Long term rivastigmine treatment produces persistent inhibition of acetyl- and butyrylcholinesterase activity in CSF of Alzheimer's patients

Poster Presentation:

Drug Studies II

S243

with mild-to-moderate AD. One study was conducted in the US (SAB-USA-25) and the other was conducted in Europe and Canada (SAB-INT-12). Both studies had similar vistt schedules while sabeluzole dosing differed between the studies. The Altheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) was used to assess cognitive function and the Disability Assessment for Dementia (DAD) scale was used to assess patients’ ADL. Results: Baseline ADAS-cog and DAD scores of the treatment groups in both studies were comparable. In both studies. there were no significant differences in change from baseline scores between placebo and wbeluaole groups for either the ADAS-cog or DAD at 12 months. The mean (SD) deterioration on the ADAS-cog for placebo-treated subjects was 6.3 (7.2) in SAB-USA-25 and 4.8 (7.2) for SAB-INT-12. On the DAD, placebo-treated subject5 declined by a mean (SD) change score of 13.1 (17.3) in SAB-USA-25 and Il.5 (18.6) (SAB-INT-12) at 12 months. Conclusions: These results indicate that there are coGstent rates of decline on hoth cognitive and tunctional instruments over 12 month& in the placeho arms of AD clinical trials. Attenuating the rates of cognitive and functional decline are likely to be clinically important in the long-term treatment of AlTheimer’\ diwxse

EFFECT OF (-)CLAUSENAMIDE ORY AND APOPTOSIS

piiq .Jw-Tim

Zhnng,

Nntionnl

Institute

Zhoo,

Institute

Inst

ON IMPAIRMENT

of Muleriu Medical. Beijing People’s

on Aging,

of Mutrriu

Baltimore. Medical,

MD:

Beijing

XueYing People’s

OF MEM-

Rep Qf Chino:

Jiang,

ShaoLin

Liu,

W. D~mn. MingRui

Rep Of Chino

Clausenamide was iso&@ from Clausena Lanaium (Low.) skeels, and was synthesi,zd and resolved into (-)Clausenamide and (+)Clausenamide. The nootropic potency of (-1 Clausenamide (5, IO @kg) was 50.100 times more than that of piracetam in improving amnesia induced by an&dine, cyclohexmide and AP (25.35). (+)Clausenamide showed no such effect. On the anesthetized and freely moving rata, (-)Clausenamide (I and 4 nmol i.c.v or 8,40 mg/kg, p.o) dose-dependently enhanced the basic synaptic transmission and the magnitude of LTP induced by HFS Whereas the (+)Clausenamide showed no effect even produced inhibitory effect at dose of 4 nmol i.c.v. Piracetam 20 nmol could not potentiate PS or HFS induced LTP. The mechanism of action of (-) Clausenamide in improving memory and potentiating LTP may he 8s follows: (I) Increase of [Ca’+]i and calcium-dependent release of glutamate. (2) Potent&ion of cholinergic nervous system, including increase of ACh content and ChAT activity in brain. (3) Stimulation of cerebral protein synthesis and increase of BDNF expression. (4) Administered (-)Clausenamide to weaning mice for 4 weeks or to adult ratq for 10 days, (-)Clausenamide at dosage of 5 and IO mg/kg increaed thickness of cerebral cortex and synaptic density significantly in the dentate cell\ over pyramidal cells in hippocampal region. (-)Clauaenamide at doses of 8 and 40 mg/kg p.o could also enhance mossy fiber sprouting in the fascia dentate and hippocampal CA3 region of rats. It is interesting that (-)Clausenamide (0.1. IOpmol/L) inhibited apoptoaia significantly in cultured cerebellar granule neurons and the Bax-expressing PC12 cell\. (+)Clausenamide showed no such inhibltory effect. (-)Clausenamide could promote Bcl-2 gene expression and attenuate c-myc. P53 and Bax gene expression which was conridered as anti-apoptotic mechanism of (-)Clausenamide.

compared to the activity of ChE in plasma (34%). In patients treated wth 3-4.5 mg rivastigmine daily, no significant inhibition of ChE in plasma was observed. In contrast, we did find a significant inhibition of both enaymes in CSF. The inhibition of AChE activity (27O/a, pi 0.01) was significantly higher compared to BuChE activity (8%) after 3 months of rivaatigmine treatment. Conclusion; If confirmed at protein level usig western blot analysis, the result might indicate that, in contrast to tacrine, the inhibition of the enzyme activity by rivastigmine persists after at least 12 months of treatment.

SAFETY AND 111121 (DONEPEZIL)IN Joshua

R

I.ukehum

IN CSF OF ALZHEIMER’S

PATIENTS.

Rivastlgmine IYan psuedoirreversible cholinesterase inhibitor presently in clinical use for symptomatic treatment of Alzheimer’a disease(AD). It has recently been reported by A. Nordberg et al. that long term treatment with tacrme to AD patients &uses an mcrease in activity of acetylcholineateraae (AChE) in the CSF probably as a algn for upregulation of the enryme on gene level. In this study we investigated the effect of rivastigmine on AChE and butyrylcholinesterase (BuChE) activity in AD patients during a one-year period of treatment. I I AD patients (mean age 70.4+ 1.8Mv?SE) diagnosed with probable AD according to the criteria of NINCDS-ADRDA and with mild dementia (MMSE 24.9+0.X) were treated with rivastigmine for 12 months. Seven patients were titrated up to the maximal dose of 12mg daily while 4 patients remained due to side effect of higher doses on a daily dose of 3. 4.5 mg. CSF and plasma samples were taken at baseline, after 3 and I2 months of treatment respectively. Total cholinesterase (ChE) and BuChE activity was assayed by the colorimettic method of Ellman et al. The AChE activity was obtained by difference between total ChE and BuChE activities. In patients receiving 12 mg rivastigmine daily for 12 months, the inhibition of AChE and BuChE activity (40%) in CSF was higher compared to the inhibition of ChE (21%) in plasma. The inhibition of both AChE (45%) and BuChE (55 %) activity in CSF were comparable, with no significant difference, while BuChE (55 Bl activity in CSF was significantly higher (p
S Ross,

Juanita

Smith,

Mmridiun

Health

Swtem.

To investigate the safety and tolerability of high dose donepezil (Aricept) in the treatment of Alzheimer’s Disease. Methods: Alzheimer’s Diaese patients maintained on maximally recommended donepezil dosage (10 mg) for at least one year in whom caregivers/family members reported lack of efficacy, and/or cognitive/ functional deterioration. Pattenta were treated with donepezil (Aricept) at the maximum suggested dose by the manufacturer (Eisai Japan/Pfizer,USA) of IOmg once daily for 4 or more months. Higher dose Aricept (15.2Omg)waa administered to patients whose family I caregivers voiced frustration regarding lack of efficacy with the IOmg dose. Patients were informed this was a non-pharmaceutical sponsored trial. As the patients prescription plan would not allow doses higher than IOmg, samples were supplied at no charge to patients from our office drug supply. Consent from the family was obtained before high dose treatment began. After one week, patients were evaluated in the office for any adverse drug reactions. Subsequently telephone evaluations were done weekly for 1 month after each dose change. RESULTS: Twelve patients participated in the study. Seven males and 5 females. Average age: 76 years( 72-83). In 8 patients, functional and cognitive improvement with high dose donepezil treatment was reported after the first month All I2 patients were intially treated with Aricept 15mg for one month, then increased to 20mg after one additional month. After one week of treatment with Aricept 15mg, two patient5 experienced mcrease agitation and confusion. Interestingly, of the two, one patient had cognitive unprovement after stopping the treatment. Six patients were able to tolerate the additional increase from IS mg‘donepwil to 2Omg donepexil. Follow up of those patients for 2-3 weeks. showed no adverse events. CONCLUSION: High dose Aricept (donepezil) appears to he safe in higher doses then is currently used. We recommend donepezil (Aricept) be studied for safety and efficacy in 15-2Omg daily doses.

A RANDOMIZED, 111131 CLINICAL TRIAL

PLACEBO-CONTROLLED, DOUBLE-BLIND, OF SERTRALINE IN THE TREATMENT OF MAJOR DEPRESSION COMPLICATING ALZHEIMER DISEASE: INITIAL RESULTS FROM THE DIADS STUDY

Constantinr Kopunke. Ridge

TERASE ACTIVITY

Joel

NJ

Purpose:

George Johns

Institute,

Medicine.

LONG TERM RIVASTIGMINE TREATMENT PRODUCES PER111111 SISTENT INHIBITION OF ACETYL- AND BUTYRYLCHOLINES-

Shua-Haim.

TOLERABILITY OF HIGH DOSE ARICEPTPATIENTS WITH ALZHEIMER’S DISEASE

Lyketsos,

Hopkins

Sch

Sykrsville.

MD:

Baltimore.

Jeunnir-Marie

E Sheppard,

Cynthia

of Medrcinr, Baltmore. MD; Jason Brandt,

Peter

V Rubins,

A/vu

D Srrelr. S Baker,

Johns Hopkins

Suun Copper Sch of

MD

The study’s objective wa’i to evaluate the efficacy and safety of sertrahne in the treatment of major depression in patients with Alzheimer disease (AD). This was a twelve week, double-blind, placebo-controlled, randomized clinical trial of a flexible dose of sertraline (mean 81mg per day) in 22 patients with AD and major depression. Response rate, and change from baseline on the Cornell Scale for Depression in Dementia (CSDD), the Psychogeriatric Dependency Rating Scale-ADL s&scale (PGDRS-ADL). and the Mini-Mental State (MMSE) where the outcome measures: In an intent to treat analysis, 73% or participants on sertraline and 27% of those on placebo were classified as responders (p=O.O3). Pattents on sertraline had significantly greater mean declines from baseline on the CSDD at weeks 6, 9, and 12. In addition, patients on wrtraline exhibited significantly amaller ADL decline? than patients on placebo at weeks 9, and 12. There were no significant differences between the two groups on MMSE score changes or side-effects at any follow-up point. We concllude that settrahne ia superior to placebo in reducing maJor depression in patients with Alzheimer disease. In addition to depression reduction, the treatment of depression appears to he associated with delays in ADL decline, which might delay the functional decline of the disease.