Sl26 THIRD INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE

dkposltlon half-life WCIS long. averaglng >70 hrs. There “OS no evidence of nonllr~rlty in drug dispositin. Inhlbil!on of rbc AChE WCIS posltlvely correlated with plavna E2020 concentration% while plasma ChE was not InhIbIted. thus conflrrnlng ihat E2020 Ls speclflc for AChE. The results from ttm single dose investigation were confirmed during the multlpledose study. Inhibition of AChE correlated extremely well with plasma concentrations of E2020. Slgnlncant lnhlbltlon of AChE was achieved by bott- me 3 mgldoy and 5 mg/day regimens. Average percent lnhibltion at steady-state Cma for E2020 was 37% f 22.3% and 65% f 9.6% for each dose, respectively. Concurrent plasma E2020 concentrations were 18.2 * 1 .l and 30.2 * 1.0 nglml for n-m 3 mg/- and 5 mg/day doses. Based upon the safety. PK and PD data from these studies. lnltlol Phase II testina of E2020 has been Iniiiated FOI Phase II, PK and PD anoiy%s will be linked to b& safetv and efHcacy measures in order to further delln%Ite the prOpWtk?S Of E2020 CIS they r&t63 t0 the tW&nent Of Alzhelmer’s Disease

497 NEUROPHARMACOLOGICAL PROFILE OF SR46559A, A MUSCARINIC AGONIST DEVOID OF CHOLINERGIC SYMPTOMATOLOGY. J.P. Kan. M. Heaulme. J.C. Michaud. D. Olliiro. R. Boigegraln and P. Soubri6. Sunofi Recherche. rue Pr J. Blayac, 34082 Montpelller, France. Numerous studies support the involvement of Central cholinergic SyStemS in learning and memory. In addition. a dramatic loss of presynaptic cholinergic markers has been reported In brains of patients suffering from Ahheimets disease (AD). Consequently, enhancing chollnergic function has oppeared as the main approach to Improve cognaive deflclts seen in AD. However. clinical trials with acetylcholinesterase (AChEI Inhibitors and muscarinic agonists have led to Inconclusive resuns, portly due to incidence of cholinergic side-effects and toxicity. This problem could be circumvented by the discovery of selective muscarinic Ml receptor agonists. The cholinergic activities of SR 46559A. 3-(N-(2- diethyCamin~2-methylpropyD_bphenyl-5prop~~py~d~inomine have been in- vestigated In vitro and in viva, in rodents. Using rat brain cortical membranes. SR 46559A was a competitive ligond (Ki 112 nM) at muscarinic Ml receptors, its affWy for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6 - 7 times lower. SR 46559A did not interact with brain nicotinic receptors, high affinity choline uptake sites and AChE. Up to 1 mM, SR 46559A. slightly and inconsistently stimulated inositol phospholipids breakdown ond did not inhibit the forskolin-induced activation of odenylyl cyclase activity. However, like muscorinic agonists, SR 46559A inhlbiied (K&-J # 10 vM) the K+-evoked release

of c3HlGABA from rat striotal slices and reduced at 0.5 and 1 PM. the populdion spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffets collateral commissuml pathway in rat hippocompal slices. In mice, up to sublethal doses, SR 46559A did not induce the typic01 cholinergic syndrom. Like muscaiinic agonists. SR 46559A (0.1 mg/kg F0 potentiated haloperidol-Induced catalepsy in rats and antagonized (ED% = 0.12 mg/kg PO) rotations induced in mice by lntrastriatal injectlon of pirenzepine. SR46559A ontagonhed the scopolamine- or pirenzepine-induced deficit in passive avoldance learning. (ED= = 0.25 and 0.027 mg/kg PO, respectively). Moreover. using the social memory test, SR 46559A (0.1 3 mg/kg PO) enhanced short-term retention In adult rats and improved memory deficits observed in aged mice and in rats subjected to cerebral ischemic insult SR 46559A (1 - 3 mg/kg PO) also reversed the ischemia-induced alterations of rot’s exploratory behaviour. These results suggest that SR 46559A behaves as o partial Ml muscorinic agonist with marked ability to improve experimentally Induced cognitive deficits In rodents wlthout producing chollnergic symptomatdogy. Thus SR 46559A could be a potentiol useful drug for the symptomatic treatment of AD.

498 DOES CHRONIC ORAL PHYSOSTIGMINE ALTER THE COURSE OF AL?HEIMER’S DISEASE? P. Stony. L. Harrell. L. Duke, R. Callaway and D. Marson. Depts. Neurology and Psychology. Unhrersity of Alabama and VA Medical Center. Birmingham, Alabama, USA. There has been renewed interest ln the use of chollnesterase inhibIton for the symptomatic treatment of Alzhekner’s disease (AD). Although early studies questioned the effectiveness of this therapy. more recent investigations have demonstrated short-term benefit In some AD patients. Moreover. some studies have suggested long-term ben& ln that disease pmgresslon has been reported to be slowed. these latter studies. however, suffer from small patient number (usus& <IO) and lack of controls. We sought to m-address this issue by lnvestlgating the &e&s of physosttgmine on neumpsychol~al test performance in a larger number of AD patients and comparing this to a non-treated group of AD patients. ~enty-seven probable AD patients (NINCDS-ADRDA crIterIaI entering an outpatient trial of oral chronic physostlgmine underwent dose finding. double-blind cmssover. followed by chronic therapy with the highest tolerated dose (13.2 mg/dayl. Baseline and yearly neuropsychologlcal assessment was performed with the following battery: Mattls Dementia Rating Scale; Intellteence IWAIS-subscale. Peabodv Picture Vocabularvl: Attention and Conce&ation (Wechsler Memory-R attention subsca&; Trails A. B);

Language (Boston Naming. Controlled Oral Fluencyl; Perception (Benton Visual Form Discrimination. Tactlle Form Recognition): Motor IFlnger Tappfng. Grooved Pegs): Memory (Wechsler Memory-R; Selective Reminding. Control probable AD (NINCDS-ADRD@ patients (n= 16) were matched to the treated group on age. sex. and baselIne neumpsychological performance. Eight of these patients were orIgInally entered into the physostigmine trial, but withdrew due to side effects within the first four months. The remainder chose not to participate usually due to loability to make frequent cllnlc visits. The results. analyslzed by multivariate followed by unlvariate statlstlcs. revealed that at one year those patients treated with physostigmine were slgnlflcantly better on some Mattls subscales. intelligence. attention. language. motor function and memory clusters (pc.05) than non-treated patients. Moreover, when treated patients were clIvided into responders and non-responders (see Neurology 4Ozl990. 1350). responders were found to perform better on some but not all of these variables. Prelhnlnary analysis of the small subset of patients that have returned for follow-up at year 2 and 3 stffl revealed Improved memory function in the treated compared to the non-treated group. These results suggest that physostlgmine may 1) have a more global beneficial effect on cognition than previously idenUDed and 2) may alter the progression of AD at least during the first year of therapy.

499 THE EFFECTS OF ALPHA-GLYCERYLPHOSPHORYLCHOLINE ADMINISTRATION ON THE GH SECRETION OF ELDERLY SUBJECTS AND OF PATIENTS AFFECTED BY SENILE DEMENTIA OF THE ALZHEIMER TYPE , G.P. Ceda , G.P. Marzani , E. Piovani , L. Denti , A. Banchini, E. Tarditi , F. Baggi , L. Marchini and G. Valenti. Cattedra di Gerontologia e Geriatria , University of Parma ,43 100 Parma , Italy.

GH secretion is blunted during aging in rodents and humans. Central cholinergic stimuli increase the secretion of GH from the pituitary: drugs like the cholinesterase inhibitor pyridostigmine induce GH release, potentiate the stimulatory effect of GHRH and restore the GH response after intermittent GHRH administration.These actions may be mediated by a decrease of somatostatin release. Since brain acetylcholine (Ach) synthesis declines with aging and in dementia, it may be possible to restore normal GH secretion by enhancing cholinergic tone. The putative Ach precursor, alpha- glycerylphosphorylcholine (alpha-GFC), has been used for the treatment of amnestic and cognitive disorders of aging. In order to learn what effect alpha- GFC had on GH secretion , GHRH was given to young and old human volunteers and to a group of patients affected by SDAT. 8 young (aged 32+1.9), 7 old subjects (aged 80+2 y) and 5 patients affected by SDAT (aged 79+2.1 y) were studied on separate days with I) a bolus injection of 50 pg GHRH (Geref, Serono) with blood samples taken at -15 and 0 min and at 15,30,45,60 and 90 min after the injection, and 2) a 30 min infusion of alpha- GFC (Brezal , Sandoz) (Ig in 100 ml saline) followed by a GHRH bolus injection and samples obtained at the same times. The results showed that GH responses to GHRH were greater in the younger than in the older subjects and both groups had a greater GH response to the GHRH+alpha-GFC stimulation than to GHRH alone. However the potentiating effect of alpha-GFC was more pronounced in the elderly subjects. In patients affected by SDAT both GHRH and GHRH+alpha-GFC induced GH responses similar to that observed in the elderly normal subjects. These findings confirm the observation that 1) aged individuals respond less well to GHRH than younger subjects , 2) the pituitary responsiveness to GHRH in patients affected by SDAT is similar to that of normal subjects of comparable age , and document that 3) the enhancing effects of alpha-GFC is greater in normal elderly subjects. These results provide further evidence that increased choline@ tone enhances GH release.

500

PHOSPEATIDpLsgPIQI 111 TIIB =l?lgl!T OF COCKITIVE DKCLIW OF XLDKRLY PATIEICTS ‘Bertoldin T., 2Farina C.,3Cenacchi T.,‘Cre- paldi G.,lInstitute of Internal Medicine, University of pado- va,21%ird Division of Geriatrics, Geriatric Hospital, Padova,

3Fidia Research Laborstories, Abano Terme, Italy. Phosphatfdylserine, a pharmacologically active phospholipid, has been shown to enhance the activities of membrane-bound en- zymes involved in neurotransmitter release and signal trans- duction in the CBS. Clinical trials with phosphatidylserine have reported positi_ ve effects on the Cognitive impairment and behavioral distur- bances in elderly patients with mild to severe cognitive de_ cline due to various etiologies, including Alzheimer’s disea-