NEURODEGENERATION, Vol.

4, pp 349–356 (1995)

The Pharmacotherapy of Alzheimer’s Disease Based

on the Cholinergic Hypothesis: an Update
Marta Weinstock
Department of Pharmacology, School of Pharmacy, Hebrew University Hadassah Medical
Centre, Ein Kerem, Jerusalem, Israel

Alzheimer’s disease (AD) is a neurodegenerative disorder with impairment of cognitive function

and personality. The synaptic loss, neuronal atrophy and degeneration of cholinergic nuclei in the
basal forebrain may be associated with a reduction in oxidative metabolism of glucose, a fall
in acetyl CoA and ATP. Current pharmacological strategies, aimed at increasing cholinergic ac-
tivity include acetylcholinesterase (AChE) inhibitors, cholinergic agonists, acetylcholine (ACh)
releasers and stimulants of nerve growth factors (NGF). AChE inhibitors, physostigmine and
Tacrine can slow the decline of cognitive function and memory in some patients with mild or
moderate AD, if given for at least 3–6 months in sufficient doses to inhibit brain AChE. Their
main disadvantages are low oral bioavailability, peripheral cholinergic hyperactivity and liver
toxicity with Tacrine. Newer, less toxic AChE inhibitors, with selective central activity, formu-
lations of physostigmine, selective M1 and nicotinic agonists are becoming available with
improved bioavailability and pharmacokinetics. These may increase the likelihood of therapeu-
tic benefit in AD. Nootropic drugs, e.g. piracetam, which release ACh and are relatively non-toxic
could possibly slow the progression of the disease. A combination of an AChE inhibitor, pira-
cetam and a stimulator of NGF may show additive effects on memory processes but with a lower
incidence of untoward effects.
© 1995 Academic Press Limited

Key words: acetylcholinesterase inhibitors; glucose metabolism; nicotinic agonists

ALZHEIMER’s DISEASE (AD) is a degenerative disorder,
in which there is a progressive deterioration of intel-
lectual and social functions, memory loss, personality
changes and inability for self care. Cognitive impair-
ment is invariably present and progresses over time.
On the other hand behavioural impairments are com-
mon, but may occur irregularly and do not necessarily
progress monotonically in the same way. A rational
therapeutic intervention for the treatment of AD
should take these facts into account and should be
based on an understanding of the aetiology and under-
lying pathology. Although this is still unclear, AD is
believed to result from a cascade of events involving
the loss of terminal neurites and dendrites, which in
turn leads to an atrophy of neuronal cell bodies and
neurones in the cerebral cortex, hippocampus
Received 14 February 1995; revised and accepted for publication 18
May 1995
© 1995 Academic Press Limited
1055–8330/95/040349 1 8 $12.00/0
349
(Masliah et al. 1993) and amygdala (Cuenod et al.,
1993). This loss of neurones is widespread but not uni-
form, involving the association, olfactory and entorhi-
nal cortex and also the nucleus basalis of Meynert.
Amyloid precursor protein (APP) is involved in the
regulation of cell growth and neuronal development.
The processing of APP into β/A4-protein may lead to
alterations in cell growth and could be responsible for
the cell death observed in AD. Abnormalities in the
phosphorylation of other cell proteins is also seen in
AD and may be due to a loss of protein kinase C.
Aberrant phosphorylation may also be responsible for
the formation of neurofibrillary tangles (NFT) in the
neocortex (Katzman & Saito, 1991). Recent studies on
patients at different stages of the disease have shown
a close correlation between the number of NFTs and
the severity of disease and its duration (Aggiagada et
al., 1992; Masliah et al., 1994). Although both synaptic
loss and the neuronal processing of APP into β/A4
protein occur at early stages of the disease, it is not
known which comes first, and what triggers these
changes. One possibility is a reduction in regional glu-
350
cose metabolism, which as been demonstrated by
positron emission tomography in parts of the frontal
lobes early in the disease (Mann et al., 1992; Hoyer,
1992). This could be due to decreases in the activities
of several enzymes of the glycolytic pathway which
appear to precede the disappearance of nerve cells
(Meier-Ruge, 1990). Deficits in glucose metabolism can
be compensated for a while by the oxidation of other
substrates, but such losses and that of ATP may even-
tually lead to a breakdown in calcium ion homeostasis
and cell death (Barger et al., 1993). Moreover, a reduc-
tion in ATP prevents the incorporation of APP into cell
membranes. This could result in the generation of
β/A4 amyloid, while the failure of repair processes
involving APP could induce nerve cell atrophy (Meier-
Ruge et al., 1994).
Deficits in Cholinergic Transmission
Since the early 1970s, a highly consistent finding in the
brains of patients with AD has been the degeneration
of neurones from the cholinergic nuclei in the basal
forebrain region and of their terminals in the hip-
pocampus (Whitehouse et al., 1982). More recently it
has been shown that the neuronal atrophy, associated
with a loss of cholinergic markers, occurs specifically
in the nucleus basalis of Meynert (NBM) (Vogels et al.,
1990). The cholinergic system is responsible for the
storage and retrieval of items in memory (Bartus et al.,
1982) and its degeneration correlates well with the
severity of cognitive and memory impairment
(Giacobini, 1990). There is also a significant reduction
in choline acetyl transferase (ChAT) (Bowen &
Davison, 1986), the enzyme responsible for synthesiz-
ing acetylcholine (ACh) from choline, and of ACh in
the cerebrospinal fluid; loss of both correlate highly
with dementia score (Khatchaturian, 1985; Toghi et al.,
1994).
While there is general agreement about a reduction
in the number of nicotinic acetylcholine receptors in
the frontal and temporal cortices in AD (Whitehouse
et al., 1988; Nordberg et al., 1992a; Shroder et al., 1991a),
a loss of muscarinic receptors is not usually found
(Schroder et al., 1991b; Nordberg et al., 1992a; Svensson
et al., 1992). However, it has been suggested that there
may be a reduction in the M1 subtype (Ogawa et al.,
1993) and a disturbance in the coupling of muscarinic
receptors to G-proteins and to the second messenger
system (Warpman et al., 1993). The mechanisms
responsible for the (relatively selective) reduction in
cholinergic transmission in the cortex and hippocam-
M. Weinstock
pus (at least in the early stages) are unknown but these
could be linked to abnormalities in glucose metabo-
lism. A decrease in brain glucose concentration below
physiological levels could impair ACh synthesis by
lowering the concentration of acetyl-CoA, this being
derived from glucose via oxidation of pyruvate.
Neuritic plaques and NFTs contain large amounts
of butyryl and acetyl cholinesterase (AChE), which
may come from neuroglia (Wright et al., 1993), and
which have different histochemical properties from
the analogous enzymes in intact neuronal cell bodies
and axons. These enzymes may play a role in the pro-
cessing of APP (Wright et al., 1993) though it remains
to be determined whether inhibition could influence
the pathogenetic course of AD.
Pharmacotherapy of AD
Since the aetiology and exact pathology of AD is still
unclear, most current therapeutic strategies have been
directed towards decreasing the deficits in the cholin-
ergic system in the hope that this will improve or pre-
serve cognitive function. Failure to show a significant
improvement with a particular treatment may be due
not only to the drug itself but also to the difficulty in
making a conclusive diagnosis of AD. Thus, many
studies will have inevitably included patients who did
not have this form of dementia, or in whom the neural
degeneration was too far advanced to obtain even
symptomatic improvement. The method of patient
assessment, e.g. the type of diagnostic scale, the rela-
tive weight given to different symptoms, and whether
the evaluation is based on clinical impression or also
takes into account that of caregivers, may also have
influenced the apparent efficacy or otherwise of the
drug. Other trials have not allowed an adequate time
to elapse between placebo and drug treatments, nor
have taken into account the natural but variable
decline induced by the disease (see below). The qual-
ity of future drug trials should be improved by imple-
mentation of universally standardized diagnostic
criteria and assessment strategies (Farlow, 1994).
Inhibitors of acetylcholinesterase
ACh is rapidly destroyed by AChE after its release;
inhibitors of this enzyme can significantly prolong its
action. In the early stages of the disease, before there
is substantial loss of cholinergic neurone, AChE
inhibitors may be more efficacious than either mus-
carinic or nicotinic agonists, since both types of recep-
Cholinergic drugs in Alzheimer’s disease
tor appear to be involved in the mediation of memory.
Two anti-AChEs, physostigmine and tetra-
hydroaminoacridine (tacrine), were actually available
for clinical use even before the deficit in cholinergic
transmission was discovered in AD. This has facili-
tated their clinical evaluation in the treatment of AD
without the need for usual extensive preliminary test-
ing.
Physostigmine. The demonstration that physostigmine
given orally (Thal et al., 1983; Sano et al., 1993), or by
intravenous infusion (Gustafson et al., 1987) to patients
with AD produced some improvement in memory and
cognitive function but not in mood or personality
(Sano et al., 1993) provided support for the choliner-
gic deficit in this disease. Failure to obtain a thera-
peutic effect in some trials could have been due to
insufficient dosage which precluded adequate inhibi-
tion of the brain enzyme (Thal et al., 1983). The likeli-
hood of obtaining a significant clinical improvement
with physostigmine in comparison with a separate
placebo-treated group increased when the drug was
given for longer periods (3–6 months). An increase in
memory scores of 12% from baseline in the physostig-
mine-treated patients became ever more significant
when compared to the decline of 15–21% in those on
placebo (Sano et al., 1993).
Physostigmine, however induces a high incidence
of side effects and has a narrow therapeutic window
which limits the dose in which it can be given. Toxic
symptoms result mainly from peripheral cholinergic
hyperactivity and include, diaphoresis, muscle fasci-
culations or cramps, nausea, vomiting, bradycardia
and arrhythmias in a significant proportion of subjects
(Stern et al., 1987). Its oral bioavailability is low and
unpredictable and the drug has a very short duration
of action (Christie et al., 1981). Attempts are being
made to overcome some of these shortcomings by
altering the formulation of the drug in oral sustained
release (Forest Laboratories) or by using transdermal
preparations (Levy et al., 1994). Many of the side effects
can be prevented by the concomitant administration
of a peripherally-acting muscarinic antagonist such as
glycopyrrolate.
Tacrine. Tacrine is a competitive inhibitor of AChE with
a longer duration of action than physostigmine. It con-
centrates in the brain because of its relatively greater
lipid solubility (Nielsen et al., 1989); it interacts directly
with muscarinic receptors (Adem, 1993) and also
inhibits monoamine oxidase A and B (Adem et al.,
1989). One of the first placebo-controlled crossover
351
trials of oral tacrine in doses up to 200 mg/day plus
lecithin, .10 gm/day in 17 subjects showed a dramatic
and objective improvement in several psychometric
tests of cognitive function in 10 patients (Summers et
al., 1986). Failure of others to show any change in cog-
nitive function was associated with serum tacrine
levels below 7 ng/ml and the clinical response in these
was reported to increase dramatically when the dose
was raised. Subsequent studies in larger numbers of
patients have not shown any improvement with this
drug combination (Chatellier & Lacomblez, 1990;
Gauthier et al., 1990) nor a statistically significant effect
for the whole group in comparison with placebo when
tacrine was given alone, although individual patients
did clearly improve in tests of attention, working and
visual memory (Davis et al., 1992; Wilcock et al., 1993;
Nyback et al., 1993). The lack of effect could have been
due to an inadequate washout between drug and
placebo phases (Chatellier & Lacomblez, 1990) insuf-
ficient drug (Gauthier et al., 1990), since the maximum
amount of tacrine given was only 100 mg/day, or the
natural decline in cognitive function which may have
influenced the interpretation of the results if patients
were first given placebo and then tacrine (Wilcock et
al., 1993).
When the drug was evaluated by a combination of
objective cognitive tests, clinician and caregiver global
assessments and activities of daily living in a parallel
design, with each group receiving either drug or
placebo, a significant drug benefit was seen after 18
weeks at a dose of 160 mg/day (Knapp et al., 1994).
However, fewer than 50% of patients completed the
study because of side effects. As with physostigmine,
the ‘therapeutic effect’ was due as much to the decline
in the placebo-treated group as to an improvement in
the drug group. The betterment of cognitive function
by tacrine in other trials was associated with increases
in the number of nicotine binding sites, glucose metab-
olism (Nordberg et al., 1992b), HIAA, HVA or somato-
statin in the CSF (Alheinen & Riekkenen, 1993). Tacrine
responders were also distinguished in the latter study
by a significant increase in the alpha/theta ratio of
their quantitative EEG.
Tacrine has a low oral bioavailability with plasma
levels fluctuating widely between individuals. This
can be significantly improved by titration of the dose
for each patient to a given plasma level and by rectal
administration which increases bioavailability from
19% to 34% (Nyback et al., 1993). Like physostigmine,
tacrine causes a high incidence of peripheral cholin-
ergic toxicity, probably because it is a more potent
inhibitor of butyryl than acetylcholinesterase (Adem,
352
1993). In addition, it increases liver enzyme levels in
up to 50% of subjects which reaches clinical signifi-
cance in at least 25%, requiring cessation of treatment.
This adverse effect is not related to its AChE inhibi-
tion but is reversible (Gautier & Gautier, 1993). The
general impression gained from numerous clinical
trials is that despite the relatively low proportion of
responders and the high incidence of adverse effects,
tacrine may slow the decline in cognitive function in a
significant proportion of subjects if enough is given to
maintain an adequate blood level over a sufficient
period of time. Adverse effects may be reduced if the
dose is increased slowly at 6-week intervals (Knapp et
al., 1994) and liver toxicity prevented if serum transam-
inase is monitored weekly (Wagstaff & McTavish, 1994).
Novel cholinesterase inhibitors. Clinical experience with
physostigmine and tacrine stimulated the search for
new AChE inhibitors which have a more reliable oral
bioavailability, a longer duration of action and an
improved safety margin. Since the liver toxicity is
unrelated to cholinesterase inhibition, but is associ-
ated with the aminoacridine moiety, this has not been
encountered with different structures. Several of the
novel drugs have completed phase I or II of clinical
studies. They include velnacrine, heptylphysostig-
mine (eptastigmine), huperazine A, galanthamine,
E2020 and SDZ ENA 713. All of them show a better
oral bioavailability than physostigmine or tacrine and
a longer duration of action, but several of them do not
show a significantly higher safety profile to justify
their substitution for tacrine.
Velnacrine is a hydroxy derivative of tacrine with a
similar adverse reaction profile, including cholinergic
hyperactivity, rash and liver reactions (Murphy et al.,
1991). Eptastigmine showed a promising pharmaco-
logical profile in preclinical studies but recent evi-
dence of haematological toxicity has precluded further
development (Iversen, 1993). It is not known whether
this latter effect is related to its AChE inhibitory activ-
ity or is independent of it. Although both acetyl- and
butyrylcholinesterase are present in developing blood
cells (Paoletti et al., 1992), blood dyscrasias have not
been reported in patients receiving either physostig-
mine or tacrine. The latter drugs may have a lower
affinity than eptastigmine for the form of enzyme pre-
sent in developing blood cells.
Galathamine and huperazine are both plant alka-
loids which produce a relatively long-lasting inhibi-
tion of brain AChE in mice or rats (Bickel et al., 1991;
Tang et al., 1989). However at doses that inhibit corti-
cal AChE by 30–40%, peripheral cholinergic side
M. Weinstock
effects occur with both drugs (Sweeney et al., 1989),
including muscle fasciculations with huperazine A
(Tang et al., 1989). This suggests that the latter may
induce some measure of respiratory paralysis through
its action on AChE in muscle and that neither drug
is particularly selective for brain AChE. E2020,
(R,S)-1-benzyl-4[5,6-dimethoxy-1-indanon)-2-yl]
methylpiperidine hydrochloride is a synthetic drug
which also shows a much longer duration of AChE
inhibition than either physostigmine or tacrine. In
human subjects, over 90% of an oral dose is bound to
plasma proteins (Mihara et al., 1993) and it may delay
the attainment of adequate inhibition of the enzyme
in the brain.
SDZ ENA 713 is the 1-isomer of N-methyl,
N-ethyl,dimethylamino-ethyl-phenyl carbamate and
is distinguished from other anticholinesterase agents
by its ability to inhibit the enzyme in the cerebral cor-
tex and hippocampus by more than 40% at doses that
have little or no effect on that in plasma, heart,
skeletal muscle or other brain regions (Weinstock et al.,
1986). Moreover, in contrast to physostigmine and
tacrine, SDZ ENA 713 inhibits preferentially the G1
form of AChE (Enz et al., 1993) which unlike the G4
form, is not lost from the brains in AD (Siek et al., 1990).
This brain selectivity gives the drug a much wider safety
margin with a therapeutic ratio more than double those
of physostigmine and tacrine (Weinstock et al., 1994).
The brain selectivity is also seen in normal human sub-
jects in whom there are no symptoms of peripheral
cholinergic hyperactivity at doses that significantly
affect hippocampal cholinergic transmission (Enz et al.,
1993). So far, there have been no reports of hepatotoxi-
city, or blood dyscrasias. It may be significant that in
contrast to heptylphysostigmine, galanthamine and
huperazine A, it is a relatively poor inhibitor of AChE
in human erythrocytes (Weinstock et al., 1994).
Acetyl choline precursors
Lecithin is a membrane lipid which serves as a pre-
cursor to choline. When given alone it does not appear
to have any measurable beneficial effect on cognitive
function in AD (Heyman et al., 1987), but it may
increase the efficacy of other drugs, such as Tacrine
and physostigmine (Thal et al., 1983; Summers et al.,
1986; Gauthier et al., 1990).
Muscarinic agonists
Although five different types of muscarinic recep-
tors have been cloned, four of which are present in the
Cholinergic drugs in Alzheimer’s disease
neocortex and hippocampus, it is not yet clear which
of these is involved in mediating the effects of ACh on
memory. Muscarinic receptors may play a role in the
processing of APP and may prevent formation of β/A4
protein since stimulation of M1 and M3 subtypes in cul-
tured PC12 cells increased the basal release of APP
derivatives (Nitsch et al., 1992). Clinical trials with
known muscarinic agonists, arecholine, oxotremorine
and RS86 in AD have failed to demonstrate any
improvement in cognitive function (Winblad et al.,
1993). Their poor oral bioavailability, short duration of
action and high incidence of cholinergic side effects
have precluded their further use. All these drugs in
any case have a higher affinity for the M2 subtype, acti-
vation of which decreases ACh release in the brain
and produces unwanted cardiovascular side-effects.
Attempts to synthesize selective M1 agonists which
penetrate the CNS have yielded compounds, AF102B
(Fisher et al., 1993) and PD 142505 (Davis et al., 1993).
The former is a rigid analogue of ACh with a selective
agonist activity on M1 receptors, improves memory in
animal models and has a wider margin of safety than
other muscarinic agents (Fisher et al., 1993). PD 142505
speeds learning in mice and has a lower incidence of
peripheral toxicity than non-selective muscarinic
agonists (Davis et al., 1993). Results of clinical trials
using these M1 agonists are not yet available and at
present it is not possible to assess their practicality in
this therapeutic approach.
Nicotinic agonists
Nicotinic and muscarinic receptors have been found
to be colocalized in many cholinoceptive pyramidal
neurones, but it is only the nicotinic receptors that are
consistently lost in AD (Shroder et al., 1991). There are
several different types of nicotinic receptors in the
brain but their precise distribution and function are
not yet known (Heinemann et al., 1991). Stimulation
of nicotinic receptors on cholinergic terminals
increases ACh release, this being diminished in AD
(Nordberg et al., 1988). The loss of nicotinic receptors
on cholinergic terminals suggests that nicotinic ago-
nists may be ineffective for the treatment of AD.
However, tacrine was able to restore nicotinic binding
sites in the brain in, parallelling its beneficial effect on
neuropsychological performance (Nordberg et al.,
1992b), and to increase release of ACh from brain slices
(Nordberg et al., 1988).
Nicotine itself can improve attention, memory and
problem solving in normal individuals and in those
suffering from AD (Sahakian et al., 1989; Jones et al.,
353
1992). There have also been reports that AD is less
prevalent in smokers (Le Houezec & Benowitz, 1991),
though this may be due to other factors. Nicotine is
unsuitable for long-term administration to suffers of
AD because of its action on peripheral receptors and
its relatively high toxicity. A novel agent has recently
been developed with selective agonist activity on the
α-4/β-2 subtype of neuronal nicotinic ACh receptor
found in mammalian brain, (S)-3-methyl-5-(1-methyl-
2-pyrrolidinyl) isoxazole (ABT) 418) (Arneric et al.,
1994; Decker et al., 1994). It does not interact with the
receptor in skeletal muscle and is 10 times more potent
than nicotine in improving retention of memory
in mice, but much less potent in inducing seizures
and hypothermia. ABT 418 also has significant anti-
anxiety activity in animal models, a potentially desir-
able property for the therapeutic management of AD.
It remains to be determined whether the compound
displays these same beneficial effects on cognitive
function and behaviour in patients with AD.
Nerve growth factor
Nerve growth factor (NGF) plays an important role
in the survival and maintenance of cholinergic
neurons in the central nervous system. The loss of
NGF receptors appears to precede that of cholinergic
cells in AD (Strada et al., 1992) and this could
explain the (selective) degeneration of such neurones.
NGF does not reach the brain after parenteral or
oral administration but its potential as a treatment has
been assessed in one patient with AD following
intracranial infusion for 3 months. Treatment
improved verbal and episodic memory, increased
cerebral blood flow and nicotine binding, but did not
affect cognitive function (Sieger et al., 1993), possibly
because of the relatively long duration of the demen-
tia (8 years).
Two novel agents TMQ, 6-(4-hydroxybutyl)-2,3,5-
trimethyl,1,4-benzoquinone and propentofylline
stimulate NGF synthesis in astrocytes and increase
NGF levels selectively in the hippocampus after par-
enteral administration in mice. TMQ increased ChAT
activity and improved memory in forebrain-lesioned
rats (Nitta et al., 1993), and pentofylline restored NGF
levels when given orally to aged rats (Nabeshima et
al., 1993). These agents may represent more specific,
less toxic treatments for memory impairments associ-
ated with loss of cholinergic neurons and might be
of benefit in the early stages of the disease when
NGF may still be able to prevent a further decline in
cholinergic function.
354
Nootropic drugs
This is a general term given to a group of drugs that
are said to improve nerve cell function by stimulating
phospholipid turnover and protein synthesis
(Nickolson & Wolthius, 1976). One of these, piracetam
augments ACh release and prevents the amnesia
induced by hypoxia or electroconvulsive shock in
experimental animals (Giurgea et al., 1971; Sara and
Davil-Remacle 1974). Piracetam has been available for
a number of years and is distinguished by producing
almost no adverse effects even after longterm treat-
ment. Administered alone or in combination with
lecithin in doses of 2.4–4.8 gm/day, it was without any
clear effects on memory, although it did appear to
increase alertness. In a recent placebo-controlled trial
in which 8 gm were given daily for 12 month, pirac-
etam significantly slowed deterioration in recent and
remote memory, although it did not improve perfor-
mance in any cognitive test (Croisilie et al., 1993).
Glucose
A disturbance of oxidative metabolism of glucose has
been suggested in AD (Hoyer, 1992; Mann et al., 1992).
Glucose is the only substrate used in the CNS for the for-
mation of acetyl-CoA; it reaches the brain through an
insulin-dependent carrier-mediated transport mecha-
nism (Hertz & Paulson, 1983). Patients with AD may
have fewer glucose transporters in the cerebral
microvessels (Horwood and Davies, 1994). In addition
to its action in promoting ACh synthesis, glucose is also
an important energy source for neurons. Parenteral or
intraventricular administration of glucose improved
memory retention in old rats (Gold, 1986; Leeet al., 1988).
When given orally to patients with AD with moderate
or severe dementia it significantly enhanced perfor-
mance on several tests of memory (Manning et al., 1993).
Although adrenaline does not penetrate the blood brain
barrier it improves memory retention in animals. This
appears to be due to the release of glucose from the liver
since its effects both on blood glucose and on memory
are blocked by adrenergic receptor antagonists (Gold,
1986). AChE inhibitors, nicotinic and muscarinic ago-
nists stimulate the release of adrenaline from the adrenal
medulla and elevate blood glucose. This may contribute
to their beneficial effects on memory in AD.
Conclusions
AD is a multisystem disorder. A rational therapy
should be directed towards preventing the nerve
M. Weinstock
cell damage leading to their loss or shrinkage and in so
doing correcting abnormalities in all neurotransmitter
systems. However, until this is found, one should at least
try to reduce the decline in memory and cognitive func-
tion and ameliorate the behavioural disabilities. This
might be possible by increasing cholinergic activity in
the cortex and hippocampus with the newer, brain-selec-
tive, less toxic cholinesterase inhibitors, and the nicotinic
and muscarinic agonists. These agents may be given
together in smaller doses along with glucose, lecithin,
NGF synthesis stimulators, and/or piracetam. Since the
adverse effects of the individual drugs differ but are
dose-related, it is possible that such additive combina-
tions could be more efficacious and at the same time be
less toxic than the individual drug therapy.
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