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Invited Review Cholinesterase inhibitors for Alzheimer’s disease therapy: from tacrine to future applications
NEUROCHEMISTRY International Neurochem[ Int[ 21 "0887# 302Ð308
Invited Review Cholinesterase inhibitors for Alzheimer|s disease therapy] from tacrine to future applications Ezio Giacobini HUG\ Belle!Idee\ Department of Geriatrics\ University Hospitals of Geneva\ Route de Mon!Idee\ CH!0115 Thonex\ Geneva\ Switzerland Received 14 June 0886^ accepted 04 September 0886
Abstract This review starts with an historical background of the pharmacological development of tacrine almost _fty years ago "0838#[ Tacrine is the _rst drug to be tested\ clinically\ on a large scale and to be registered "0882# for treatment of Alzheimer|s disease[ For the _rst time\ clinical results of four second generation cholinesterase inhibitors "ChEI# "donepezil\ ENA 602\ eptastigmine and metrifonate# are reviewed and compared with other ChEI such as tacrine\ physostigmine and galanthamine[ Data based on more than 5999 patients show that second generation drugs are well tolerated and show evidence of clinical e.cacy[ Di}erences are mainly due to frequency of side e}ects\ number of drop outs and percentage of improved patients[ These results also demonstrate the presence of clinical e.cacy for all ChEI tested so far[ Clinical mechanism of action\ levels of e.cacy and di}erences among various ChEI are discussed[ Future potential indications are suggested[ The present data indicate that optimization of e}ects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties[ Þ 0887 Elsevier Science Ltd[ All rights reserved[
0[ A historical note Cholinergic de_cits in Alzheimer|s Disease "AD# have been well documented "cf[ Giacobini\ 0889#[ The reduction of cortical and CSF cholinergic markers are correlated with the extent of the neuropathology and with the severity of cognitive impairment[ It is assumed that insu.cient levels of acetylcholine "ACh# at cortical synapses will severely impair the neuromodulatory func! tion of this neurotransmitter[ We calculated that the di}erence in cortical ACh levels between normal elderly controls and AD patients is of the order of 49) "Giacobini 0884#[ We can therefore postulate that a chol! inesterase inhibitor "ChEI# capable of doubling ACh lev! els from approximately 049 nM to 299 nM would re! establish a close to normal level of neurotransmitter[ All ChEIs tested in our laboratory with intracortical mic! rodialysis have shown this capability "Giacobini\ 0885# and therefore\ theoretically\ they should be able to pro! duce cognitive improvement in AD patients[ In aged rats\ Scali et al[ "0886#\ demonstrated a direct correlation between levels of AChE inhibition\ increase of extra! cellular ACh in cortex and hippocampus and cognitive improvement[ ChEIs have a long history\ but clinical application of ChEI in the _eld of AD started only in the early 0879s 9086Ð9075:87 ,08[99 Þ 0887 Elsevier Science Ltd[ All rights reserved PII] S 9 0 8 6 Ð 9 0 7 5 " 8 6 # 9 9 0 1 3 Ð 0
with the oral and intravenous administration of physo! stigmine "Davis and Mohs\ 0871^ Thal et al[\ 0872#[ The results of these _rst experimental treatments were encour! aging as they clearly demonstrated the potential of this pharmacological approach in reducing decline of cog! nitive function[ However\ the e}ect of physostigmine was too short in duration and the cholinergic side e}ects too frequent and pronounced[ An historical breakthrough in long term treatment of AD with ChEIs occurred in the middle 0879s with the publication of the paper of Summers et al[ "0875# in the New En`land Journal of Medicine using a di}erent drug[ They reported the e}ect of oral administration of tetra! hydroaminoacridine "THA\ tacrine# during a period of 01[5 months on 06 patients[ This study was preceded by a short!term pilot trial with the same drug administered intravenously to 01 AD patients "Summers et al[\ 0870#[ It is interesting to note that tacrine was never intended to be a treatment for AD and even less a ChEI[ Tacrine was _rst described pharmacologically by Shaw and Bentley "0838# in Australia as an analeptic capable of causing rapid arousal of morphinized dogs and cats[ Early clinical applications of tacrine were in the treatment of anaesthetic induced delirium "Albin et al[\ 0863# and potentiation of the muscle relaxing e}ect of suc! cinylcholine "Gordh and Walin\ 0850#[ Shaw and Bentley
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"0842# had shown that tacrine is almost as powerful a ChEI as eserine or neostigmine\ producing 49) inhi! bition of ChE at concentrations of 09−6 M[ However it was not known whether the synergism of ChEI with succinylcholine depended upon a direct cholinergic e}ect or on inhibition of the enzymatic breakdown of the drug[ Heilbronn "0850# characterized for the _rst time the e}ect of tacrine upon acetylcholinesterase "AChE# and buty! rylcholinesterase "BuChE#[ She demonstrated that the compound acts as a reversible inhibitor being partly com! petitive with the substrate ACh and a more potent inhibi! tor of BuChE than of AChE[ The clinical e}ect demonstrated by tacrine has substantiated this view[
1[ Cholinesterase inhibitors] how do they work in AD< Is there a difference among compounds< ChEIs presently in clinical trials in Japan\ U[S[A[ and Europe include less than a dozen compounds\ most of which have already advanced to clinical phase III and three ChEIs "tacrine\ ENA 602 and donepezil# are regis! tered in U[S[A[ and:or in Europe0"cf[ Giacobini\ 0885#[ It is likely in that the 1!year period "0886Ð0888# at least three ChEIs will be registered world!wide[ The second generation of ChEIs\ in order to replace tacrine\ will have to ful_l speci_c requirements of e.cacy and safety "cf[ Giacobini\ 0885#[ After analysing the results emerging from clinical trials of 5 month duration\ the _rst question to be answered is] do ChEIs work in the AD patient as suggested by the early pharmacological studies< And if they work\ how do they work< A second question is] are there major di}erences among various compounds with regard to e.cacy\ percentage of treatable patients\
duration of clinical e}ects and side e}ects< These two fundamental questions can be partially answered by com! paring recent clinical data "Table 0#[ Table 0 reports data on the e}ect of six ChEIs on ADAS!cog test using ITT "intention to treat# criteria[ The duration of these ran! domized\ placebo!controlled double blind trials varied between 01 and 29 weeks and the number of patients treated with such drugs has surpassed 5999[ Based on the data reported in these clinical phase III studies\ the answer to the _rst question is de_nitively a.rmative[ All six ChEIs produce statistically signi_cant improvements evaluated with scales of standardized and internationally validated measures of both cognitive and non!cognitive function[ Cognitive items have been most widely used in these investigations[ One immediate observation is the simi! larity in size of cognitive e}ect for all six drugs when expressed as a di}erence between drug! and placebo! treated patients[ Maximal di}erences in ADAS!cog between drug "at all doses# and placebo!treated patients average 2[5 points "ADAS!cog# and a average di}erence of 0[1 points is seen at the study end point[ Di}erences at the study end point vary from a gain of 9[4 points "metrifonate high dose# to a maximum of 1[7 "tacrine high dose#[ This similarity in cognitive e}ects suggest a ceiling value of approximately 4 ADAS!cog points aver! age for ChEIs at mild to moderate stages "CDR 0Ð0[4# of the disease[ It could also suggest that some drugs may have not been tested at their full capacity[ For tacrine\ the high percentage of drop!outs and side!e}ects seem to indicate a limit in ChE inhibition as well as in drug e}ect[ For other drugs "e[g[ metrifonate and donepezil#\ producing higher ChE inhibition "up to 79)#\ severity of side!e}ects does not seem to represent a limiting factor[
Table 0 Comparison of the e}ect of six cholinesterase inhibitors on ADAS!cog test "ITT#
Drug ref[
Dose mg:day
Duration of study weeks
Tacrine0 Eptastigm[1 Donepezil2 ENA 6023 Metrifonate4\5 Galanthamine6
019Ð059 34 4Ð09 5Ð01 14Ð64 29
29 14 13 13 01Ð15 01
Treatment di}erence from from PLACEBO BASELINE
Improved patients )
Drop!out )
Side e}ects )
3[9Ð4[2 3[6 1[7Ð2[0 0[8Ð3[8 1[7Ð2[0 2[2
29Ð49 29 47 14 24 *
44Ð62 01 04Ð29 04Ð16 1Ð10 22
39Ð47 24 02 17 1Ð01 *
9[7Ð1[7 0[7 9[6Ð0 9[6 9[64Ð9[4 0[7
ADAS!cog AD Assessment Scale!cognitive subscale[ ITT intention to treat[ study endpoint vs placebo[ study end point vs baseline[ Drugs] Tacrine "THA#\ Eptastigmine\ Donepezil "E 1919#\ ENA 602 "rivastigmine#\ Metrifonate\ Galanthamine[ 0 Farlow et al[ "0881#^ Knapp et al[ "0883#[ 1 Canal and Imbimbo "0885#^ Imbimbo "0885#[ 2 Roger and Friedho} "0885#^ Rogers et al[ "0885#[ 3 Anand et al[ "0885#[ 4 Becker et al[ "0885a\ 0885b#[ 5 Morris et al[ "0886#[ 6 Wilkinson "0886#[
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The percentage of improved patients varies from 14) "ENA 602\ high dose# to 47) "donepezil\ high dose# with an average of 27)[ It should be noted that a certain percentage of patients do not improve at all on the ADAS!cog[ These data indicate that more than one third of treated patients show a positive response to ChEIs[ While this is not an impressive _gure it may still improve signi_cantly if the percentage of treatable patients could be increased to 79Ð89) by using ChEIs producing less severe side!e}ects at higher dosage[
2[ Symptomatic effect of disease stabilization< Analysing the available 5 months data shown in Table 0\ it is possible to observe that patients treated with the active compound change little cognitively from baseline at the beginning treatment[ As an example in a U[S[A[ study with ENA 602\ patients administered placebo for 15 weeks deteriorated over 3 points on the ADAS!cog compared to only 9[2 in patients given 5Ð01 mg:day of the drug "Anand et al[\ 0885#[ The same is true for metri! fonate treatment[ This suggests that the di}erence seen after 5 months between placebo!treated and drug treated groups may depend more on the di}erence with the rate of cognitive deterioration of the placebo group "1Ð3 points# than on a real improvement[ This interpretation suggests a stabilization e}ect of the drug! contrasting deterioration rather than a purely symptomatic e}ect[ This putative protective e}ect could be primary and structural leading to a stabilization of cholinergic func! tion as re~ected by the cognitive improvement measured by ADAS!cog\ or be a secondary e}ect[ Tacrine and donepezil\ on the other hand\ seem to show a real initial improvement "1Ð2 points# as compared to the placebo group[ This e}ect may last from 3Ð13 weeks\ depending on the dose "Farlow et al[\ 0881^ Knapp et al[\ 0883^ Roger and Friedho}\ 0885#[ It remains to be dem! onstrated whether or not this improvement represents a real di}erence in drug e}ect[ As indicated by open long! term studies of up to 13 months "cf[ Becker et al[\ 0885a\b^ and Table 2# it seems possible to maintain the di}erence between placebo! and drug!treated subjects beyond the present 5 months limit[ This represents a signi_cant gain for both patient and caregiver[
3[ Can the clinical ef_cacy of various ChEIs be compared< ChEIs could di}er from one another with respect to magnitude and duration of e}ect[ In comparing present results of clinical trials and di}erent drugs one should take into consideration the fact that these studies may di}er from one another\ depending on di}erences in selec! tion criteria\ age of subjects\ severity of disease\ con!
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comitant illnesses and medications\ variable instruments of assessment and side e}ect evaluation[ In addition to these variables\ in order to evaluate real di}erences in e}ect between drugs one has to take into consideration the rate of deterioration of the placebo!exposed group which is compared with the treatment!group[ This rate of deterioration seems to be highly variable in the present studies "0Ð3 points at 13 weeks# among di}erent studies[ Also\ by using {completers| instead of ITT\ the analysis could produce somewhat higher e}ects[ Thus\ clinical studies are not entirely comparable and conclusions at this stage can be considered only as indicative[ Given these limitations\ the next goal to be achieved in a future ChEI treatment would be to enhance the e}ect up to 5Ð7 ADAS!cog points and to a 9[5Ð9[6 point gain "averaging presently 9[3# on Clinical Interview!Based Impression of Change "CIBIC# during a 5 months treatment period[ At least 49) of this e}ect should be maintained for 01 months\ the number of drop!out patients should be no higher than 09) and the level of side e}ects very low[ That this an achievable goal is suggested by the results of open long!term studies "Table 2#[ The fact that in several trials reported in Table 0 a certain percentage of patients reached much higher levels of cognitive improvement "6Ð 00 ADAS!cog points# and have not immediately deterio! rated after drug withdrawal supports this optimistic view[
4[ What makes the difference between various ChEIs< The relation between percentage of peripheral ChE inhi! bition and cognitive "ADAS!cog# or global impression of change rated by the clinician "CGIC# e}ect is a relevant factor which is reported in Table 1[ The data presented in Table 1 supports the pharmacological knowledge that brain ChE inhibition relates directly to an improvement of functional ACh levels[ This relationship might vary quantitatively for each drug and each compound may produce various levels of cognitive improvement and therapeutic e}ect "Giacobini et al[\ 0877\ 0884^ Giacobini\ 0885#[ This hypothesis is in agreement with pharma! cological data in animals "Mattio et al[\ 0875^ Giacobini et al[\ 0878# and in humans "Giacobini et al[\ 0877#[ The level of peripheral enzyme inhibition which has been measured in the patient "AChE activity in eryth! rocytes or plasma BuChE activity# producing a di}erence on the cognitive test varies between 29) and 79) depending on kinetic and pharmacological characteristics of the compound "Table 2#[ For some drugs "see done! pezil and metrifonate# the achievable level of non!toxic ChE inhibition can be as high as 89)[ As predicted by pharmacological and behavioral data\ there is a clear correlation between ChE inhibition "or drug plasma con! centration# and cognitive e}ect "Giacobini et al[\ 0878^ Giacobini and Cuadra\ 0883#[ Drugs producing mild cholinergic side e}ects\ even at high dosage and a high
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E[ Giacobini:Neurochem[ Int[ 21 "0887# 302Ð308 Table 1 Relation between percent ChE inhibition and e}ect on ADAS!cog or CGIC Drug ref[
Dose mg:day
Steady state ) inhibition
Optimal ) inhibition
Correlation ChEI: ADAS!cog or CGIC
Physostigm[0 Eptastigm[1 Metrifonate2 Donepezil3 Tacrine4
2Ð05 29Ð59 29 4 059
39Ð59 "BuChE# 02Ð43 "AChE# 24Ð64 "AChE# 53 "AChE# 39 "BuChE# 59 "AChE# 49Ð59 "AChE#
29Ð39 29Ð24 54Ð79 59 29
U!shaped U!shaped U!shaped linear linear
49
U!shaped
Galanthamine5
19Ð49
ADAS!cog AD Assessment Scale!cognitive subscale[ CGIC Clinician Global Impression of Change[ Drugs] Physo! stigmine\ Eptastigmine\ Metrifonate\ Donepezil "E1919#\Tacrine "THA#\ Galanthamine[ 0 Thal et al[ "0872#[ 1 Imbimbo and Lucchelli "0883#^ Canal and Imbimbo "0885#[ 2 Becker et al[ "0889#[ 3 Roger and Friedho} "0885#[ 4 Farlow et al[ "0881#^ Knapp et al[ "0880\ 0883#[ 5 Wilkinson "0886#[
level of brain ChE inhibition\ may be tested in the patient within their full range of therapeutic potential[ For some ChEIs "physostigmine\ galanthamine\ eptastigmine and metrifonate# the relation between ChE inhibition and cognitive e}ect is inversely U!shaped\ while for other ChEIs "such as tacrine\ ENA 602 and donepezil# this relation seems to be linear[ The U!shaped form can be explained by the fact that by increasing the dose of the inhibitor one obtains progressively increasing e.cacy until adverse e}ects do not become a limiting factor[ Metrifonate could represent an exception since it shows low cholinergic toxicity even at high "79Ð89)# levels of AChE inhibition[ Another reason for the U!shaped curve is the speci_c inhibition kinetic of the inhibitor! and the substrate!induced saturation e}ect of ChEs[ The level of ACh brain elevation varies according to brain ChE inhibition "Giacobini\ 0883\ 0884\ 0885#[ With increased brain concentrations of ACh\ substrate inhibition of
enzyme activity becomes a phenomenon of particular importance[ It is observed in brain tissue in vitro and is probably present also in vivo "Giacobini\ 0883#[ Plotting velocity of enzymatic reaction against substrate "ACh# concentration\ a bell!shaped curve with a de_ned peak in case of AChE activity "brain and erythrocytes# and a sigmoid curve in case of BuChE activity "serum# are observed[ Thus\ AChE is inhibited by a large excess of ACh such as it can be produced by a high inhibition of brain AChE in AD!a}ected patients[ The substrate elevation has the e}ect of decreasing the catalytic potency of the enzyme and subsequently its pharmacological and therapeutical e}ect[ From this relationship it can be pre! dicted that a high ChE inhibition reached rapidly in time during treatment "rapid passage of the drug into the brain and fast accumulation in CNS# will not further increase e.cacy but only augment CNS dependent side!e}ects "drowsiness\ nausea\ vomit etc[#[ It should be an advan!
Table 2 Long!term cognitive e}ects of tacrine and eptastigmine on Alzheimer Disease progression
Reference
Daily dose "mg#
Test
Amberla et al[ 0882 Wilcock et al[ 0883 Eagger et al[ 0883 Solomon et al[ 0885 Knopman et al[ 0885 Imbimbo et al[ 0886
79Ð059 79 49Ð049 059 79Ð019 29
Buschke MMSE\ CAMCOG AMTS ADASÐCog NHP ADASÐCog MSE IADL
Di}erence between treatment and baseline at 00Ð04 mo[ at 06Ð13 month no change no change no change no change
AMTS Abbreviated Mental Test Score\ NHP Nursing Home Placement Tacrine[ Eptastigmine\ IADL Instrumental Activity of Daily Living[ Study end point vs baseline[
* * * 1[7 delay 5[3 2[8 3[7
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tage to use a slow!release type of ChEI inhibiting both brain enzymes "AChE and BuChE# at a slow pace in order to reach gradually steady!state levels of brain Ach[ Such a procedure may also lower the risk of cholinergic receptor down!regulation and enzyme induction[ Indeed\ there is an excellent agreement between clinical and ani! mal data for both physostigmine and tacrine with regard to dose:behavioral e}ects relationships[ Rupniak et al[ "0889# using two primate models "rhesus monkeys# found that both tacrine and physostigmine improved visual rec! ognition memory signi_cantly[ Both drugs showed a clear inverse U!shaped relationship with a maximal e}ect at around 9[9909Ð9[91 mg:kg i[m[ for physostigmine and 9[7Ð0 mg:kg for tacrine[ Lower or higher doses did not improve performance but only increased side e}ects[ Cen! tral cholinergic side e}ects which may develop early in the treatment are not related directly to brain AChE inhibition but to a rapid elevation of ACh levels[ In rat brain\ this increase is not directly correlated to AChE inhibition "Giacobini\ 0883\ 0884#[ Peripheral side!e}ects may also occur depending on a rapid redistribution of the drug "or its metabolites# between non!CNS "peripheral organs and muscles# and CNS compartments[ Therefore\ the presence of active metabolites is important in explain! ing the origin of these side e}ects[
5[ Is there a tolerance to the effects of AChEIs< A combination of pharmacokinetic and pharmaco! dynamic e}ects of the drug such as down!regulation of muscarinic and nicotinic receptors and decreased ChE inhibition due to new enzyme synthesis\ may be respon! sible for the tolerance to therapeutic e}ects seen in exper! imental animals and patients treated with ChEIs for 13 weeks or longer[ Last but not least\ a problem of ChEI therapy is the early identi_cation of those patients most likely to bene_t from therapy[ Correlation of therapy e}ectiveness to gen! etic risk factors "APOE!allele# represents a _rst attempt in this direction[ Choosing the proper responder to cho! linomimetics and selecting patients at earlier stages of the disease at which to start medication may be crucial for the success of the therapy[
6[ General Conclusions
306
involved clinical trials of six di}erent ChEIs using the same scales under relatively uniform conditions[ Soon available data on these drugs originate from more than 5999 patients treated in 13Ð29 week phase III double! blind placebo controlled trials conducted world!wide[ In spite of obvious di}erences in patient and placebo popu! lations all six drugs have shown cognitive e}ects of a similar magnitude[ Major di}erences seem to relate not to cognitive e}ects but to severity and frequency of side e}ects and to percentage of responding patients and drop outs[ It is suggested that these di}erences depend on the possibility of reaching higher AChE and BuChE brain inhibition at low levels of cholinergic toxicity[ Dose e}ects are also important[ The data suggest that opti! mization of e.cacy and prolongation of clinical gains for one year or more are possible[ Further progress will depend on our knowledge of pharmacodynamic e}ects of long!term treatment[ Cholinesterase inhibitors\ par! ticularly second generation\ "post!physo and post!tacrine compounds#\ a}ect cortical as well as sub!cortical neuro! transmitters other than ACh "Giacobini\ 0885#[ Their e}ects on NE and DA are of particular clinical relevance[ A newly demonstrated feature of ChEIs is their ability to enhance the release of non!amyloidogenic soluble deriva! tives of APP in vitro and in vivo and possibly to slow down formation of amyloidogenic compounds in brain "Mori et al[\ 0884#[ This process might also slow down cognitive deterioration of the patient as indicated by the analysis of recent clinical data from open long!term trials "Table 2#[ Cholinomimetic alternatives other than ChE inhibition are being explored[ Drugs most investigated are those showing direct stimulation of postsynaptic M0 and M2 muscarinic receptors or nicotinic agonists of a! 3!b!1 and a!6 receptors[ This attractive line of cholinergic therapy has not yet produced convincing clinical results mainly depending on gastrointestinal and cardiac side e}ects[ Depending on the success of ChEIs one can predict new potential indications for applications to di}erent stages of AD such as] "a# preclinical presymptomatic stages in at risk!individuals with MCI "minimal cognitive impairment#\ "b# early AD patients with manifested symptoms "CDR 9[4Ð0# and "c# late AD "CDR 1# patients with behavioral symptoms[ A combination of ChEIs with muscarinic or nicotinic agonists or with b!A3 processors or APP!releasers and estrogens represent another valid alternative\ particularly in case of development of tol! erance to ChEI monotreatment[
6[0[ The future of AD therapy with cholinesterase inhibi! tors ChEIs are presently the drugs of choice for AD[ In less than 09 years\ starting from non!speci_c _rst generation drugs such as physostigmine\ a second generation of more selective and better tolerated products has been developed[ The data summarized here for the _rst time
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term treatment with tacrine "THA# in Alzheimer disease evaluation of neuropsychological data[ Acta[ Neurol[ Scand "Suppl[ 038#\ 44Ð 46 Anand\ R[\ Hartman\ R[D[\ Hayes\ P[E[\ 0885[ An overview of the development of SDZ ENA 602\ a brain selective cholinesterase inhibitor[ In Becker\ R[\ Giacobini\ E[ "Eds#\ Alzheimer Disease] From Molecular Biology to Therapy[ Birkhauser\ Boston\ pp[ 128Ð 132[ Becker\ R[\ Colliver\ J[\ Elbe\ R[\ 0889[ E}ects of Metrifonate\ a long! acting cholinesterase inhibitor[ Drug Devel[ Res[ 08\ 314Ð323[ Becker\ R[\ Moriearty\ P[\ Unni\ L[\ 0880[ The second generation of cholinesterase inhibitors] Clinical and pharmacological e}ects[ In Becker\ R[\ Giacobini\ E[ "Eds#\ Cholinergic Basis for Alzheimer Therapy[ Birkhauser\ Boston\ pp[ 152Ð185[ Becker\ R[\ Colliver\ J[A[\ Markwell\ S[J[\ Moriearty\ P[\ Unni\ L[K[\ Vicari S[\ 0885a[ Double!blind\ placebo!controlled study of metri! fonate\ an acetylcholinesterase inhibitor\ for Alzheimer disease[ Alz[ Dis[ and Assoc[ Dis[ 09\ 013Ð020[ Becker\ R[\ Moriearty\ P[\ Unni\ L[\ Vicari\ S[\ 0885b[Cholinesterase inhibitors as therapy in Alzheimer|s disease] bene_t to risk con! siderations in clinical application[ In Becker\ R[\ Giacobini\ E[ "Eds#\ Alzheimer Disease] From Molecular Biology to Therapy[ Birk! hauser\ Boston\ pp[ 146Ð155[ Canal\ I[\ Imbimbo\ B[P[\ 0885[ Clinical trials and therapeutics] Relationship between pharmacodynamic activity and cognitive e}ects of eptastigmine in patients with Alzheimer|s disease[ Clin[ Pharm[ Therap[ 04"01#\ 38Ð48 Davis\ K[L[\ Mohs\ R[S[\ 0871[ Enhancement of memory processes in Alzheimer|s disease with multiple!dose intravenous physostigmine[ Am[ J[ Psychiatry[ 028\ 0310Ð0313[ Eagger\ S[\ Richards\ M[\ Levy R[\ 0883[ Long!term e}ects of tacrine in Alzheimers|s disease] an open study[ Intern[ J[ Ger[ Psych[ 8\ 532Ð536[ Farlow\ M[\ Gracon\ S[I[\ Hershey\ L[A[\ Lewis\ K[W[\ Sadowski\ C[H[\ Dolan!Ureno\ J[A[\ 0881[ Controlled trial of tacrine in Alzheimer|s disease[ J[ Am[ Med[ Ass[ 157\ 1412Ð1418[ Giacobini\ E[\ 0889[ The cholinergic system in Alzheimer disease[ In Aquilonius\ S[!M[\ Gillberg\ P\!G[ "Eds#\ Cholinergic transmission] functional and clinical aspects[ Elsevier\ Amsterdam\ Prog[ in Brain Res[ 73\ 210Ð221[ Giacobini\ E[\ 0883[ Cholinomimetic therapy of Alzheimer|s disease] does it slow down deterioration< In Racagni\ G[\ Brunello\ N[\ Langer\ S[Z[ "Eds#\ Recent Advances in the Treatment of Neu! rodegenerative Disorders and Cognitive Dysfunction International Academy of Biomedical Drug Research[ Karger\ New York\ pp[ 40Ð46[ Giacobini\ E[\ 0884[ Cholinesterase inhibitors] From preclinical studies to clinical e.cacy in Alzheimer|s disease[ In Quinn\ D[\ Bal! asubramaniam\ A[S[\ Doctor\ B[P[\ Taylor\ P[ "Eds#\ Enzymes of the Cholinesterase Family[ Plenum Press\ New York\ pp[ 352Ð358[ Giacobini\ E[\ 0885[ Cholinesterase inhibitors do more than inhibit cholinesterase[ In Becker\ R[\ Giacobini\ E[ "Eds#\ Alzheimer|s Dis! ease] From Molecular Biology to Therapy[ Birkhauser\ Boston\ pp[ 076Ð193[ Giacobini\ E[\ Becker\ R[\ McIlhany\ M[\ Kumar\ V[\ 0877[ Inter! acerebroventricular administration of cholinergic drugs] preclinical trials and clinical experience in Alzheimer patients[ In Giacobini\ E[\ Becker\ R[ "Eds#\ Current Research in Alzheimer Therapy[ Taylor and Francis\ New York\ pp[ 002Ð011[ Giacobini\ E[\ Cuadra\ G[\ 0883[ Second and third generation chol! inesterase inhibitors] From preclinical studies to clinical e.cacy[ In Giacobini\ E[\ Becker\ R[ "Eds#\ Alzheimer Disease] Therapeutic Strategies[ BirkhafadiŁuser\ Boston\ pp[ 044Ð060[ Giacobini\ E[\ DeSarno\ P[\ Clark\ B[\ McIlhany\ M[\ 0878[ The chol! inergic receptor system of the human brain*Neurochemical and pharmacological aspects in aging and Alzheimer[ In Nordberg\ A[\
Fuxe\ K[\ Holmstedt\ B[ "Eds#\ Prog[ in Brain Res[ Elsevier\ Amster! dam\ pp[ 224Ð232[ Gordh\ T[\ Walin\ A[\ 0850[ Potentiation of the neuromuscular e}ect of succinylcholine by tetrahydro!aminoacridine[ Acta Anaesth[ Scand[ 4\ 44Ð50[ Heilbronn\ E[ 0850[ Inhibition of Cholinesterase by tetrahydro! aminoacrin[ Acta Chem[ Scand[ 04\ 0275Ð0289[ Imbimbo\ B[P[\ 0885[ Eptastigmine] A cholinergic approach to the treatment of Alzheimer|s disease[ In Becker\ R[\ Giacobini\ E[ "Eds#\ Alzheimer Disease] From Molecular Biology to Therapy[ Birk! hauser\ Boston\ pp[ 112Ð129[ Imbimbo\ B[P[\ Lucchelli\ P[E[\ 0883[ A pharmacodynamic strategy to optimize the clinical response to eptastigmine[ In Becker\ R[\ Giacobini\ E[ "Eds#\ Alzheimer Disease] Therapeutic Strategies[ Birkhauser\ Boston\ pp[ 112Ð129[ Imbimbo\ B[P[\ Perini\ M[ Verdelli\ G[\ Troetel W[M[\ 0886[ XVth World Congress of Neurology\ Buenos Aires[ Sept[ 0886[ Abstr[ 014[ Knapp\ S[ Wardlow\ M[L[ Albert\ W[\ Wazters[ D[\ Thal\ J[\ 0880[ Correlation between plasma physostigmine concentrations and per! centage of acetylcholinesterase inhibition over time after controlled release of physostigmine in volunteer subjects[ Drug Metab[ Disp[ 08"1#\ 399Ð393[ Knapp\ M[J[\ Knopman\ D[S[\ Solomon\ P[R[\ 0883[ A 29 week ran! domized controlled trial of high!dose tacrine in patients with Alz! heimer|s disease[ J[ Am[ Med[ Ass[ 160\ 874Ð880[ Knopman\ D[\ Schneider\ L[\ Davis\ K[\ 0885[ Long!term tacrine "Cognex# treatment] e}ects on nursing home placement and mortality[ Neurol[ 36\ 055Ð066[ Mattio\ T[\ McIlhany\ M[\ Giacobini\ E[\ Hallak\ M[\ 0875[ The e}ects of physostigmine on acetylcholinesterase activity of CSF\ plasma and brain[ A comparison of intravenous and intraventricular admin! istration in beagle dogs[ Neuropharm[ 14\ 0056Ð0066[ Mori\ F[\ Lai\ C[C[\ Fusi\ F[\ Giacobini\ E[\ 0884[ Cholinesterase inhibi! tors increase secretion of APPs in rat brain cortex[ Neuro Rep[ 5"3#\ 522Ð525[ Morris\ J[ Cyrus\ P[ Orazem\ J[\ Mas\ J[ Bieber\ F[\ Gulanski\ B[\ 0886[ Metrifonate] potential therapy for Alzheimer|s Disease[ Amer[ Soc[ Neurol[ Meeting "Boston\ U[S[A[# Abstr[ 044[ Roger\ S[L[\ Friedho}\ T[\ 0885[ The e.cacy and safety of Donepezil in patients with Alzheimer|s disease] Results of a U[S[ multicentre\ randomized\ double!blind\ placebo!controlled trial[ Dementia 6\ 182Ð299[ Roger\ S[L[\ Doody\ R[\ Mohs[ R[\ Friedho}\ L[T[\ 0885[ E1919 pro! duces both clinical global and cognitive test improvement[ Neur! ology 35\ Abstr[ 106[ Rupniak\ N[M[J[\ Field\ M[J[\ Samson\ N[A[\ Steventon\ M[J[\ Iversen\ S[D[\ 0889[ Direct comparison of cognitive facilitation by physo! stigmine and tetrahydroaminoacridine in two primate models[ Neu! robiol[ of Aging 00\ 598Ð502[ Scali\ C[\ Giovannini\ M[G[\ Bartolini\ L[\ Prosperi\ C[\ Hinz\ V[\ Schmidt\ B[\ Pepeu\ G[\ 0886[ E}ect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats[ Eur[ J[ Pharmacology 214\ 062Ð079[ Shaw\ H[\ Bentley\ G[\ 0842[ Anticholinesterase properties of tetra! hydroaminacridine[ Aust[ J[ exp[ Biol[ 20\ 462Ð467[ Shaw\ H[\ Bentley\ G[\ 0838[ Some aspects of the pharmacology of morphine with special reference to its antagonism by 4!amino! acridine and other chemically related compounds[ Med[ J[ auts[ 1\ 757Ð764[ Solomon\ P[R[\ Knapp\ M[J[\ Gracon\ S[J[\ Groccia\ M[\ Pendlebury\ W[W[\ 0885[ Long!term tacrine treatment in patients with Alzh! eimer|s disease[ Lancet 237\ 164Ð165[ Summers\ W[K[\ Viesselman\ J[O[\ Marsh\ G[M[\ Candelora\ K[\ 0870[ Use of THA in treatment of Alzheimer!like dementia] pilot study in twelve patients[ Biol[ Psych[ 15\ 034Ð042[ Summers\ W[K[\ Majowski\ L[V[\ Marsh\ G[M[\ Tachiki\ K[\ Kling\
E[ Giacobini:Neurochem[ Int[ 21 "0887# 302Ð308 A[\ 0875 Oral tetrahydroaminoacridine in long!term treatment of senile dementia\ Alzheimer type[ New England J[ of Med[ 204\ 0130Ð 0134[ Thal\ L[\ Fuld\ P[A[\ Masur\ D[M[\ Sharpless\ N[S[\ 0872[ Oral physo! stigmine and lecithin improve memory in Alzheimer disease[ Ann[ Neurol[ 02\ 380Ð385[
308
Wilcock\ G[K[\ Scott\ M[\ Pearsall\ T[\ 0883[ Long!term use of tacrine[ Lancet 232\ 183[ Wilkinson\ D[\ 0886[ Galanthamine hydrobromide*Results of a group study[ Eight Congress Int[ Psychoger[ "Jerusalem# Abstr[ p[ 69[
Invited Review Cholinesterase inhibitors for Alzheimer|s disease therapy] from tacrine to future applications Ezio Giacobini HUG\ Belle!Idee\ Department of Geriatrics\ University Hospitals of Geneva\ Route de Mon!Idee\ CH!0115 Thonex\ Geneva\ Switzerland Received 14 June 0886^ accepted 04 September 0886
Abstract This review starts with an historical background of the pharmacological development of tacrine almost _fty years ago "0838#[ Tacrine is the _rst drug to be tested\ clinically\ on a large scale and to be registered "0882# for treatment of Alzheimer|s disease[ For the _rst time\ clinical results of four second generation cholinesterase inhibitors "ChEI# "donepezil\ ENA 602\ eptastigmine and metrifonate# are reviewed and compared with other ChEI such as tacrine\ physostigmine and galanthamine[ Data based on more than 5999 patients show that second generation drugs are well tolerated and show evidence of clinical e.cacy[ Di}erences are mainly due to frequency of side e}ects\ number of drop outs and percentage of improved patients[ These results also demonstrate the presence of clinical e.cacy for all ChEI tested so far[ Clinical mechanism of action\ levels of e.cacy and di}erences among various ChEI are discussed[ Future potential indications are suggested[ The present data indicate that optimization of e}ects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties[ Þ 0887 Elsevier Science Ltd[ All rights reserved[
0[ A historical note Cholinergic de_cits in Alzheimer|s Disease "AD# have been well documented "cf[ Giacobini\ 0889#[ The reduction of cortical and CSF cholinergic markers are correlated with the extent of the neuropathology and with the severity of cognitive impairment[ It is assumed that insu.cient levels of acetylcholine "ACh# at cortical synapses will severely impair the neuromodulatory func! tion of this neurotransmitter[ We calculated that the di}erence in cortical ACh levels between normal elderly controls and AD patients is of the order of 49) "Giacobini 0884#[ We can therefore postulate that a chol! inesterase inhibitor "ChEI# capable of doubling ACh lev! els from approximately 049 nM to 299 nM would re! establish a close to normal level of neurotransmitter[ All ChEIs tested in our laboratory with intracortical mic! rodialysis have shown this capability "Giacobini\ 0885# and therefore\ theoretically\ they should be able to pro! duce cognitive improvement in AD patients[ In aged rats\ Scali et al[ "0886#\ demonstrated a direct correlation between levels of AChE inhibition\ increase of extra! cellular ACh in cortex and hippocampus and cognitive improvement[ ChEIs have a long history\ but clinical application of ChEI in the _eld of AD started only in the early 0879s 9086Ð9075:87 ,08[99 Þ 0887 Elsevier Science Ltd[ All rights reserved PII] S 9 0 8 6 Ð 9 0 7 5 " 8 6 # 9 9 0 1 3 Ð 0
with the oral and intravenous administration of physo! stigmine "Davis and Mohs\ 0871^ Thal et al[\ 0872#[ The results of these _rst experimental treatments were encour! aging as they clearly demonstrated the potential of this pharmacological approach in reducing decline of cog! nitive function[ However\ the e}ect of physostigmine was too short in duration and the cholinergic side e}ects too frequent and pronounced[ An historical breakthrough in long term treatment of AD with ChEIs occurred in the middle 0879s with the publication of the paper of Summers et al[ "0875# in the New En`land Journal of Medicine using a di}erent drug[ They reported the e}ect of oral administration of tetra! hydroaminoacridine "THA\ tacrine# during a period of 01[5 months on 06 patients[ This study was preceded by a short!term pilot trial with the same drug administered intravenously to 01 AD patients "Summers et al[\ 0870#[ It is interesting to note that tacrine was never intended to be a treatment for AD and even less a ChEI[ Tacrine was _rst described pharmacologically by Shaw and Bentley "0838# in Australia as an analeptic capable of causing rapid arousal of morphinized dogs and cats[ Early clinical applications of tacrine were in the treatment of anaesthetic induced delirium "Albin et al[\ 0863# and potentiation of the muscle relaxing e}ect of suc! cinylcholine "Gordh and Walin\ 0850#[ Shaw and Bentley
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"0842# had shown that tacrine is almost as powerful a ChEI as eserine or neostigmine\ producing 49) inhi! bition of ChE at concentrations of 09−6 M[ However it was not known whether the synergism of ChEI with succinylcholine depended upon a direct cholinergic e}ect or on inhibition of the enzymatic breakdown of the drug[ Heilbronn "0850# characterized for the _rst time the e}ect of tacrine upon acetylcholinesterase "AChE# and buty! rylcholinesterase "BuChE#[ She demonstrated that the compound acts as a reversible inhibitor being partly com! petitive with the substrate ACh and a more potent inhibi! tor of BuChE than of AChE[ The clinical e}ect demonstrated by tacrine has substantiated this view[
1[ Cholinesterase inhibitors] how do they work in AD< Is there a difference among compounds< ChEIs presently in clinical trials in Japan\ U[S[A[ and Europe include less than a dozen compounds\ most of which have already advanced to clinical phase III and three ChEIs "tacrine\ ENA 602 and donepezil# are regis! tered in U[S[A[ and:or in Europe0"cf[ Giacobini\ 0885#[ It is likely in that the 1!year period "0886Ð0888# at least three ChEIs will be registered world!wide[ The second generation of ChEIs\ in order to replace tacrine\ will have to ful_l speci_c requirements of e.cacy and safety "cf[ Giacobini\ 0885#[ After analysing the results emerging from clinical trials of 5 month duration\ the _rst question to be answered is] do ChEIs work in the AD patient as suggested by the early pharmacological studies< And if they work\ how do they work< A second question is] are there major di}erences among various compounds with regard to e.cacy\ percentage of treatable patients\
duration of clinical e}ects and side e}ects< These two fundamental questions can be partially answered by com! paring recent clinical data "Table 0#[ Table 0 reports data on the e}ect of six ChEIs on ADAS!cog test using ITT "intention to treat# criteria[ The duration of these ran! domized\ placebo!controlled double blind trials varied between 01 and 29 weeks and the number of patients treated with such drugs has surpassed 5999[ Based on the data reported in these clinical phase III studies\ the answer to the _rst question is de_nitively a.rmative[ All six ChEIs produce statistically signi_cant improvements evaluated with scales of standardized and internationally validated measures of both cognitive and non!cognitive function[ Cognitive items have been most widely used in these investigations[ One immediate observation is the simi! larity in size of cognitive e}ect for all six drugs when expressed as a di}erence between drug! and placebo! treated patients[ Maximal di}erences in ADAS!cog between drug "at all doses# and placebo!treated patients average 2[5 points "ADAS!cog# and a average di}erence of 0[1 points is seen at the study end point[ Di}erences at the study end point vary from a gain of 9[4 points "metrifonate high dose# to a maximum of 1[7 "tacrine high dose#[ This similarity in cognitive e}ects suggest a ceiling value of approximately 4 ADAS!cog points aver! age for ChEIs at mild to moderate stages "CDR 0Ð0[4# of the disease[ It could also suggest that some drugs may have not been tested at their full capacity[ For tacrine\ the high percentage of drop!outs and side!e}ects seem to indicate a limit in ChE inhibition as well as in drug e}ect[ For other drugs "e[g[ metrifonate and donepezil#\ producing higher ChE inhibition "up to 79)#\ severity of side!e}ects does not seem to represent a limiting factor[
Table 0 Comparison of the e}ect of six cholinesterase inhibitors on ADAS!cog test "ITT#
Drug ref[
Dose mg:day
Duration of study weeks
Tacrine0 Eptastigm[1 Donepezil2 ENA 6023 Metrifonate4\5 Galanthamine6
019Ð059 34 4Ð09 5Ð01 14Ð64 29
29 14 13 13 01Ð15 01
Treatment di}erence from from PLACEBO BASELINE
Improved patients )
Drop!out )
Side e}ects )
3[9Ð4[2 3[6 1[7Ð2[0 0[8Ð3[8 1[7Ð2[0 2[2
29Ð49 29 47 14 24 *
44Ð62 01 04Ð29 04Ð16 1Ð10 22
39Ð47 24 02 17 1Ð01 *
9[7Ð1[7 0[7 9[6Ð0 9[6 9[64Ð9[4 0[7
ADAS!cog AD Assessment Scale!cognitive subscale[ ITT intention to treat[ study endpoint vs placebo[ study end point vs baseline[ Drugs] Tacrine "THA#\ Eptastigmine\ Donepezil "E 1919#\ ENA 602 "rivastigmine#\ Metrifonate\ Galanthamine[ 0 Farlow et al[ "0881#^ Knapp et al[ "0883#[ 1 Canal and Imbimbo "0885#^ Imbimbo "0885#[ 2 Roger and Friedho} "0885#^ Rogers et al[ "0885#[ 3 Anand et al[ "0885#[ 4 Becker et al[ "0885a\ 0885b#[ 5 Morris et al[ "0886#[ 6 Wilkinson "0886#[
E[ Giacobini:Neurochem[ Int[ 21 "0887# 302Ð308
The percentage of improved patients varies from 14) "ENA 602\ high dose# to 47) "donepezil\ high dose# with an average of 27)[ It should be noted that a certain percentage of patients do not improve at all on the ADAS!cog[ These data indicate that more than one third of treated patients show a positive response to ChEIs[ While this is not an impressive _gure it may still improve signi_cantly if the percentage of treatable patients could be increased to 79Ð89) by using ChEIs producing less severe side!e}ects at higher dosage[
2[ Symptomatic effect of disease stabilization< Analysing the available 5 months data shown in Table 0\ it is possible to observe that patients treated with the active compound change little cognitively from baseline at the beginning treatment[ As an example in a U[S[A[ study with ENA 602\ patients administered placebo for 15 weeks deteriorated over 3 points on the ADAS!cog compared to only 9[2 in patients given 5Ð01 mg:day of the drug "Anand et al[\ 0885#[ The same is true for metri! fonate treatment[ This suggests that the di}erence seen after 5 months between placebo!treated and drug treated groups may depend more on the di}erence with the rate of cognitive deterioration of the placebo group "1Ð3 points# than on a real improvement[ This interpretation suggests a stabilization e}ect of the drug! contrasting deterioration rather than a purely symptomatic e}ect[ This putative protective e}ect could be primary and structural leading to a stabilization of cholinergic func! tion as re~ected by the cognitive improvement measured by ADAS!cog\ or be a secondary e}ect[ Tacrine and donepezil\ on the other hand\ seem to show a real initial improvement "1Ð2 points# as compared to the placebo group[ This e}ect may last from 3Ð13 weeks\ depending on the dose "Farlow et al[\ 0881^ Knapp et al[\ 0883^ Roger and Friedho}\ 0885#[ It remains to be dem! onstrated whether or not this improvement represents a real di}erence in drug e}ect[ As indicated by open long! term studies of up to 13 months "cf[ Becker et al[\ 0885a\b^ and Table 2# it seems possible to maintain the di}erence between placebo! and drug!treated subjects beyond the present 5 months limit[ This represents a signi_cant gain for both patient and caregiver[
3[ Can the clinical ef_cacy of various ChEIs be compared< ChEIs could di}er from one another with respect to magnitude and duration of e}ect[ In comparing present results of clinical trials and di}erent drugs one should take into consideration the fact that these studies may di}er from one another\ depending on di}erences in selec! tion criteria\ age of subjects\ severity of disease\ con!
304
comitant illnesses and medications\ variable instruments of assessment and side e}ect evaluation[ In addition to these variables\ in order to evaluate real di}erences in e}ect between drugs one has to take into consideration the rate of deterioration of the placebo!exposed group which is compared with the treatment!group[ This rate of deterioration seems to be highly variable in the present studies "0Ð3 points at 13 weeks# among di}erent studies[ Also\ by using {completers| instead of ITT\ the analysis could produce somewhat higher e}ects[ Thus\ clinical studies are not entirely comparable and conclusions at this stage can be considered only as indicative[ Given these limitations\ the next goal to be achieved in a future ChEI treatment would be to enhance the e}ect up to 5Ð7 ADAS!cog points and to a 9[5Ð9[6 point gain "averaging presently 9[3# on Clinical Interview!Based Impression of Change "CIBIC# during a 5 months treatment period[ At least 49) of this e}ect should be maintained for 01 months\ the number of drop!out patients should be no higher than 09) and the level of side e}ects very low[ That this an achievable goal is suggested by the results of open long!term studies "Table 2#[ The fact that in several trials reported in Table 0 a certain percentage of patients reached much higher levels of cognitive improvement "6Ð 00 ADAS!cog points# and have not immediately deterio! rated after drug withdrawal supports this optimistic view[
4[ What makes the difference between various ChEIs< The relation between percentage of peripheral ChE inhi! bition and cognitive "ADAS!cog# or global impression of change rated by the clinician "CGIC# e}ect is a relevant factor which is reported in Table 1[ The data presented in Table 1 supports the pharmacological knowledge that brain ChE inhibition relates directly to an improvement of functional ACh levels[ This relationship might vary quantitatively for each drug and each compound may produce various levels of cognitive improvement and therapeutic e}ect "Giacobini et al[\ 0877\ 0884^ Giacobini\ 0885#[ This hypothesis is in agreement with pharma! cological data in animals "Mattio et al[\ 0875^ Giacobini et al[\ 0878# and in humans "Giacobini et al[\ 0877#[ The level of peripheral enzyme inhibition which has been measured in the patient "AChE activity in eryth! rocytes or plasma BuChE activity# producing a di}erence on the cognitive test varies between 29) and 79) depending on kinetic and pharmacological characteristics of the compound "Table 2#[ For some drugs "see done! pezil and metrifonate# the achievable level of non!toxic ChE inhibition can be as high as 89)[ As predicted by pharmacological and behavioral data\ there is a clear correlation between ChE inhibition "or drug plasma con! centration# and cognitive e}ect "Giacobini et al[\ 0878^ Giacobini and Cuadra\ 0883#[ Drugs producing mild cholinergic side e}ects\ even at high dosage and a high
305
E[ Giacobini:Neurochem[ Int[ 21 "0887# 302Ð308 Table 1 Relation between percent ChE inhibition and e}ect on ADAS!cog or CGIC Drug ref[
Dose mg:day
Steady state ) inhibition
Optimal ) inhibition
Correlation ChEI: ADAS!cog or CGIC
Physostigm[0 Eptastigm[1 Metrifonate2 Donepezil3 Tacrine4
2Ð05 29Ð59 29 4 059
39Ð59 "BuChE# 02Ð43 "AChE# 24Ð64 "AChE# 53 "AChE# 39 "BuChE# 59 "AChE# 49Ð59 "AChE#
29Ð39 29Ð24 54Ð79 59 29
U!shaped U!shaped U!shaped linear linear
49
U!shaped
Galanthamine5
19Ð49
ADAS!cog AD Assessment Scale!cognitive subscale[ CGIC Clinician Global Impression of Change[ Drugs] Physo! stigmine\ Eptastigmine\ Metrifonate\ Donepezil "E1919#\Tacrine "THA#\ Galanthamine[ 0 Thal et al[ "0872#[ 1 Imbimbo and Lucchelli "0883#^ Canal and Imbimbo "0885#[ 2 Becker et al[ "0889#[ 3 Roger and Friedho} "0885#[ 4 Farlow et al[ "0881#^ Knapp et al[ "0880\ 0883#[ 5 Wilkinson "0886#[
level of brain ChE inhibition\ may be tested in the patient within their full range of therapeutic potential[ For some ChEIs "physostigmine\ galanthamine\ eptastigmine and metrifonate# the relation between ChE inhibition and cognitive e}ect is inversely U!shaped\ while for other ChEIs "such as tacrine\ ENA 602 and donepezil# this relation seems to be linear[ The U!shaped form can be explained by the fact that by increasing the dose of the inhibitor one obtains progressively increasing e.cacy until adverse e}ects do not become a limiting factor[ Metrifonate could represent an exception since it shows low cholinergic toxicity even at high "79Ð89)# levels of AChE inhibition[ Another reason for the U!shaped curve is the speci_c inhibition kinetic of the inhibitor! and the substrate!induced saturation e}ect of ChEs[ The level of ACh brain elevation varies according to brain ChE inhibition "Giacobini\ 0883\ 0884\ 0885#[ With increased brain concentrations of ACh\ substrate inhibition of
enzyme activity becomes a phenomenon of particular importance[ It is observed in brain tissue in vitro and is probably present also in vivo "Giacobini\ 0883#[ Plotting velocity of enzymatic reaction against substrate "ACh# concentration\ a bell!shaped curve with a de_ned peak in case of AChE activity "brain and erythrocytes# and a sigmoid curve in case of BuChE activity "serum# are observed[ Thus\ AChE is inhibited by a large excess of ACh such as it can be produced by a high inhibition of brain AChE in AD!a}ected patients[ The substrate elevation has the e}ect of decreasing the catalytic potency of the enzyme and subsequently its pharmacological and therapeutical e}ect[ From this relationship it can be pre! dicted that a high ChE inhibition reached rapidly in time during treatment "rapid passage of the drug into the brain and fast accumulation in CNS# will not further increase e.cacy but only augment CNS dependent side!e}ects "drowsiness\ nausea\ vomit etc[#[ It should be an advan!
Table 2 Long!term cognitive e}ects of tacrine and eptastigmine on Alzheimer Disease progression
Reference
Daily dose "mg#
Test
Amberla et al[ 0882 Wilcock et al[ 0883 Eagger et al[ 0883 Solomon et al[ 0885 Knopman et al[ 0885 Imbimbo et al[ 0886
79Ð059 79 49Ð049 059 79Ð019 29
Buschke MMSE\ CAMCOG AMTS ADASÐCog NHP ADASÐCog MSE IADL
Di}erence between treatment and baseline at 00Ð04 mo[ at 06Ð13 month no change no change no change no change
AMTS Abbreviated Mental Test Score\ NHP Nursing Home Placement Tacrine[ Eptastigmine\ IADL Instrumental Activity of Daily Living[ Study end point vs baseline[
* * * 1[7 delay 5[3 2[8 3[7
E[ Giacobini:Neurochem[ Int[ 21 "0887# 302Ð308
tage to use a slow!release type of ChEI inhibiting both brain enzymes "AChE and BuChE# at a slow pace in order to reach gradually steady!state levels of brain Ach[ Such a procedure may also lower the risk of cholinergic receptor down!regulation and enzyme induction[ Indeed\ there is an excellent agreement between clinical and ani! mal data for both physostigmine and tacrine with regard to dose:behavioral e}ects relationships[ Rupniak et al[ "0889# using two primate models "rhesus monkeys# found that both tacrine and physostigmine improved visual rec! ognition memory signi_cantly[ Both drugs showed a clear inverse U!shaped relationship with a maximal e}ect at around 9[9909Ð9[91 mg:kg i[m[ for physostigmine and 9[7Ð0 mg:kg for tacrine[ Lower or higher doses did not improve performance but only increased side e}ects[ Cen! tral cholinergic side e}ects which may develop early in the treatment are not related directly to brain AChE inhibition but to a rapid elevation of ACh levels[ In rat brain\ this increase is not directly correlated to AChE inhibition "Giacobini\ 0883\ 0884#[ Peripheral side!e}ects may also occur depending on a rapid redistribution of the drug "or its metabolites# between non!CNS "peripheral organs and muscles# and CNS compartments[ Therefore\ the presence of active metabolites is important in explain! ing the origin of these side e}ects[
5[ Is there a tolerance to the effects of AChEIs< A combination of pharmacokinetic and pharmaco! dynamic e}ects of the drug such as down!regulation of muscarinic and nicotinic receptors and decreased ChE inhibition due to new enzyme synthesis\ may be respon! sible for the tolerance to therapeutic e}ects seen in exper! imental animals and patients treated with ChEIs for 13 weeks or longer[ Last but not least\ a problem of ChEI therapy is the early identi_cation of those patients most likely to bene_t from therapy[ Correlation of therapy e}ectiveness to gen! etic risk factors "APOE!allele# represents a _rst attempt in this direction[ Choosing the proper responder to cho! linomimetics and selecting patients at earlier stages of the disease at which to start medication may be crucial for the success of the therapy[
6[ General Conclusions
306
involved clinical trials of six di}erent ChEIs using the same scales under relatively uniform conditions[ Soon available data on these drugs originate from more than 5999 patients treated in 13Ð29 week phase III double! blind placebo controlled trials conducted world!wide[ In spite of obvious di}erences in patient and placebo popu! lations all six drugs have shown cognitive e}ects of a similar magnitude[ Major di}erences seem to relate not to cognitive e}ects but to severity and frequency of side e}ects and to percentage of responding patients and drop outs[ It is suggested that these di}erences depend on the possibility of reaching higher AChE and BuChE brain inhibition at low levels of cholinergic toxicity[ Dose e}ects are also important[ The data suggest that opti! mization of e.cacy and prolongation of clinical gains for one year or more are possible[ Further progress will depend on our knowledge of pharmacodynamic e}ects of long!term treatment[ Cholinesterase inhibitors\ par! ticularly second generation\ "post!physo and post!tacrine compounds#\ a}ect cortical as well as sub!cortical neuro! transmitters other than ACh "Giacobini\ 0885#[ Their e}ects on NE and DA are of particular clinical relevance[ A newly demonstrated feature of ChEIs is their ability to enhance the release of non!amyloidogenic soluble deriva! tives of APP in vitro and in vivo and possibly to slow down formation of amyloidogenic compounds in brain "Mori et al[\ 0884#[ This process might also slow down cognitive deterioration of the patient as indicated by the analysis of recent clinical data from open long!term trials "Table 2#[ Cholinomimetic alternatives other than ChE inhibition are being explored[ Drugs most investigated are those showing direct stimulation of postsynaptic M0 and M2 muscarinic receptors or nicotinic agonists of a! 3!b!1 and a!6 receptors[ This attractive line of cholinergic therapy has not yet produced convincing clinical results mainly depending on gastrointestinal and cardiac side e}ects[ Depending on the success of ChEIs one can predict new potential indications for applications to di}erent stages of AD such as] "a# preclinical presymptomatic stages in at risk!individuals with MCI "minimal cognitive impairment#\ "b# early AD patients with manifested symptoms "CDR 9[4Ð0# and "c# late AD "CDR 1# patients with behavioral symptoms[ A combination of ChEIs with muscarinic or nicotinic agonists or with b!A3 processors or APP!releasers and estrogens represent another valid alternative\ particularly in case of development of tol! erance to ChEI monotreatment[
6[0[ The future of AD therapy with cholinesterase inhibi! tors ChEIs are presently the drugs of choice for AD[ In less than 09 years\ starting from non!speci_c _rst generation drugs such as physostigmine\ a second generation of more selective and better tolerated products has been developed[ The data summarized here for the _rst time
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E[ Giacobini:Neurochem[ Int[ 21 "0887# 302Ð308
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