No abstract

Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a >50‐fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time‐dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10‐fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half‐lives of 8.5 and 12.6 min, respectively. In contrast, a high (>70%) and long‐lasting inhibition of AChE was achieved (half‐life >8.25 h). A comparison between the time‐dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely‐moving phenserine‐treated rats demonstrated >3‐fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long‐lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half‐life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly.

No abstract

Arecoline, a cholinergic agonist, administered at low doses by continuous intravenous infusion for up to 2 weeks, significantly and replicably improved memory in five of nine subjects with mild-moderate Alzheimer's disease. During dose finding, performance on a verbal memory task improved with an inverted U-shaped relation to dose. Six of nine subjects were classified as responders. During blinded, placebo-controlled, individualized optimal dosing for 5 days, verbal memory again improved in five of six responders but not in any non-responder. No adverse drug effects occurred. Arecoline, and possibly other cholinergic agonists, can safely improve memory in Alzheimer's disease at doses much lower than previously studied.

Column chromatography of easy available (f)-physovenine (2) on cellulose triacetate afforded (-)-and (+)-physovenine (2a and 2b, resp.). Alkaloids 2a, h required for pharmacological testing were prepared from eserolines (3a, b) by an improved procedure. Natural (-)-physovenine (2a) was equally potent in inhibiting AChE and RChE in uitro as natural physostigmine (la), and twice as potent as the unnatural antipode 2b against AChE and 14 times as potent against BChE. Several carbarnate analogs of 2a were at least as potent as the former compound in these assays. None of the compounds tested did bind to different opiate receptor or serotonine receptor preparations. Most of the compounds tested had considerable analgesic activity in the Writhing test.In search of centrally acting agents potentially useful for treating cholinergic disorders, particularly those manifested by Alzheimer's disease, we have embarked on a re-evaluation of the alkaloids from the seeds of Physostigma venenosum [la-]. Two of the alkaloids, (-)-physostigmine (la; see Scheme) and (-)-physovenine (2a), were reported to have potent anti-acetylcholinesterase (AChE) activity when assayed in vitro, measuring inhibition of AChE obtained from human erythrocytes [2], and l a is medically used to reduce intraocular tension in glaucoma, in the treatment of intestinal atony, and in the treatment of urinary retention [3]. Modification of the carbarnate group and of the Me-N(l) group in l a has afforded several potent analogs [4] [5]. We now have extended this research to another study of the lesser known (-)-physovenine (2a) and some of its carbarnate-ester analogs and of the unnatural enantiomer (+)-physovenine (2b). Natural 2a was isolated from the basic extracts of Physostigma venenosum in 1911 [6] and its structure proposed on the basis of spectral data [7] and proven to be correct by a total synthesis of racemate 2 [8]. The (3aS)-configuration of 2a and the (3aR)-configuration of antipode 2b was elaborated by their enantiospecific synthesis from (-)-physiostigmine (la) [9] and (+)-physiostigmine (la), respectively [2].

The time course and distribution of alterations in cerebral metabolic activity after haloperidol administration were evaluated in relation to the pharmacokinetics of haloperidol and the topography of the dopaminergic system in the brain. Local cerebral glucose utilization was measured, using the 2-deoxyglucose technique, in awake rats after i.p. administration of the dopamine antagonist haloperidol (0.5 or 1 mg/kg). Haloperidol significantly reduced glucose utilization in 60% of 59 brain regions examined, but produced a large increase in the lateral habenula. The regional distribution of changes in glucose utilization was not closely related to the known anatomy of the brain dopaminergic system. The time course of the effect of haloperidol on cerebral metabolism was different for the two doses studied (0.5 and 1 mg/kg), and was not simply related to estimated brain concentrations of haloperidol. However, a linear relation between the metabolic effect and the time-integrated brain concentration was demonstrated. These results show that haloperidol has an effect on CNS metabolic activity that is more widespread than would be predicted from the topography of the dopaminergic system; this may be due to indirect propagation of the primary effects of haloperidol. The metabolic response to haloperidol depends on brain concentration and duration of exposure to the drug.

These results showed that, in cognitive responders, memory enhancement by physostigmine in Alzheimer's disease is correlated directly to the magnitude of plasma cholinesterase inhibition. Furthermore, during single-dose conditions, the dynamic half-life is five-fold longer than the kinetic half-life.

Unidirectional blood-brain barrier transfer of the lipophilic anticancer agents vincristine and vinblastine was studied in anesthetized rats, using an isolated, in situ brain perfusion technique. Drug binding to plasma constituents was also measured. Despite the high lipophilicity of these agents (the log octanol/physiological saline partition coefficient equalled 2.14 and 1.68, respectively), the cerebrovascular permeability-surface area product, PA, of vincristine in plasma was only 0.49 x 10(-4) ml s-1 g-1 for parietal cerebral cortex, whereas that of vinblastine was too low for determination. These values are similar to those of water-soluble, poorly diffusible nonelectrolytes. The PAs were significantly higher in the absence of plasma protein, being 1.24 x 10(-4) and 5.36 x 10(-4) ml s-1 g-1, respectively. Even these values, determined by brain perfusion of protein-free buffer, were lower than would be expected from the lipophilicity of the agents. The results suggest that additional factors, such as steric hindrance and molecular charge distribution, related to the chemical and geometric structure and the large size of vincristine and vinblastine (molecular weight, 825 and 814 daltons, respectively) restrict their passage across the blood-brain barrier. As a consequence of their paradoxically low permeability at the blood-brain barrier and restrictive binding to plasma and blood constituents, doses of both agents that cause significant inhibition of extracerebral Walker 256 carcinosarcoma tumor implants in rat have no effect on tumor located in the brain.