor—have been reported; these effects are not considered life-threatening. One formulation of phenserine, (-)-phenserine tartrate, exhibits high bioavailability and solubility and is administered orally. Phenserine and its metabolites readily penetrate the brain due to high blood–brain barrier permeability and exhibit sustained pharmacological activity despite a relatively short plasma half-life. Posiphen ((+)-phenserine), the enantiomer of (-)-phenserine, has also been investigated as a potential therapeutic agent, either alone or in combination with (-)-phenserine, for slowing the progression of neurological diseases, particularly Alzheimer's disease.
History Phenserine was first investigated as a substitute for physostigmine which failed to satisfy the clinical standards for treating Alzheimer's disease, and developed into more compatible remedy. It was initially invented by Nigel Greig whose laboratory is affiliated with the National Institute on Aging (NIA) under the US National Institutes of Health (NIH) which subsequently released a patent of phenserine as an AChE inhibitor in 1995. During phase I in 2000, the supplementary patent regarding its inhibitory mechanism upon β-amyloid precursor protein (APP) synthesis was added. Following 6 years of phase I and II trials, Axonyx Corporation had licensed phenserine to Daewoong Pharmaceutical and QR Pharma (later adopted new corporation name, Annovis Bio) companies in 2006, which then planned to undertake phase III trial and merchandize the drug. However, the clinical deficits ̶ representatively from a double-blinded, placebo-controlled and 7-month phase III trial which had been conducted on 377 mild to moderate Alzheimer's disease patients across Austria, Croatia, Spain, and UK ̶ were discovered and no significance was exhibited for the drug efficacy. This led to the relinquishment of phenserine development, merely displaying its marketable potential.
Approval status Phenserine failed in phase III of Alzheimer's disease-aimed clinical trials and there has yet been no promise of the trial resumption since 2006. The methodological problems of trials are frequently speculated as the principal reason for the failure of FDA approval as well as the scarcity of Alzheimer's disease drugs. The underlying complications are generated by an inordinate variance in clinical outcomes and poor determination in optimal dosing. Intra and inter-site variations were incurred by a lack of baseline evaluation and longitudinal assessment on placebo groups. This produced an inadequate power and, thus, appeared to have insufficient statistical significance. In light of the dose determination, the criteria for human subject engagement was not meticulously established before dosing and the effective dose range was not completely established in phase I and II, yet still persisting to phase III. Compared to other Alzheimer's disease drugs, such as donepenzil, tacrine and metrifonate, the clinical advancement of phenserine involves comparably high compliance in outcome measures and protocol regimentation on methods and the clinical phase transition.
Dosage Clinically, the translatable dose of phenserine was primarily employed within a range of 1 to 5 mg/kg where the unit calibration took account of the body surface area. This standard dose range was generally well tolerated in long term trials by neuronal cell cultures, animal models and humans. Increment in dosing by 10 mg/kg is still tolerated without instigating any physiological implication. The maximal administration of phenserine up to 15 mg/kg was reported in rats.
Overdose The dose of 20 mg/kg and above are appraised as overdosing in which cholinergic adverse effects ensue. The symptoms of overdosing includes:
Nausea Vomiting Dizziness Tremors Bradycardia Mild symptoms were notified in clinical trials but no other seriously considerable adverse effects were expressed. Tremor was also noted as one of the dose-limiting actions.
Interactions Currently, 282 drugs have been reported to make interactions with phenserine.
Pharmacology
Pharmacokinetics Oral bioavailability of phenserine was shown to be very high, up to 100%. Its bioavailability was tested by computing the drug's delivery rate across the rat's blood brain barrier. The drug concentration, reached in the brain, is 10-fold higher than plasma levels, verifying phenserine as a brain-permeable AChE inhibitor. Relative to its short plasma half-life of 8 to 12 minutes, phenserine exhibits a long duration of action with the half-life of 8.25 hours in which the hindering effect on AChE is time-dependently faded. With the administration of phenserine, 70% or higher AChE inhibitory action in the blood was observed in preclinical studies and with systemic phenserine administration, the extracellular ACh level in the striatum increased up to three times. Through PET studies and microdialysis, the compound's brain permeability was able to be further elucidated.
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