'Cerebroactive' Drugs Clinical Pharmacology and ...

Summary

Review Article

Drugs 26: 44-69 (1983)

00 12-6667/83/0700-0044/$13.00/0 © ADIS Press Australasia Pty Ltd. All rights reserved.

'Cerebroactive' Drugs Clinical Pharmacology and Therapeutic Role in Cerebrovascular Disorders

Alberto Spagnoli and Gianni Tognoni Regional Center for Drug Information, Laboratory of Clinical Pharmacology, Istituto di Ricerche Farmacologiche 'Mario Negri', Milan

While their importance in the market-place is steadily increasing in developed (mainly continental Europe) and even in developing countries, compounds included in the broad category of 'cerebroactive' drugs hardly rate a mention in reference pharmacology and therapeutics textbooks. It is an undeniable fact, however, that the principal users or targets of this drug class, mainly elderly people, represent an increasingly worrying problem, with their often puzzling cohort of ill-definable and even less predictable neurological and mental symptoms.

The combination of the above factors cannot but produce a rather confused situation, in which the pressure to treat and the adherence to scientifically rigorous assessment are likely to prevail alternately, on a purely casual basis.

This review aims to provide sound methodological guidelines for assessment of 'cerebroactive' drugs in a not always easily accessible literature. It covers firstly the general problems of stroke, dementia and 'common symptoms' of the elderly, and then looks in detail at those compounds which have to date attracted most attention (ergot derivatives, cinnarizine, jlunarizine, vincamine, eburnamonine, naftidrofuryl, oxpentifylline, piracetam and citicoline), as well as those which are currently considered investigational (choline and lecithin). The pharmacology and available clinical studies of each drug are examined.

No therapeutic indication can be derivedfrom the available evidence, as the few positive results do not go beyond random improvement of symptoms. More fundamentally, the lines of research which need to be pursued most intensively relate to better preliminary definition of diagnostic and prognostic criteria and, with the establishment of adequate testing tools for the assessment of behaviour and neuropsychological performance, those basal conditions which are modified 'naturally' or by drugs.

The quotation marks used to justify the term chosen to describe the large group of compounds considered in this review (table I) give possibly the most appropriate key for approaching this topic. These substances constitute a large proportion of the total prescribed drugs in many countries but they are hardly used at all in others (table II). They do elicit pharmacological effects, but widely dif-

fering levels or mechanisms of action are claimed (table III), the old cornerstone of vasodilatation (tables IV and V) being transformed into therapeutic indications which cannot be viewed without some hesitation or scepticism (tables VI and VII).

Are these compounds looking for a therapeutic role or have they already found one? What is their role, for what pathology, and on what basis? The

'Cerebroactive' Drugs

Table I. Some 'cerebroactive' drugs

Bamethan

Bencyclane Betahistine

Cyclandelate Cinnarizine

Citicoline Co-dergocrine (dihydroergotoxine)

Dihydroergocristine Eburnamonine Flunarizine

Isoxsuprine

Naftidrofuryl Nicergoline

Nicotinic acid derivatives

Nylidrin Oxpentifylline (pentoxifylline)

Papaverine

Piracetam Piribedil

Raubasine Suloctidil

Vincamine

following two quotations summarise the dilemma: 1. 'The haemodynamic disturbances are ap

proached with vasodilating substances, which specifically assume the functional improvement of cortical arterial anastomoses allowing for the development of substitutive circulation. Our pharmacological armamentarium is rich with such substances, which include papaverine and ergot derivatives, raubasine and other synthetic molecules such as cetiedil, piribedil, naftidrofuryl. It has been possible to quantify their haemodyamic activity by direct measurement of cerebral blood flow' (Goutelle et al., 1980).

2. ' . . . the utility of vasodilators in reversing or delaying the deleterious effects of acute or chronic cerebrovascular insufficiency is controversial, and the case for clinical efficacy is unimpressive' (Needleman and Johnson, 1980).

The fact that the accent is no longer on vasodilatation but on subtler, less clearly defined mechanisms does not substantially alter the situation. The question is whether or not there is documented evidence of clinical benefit, and it could not be more open.

45

Techniques now available to measure baseline data and drug effects (table VIII) should be considered with particular care. Progress has been made in assessing cerebral blood flow and its interaction with basic metabolic events, and in the study of the brain's electrical activity and its morphological aspects (extremely useful for precise diagnosis). On the other hand, the whole field of behavioural and psychometric assessment must be regarded with extreme caution because of the lack of satisfactory baseline data and comparative criteria for assessment of outcome.

Table II. Usage patterns for available 'cerebroactive' drugs in various countries

Country Usage patterns

England 0.2% of all drugs prescribed by general

practitioners (Skegg. 1979) 0.6% of all drugs prescribed nationally for people of all ages in 1975 (Department of

Health and Social Security. England. 1977) 5.4% of hospital patients with stroke. TIA or

multi-infarct dementia (Spagnoli et al .• 1982)

Italy 32.0% of elderly community residents

(Colombo et al.. 1979) 48.5% of hospital patients with stroke. TIA or multi-infarct dementia (Spagnoli et al.. 1982)

Spain 4.5% of total drug expenditure in 1978 (Laporte

et al.. 1979) 33.6% of elderly community residents (Mas et

al .• 1983)

Germany 5.0% of total drug expenditure for ambulatory

medical care in 1976 (Kimbel. 1979)

Yugoslavia 71.8% of hospital patients with stroke. TIA or

multi-infarct dementia (Spagnoli et al..

1982)

Indonesia 50.0% of hospital patients with stroke. TIA or

multi-infarct dementia (Spagnoli et al .• 1982)


1. Background Pharmacological Considerations

Most of the compounds listed in table I were introduced and first tested as 'vasodilators' for peripheral circulatory disorders and for cerebrovascular pathology. The basic assumption was that an improvement of the circulation through various mechanisms was possible, real and therapeutically useful (table IV).

The availability of more precise assessment methods quickly showed that such claims were merely wishful thinking (see the 'model case' of codergocrine, table V). At the same time, increased understanding of the aetiology and pathogenesis of impairment of cerebral function made it evident that neuronal metabolism, the microcirculation and neurotransmitters might playa more important role than blood flow per se. However, there is no satisfactory representation either of interactions among various factors or of how they are acutely and/or

46

chronically modified by drugs. Metabolic or neuronal activation, increased energy utilisation, neurotransmitter modulation or substitution, and membrane modification are among the more fashionable hypotheses which certainly define challenging areas of research, but for which hard data are scarce and fragmentary (even in laboratory animals), and the search for protocols to provide reliable quantitative information in man is still in a pioneer phase.

As a general point, to which we shall come back, this change of direction in pharmacological research points more and more to phenomena arid models bordering on psychopharmacology. The switch is not marginal, as it foresees the use of these drugs for symptoms and problems whose relationship with specific functional and/or organic disturbances is somewhat tenuous (see table VII).

It is easy to forecast a long period during which planning and evaluation of clinical trials will be difficult both in terms of identifying markers of the

Table III. Suggested mechanism(s) or level(s) of action of 'cerebroactive' drugs

Drug Vasodilatation Metabolic Platelet eNS neuro- Rheological Phospholipid activation aggregation transmitters properties synthesis

of blood

Bamethan + Bencyclane + + + Betahistine + Cyclandelate + + Cinnarizine + Citilcoline + + Co-dergocrine + + + Dihydroergocristine + + + + Eburnamonine + Flunarizine + Isoxsuprine + Naftidrofuryl + + + Nicergoline + + + Nicotinic acid derivatives + + Nylidrin + Oxpentifylline + + Papaverine + Piracetam + + Piribedil + + Raubasine + Suloctidil + + Vincamine + +

'Cerebroactive' Drugs 47

Table IV. A classification of some 'cerebroactive' drugs based on their (possible) vasodilator effect

Level of vasodilator action Drugs

Arterial smooth muscle (direct action) Bamethan, bencyclane, betahistine, cyclandelate, cinnarizine, flunarizine,

isoxsuprineb , naftidrofuryl, nicotinic acid derivatives, papaverine, raubasine

Neurogenic control (indirect action) a-adrenoceptor blockade

{3-adrenoceptor stimulation

Co-dergocrineb, dihydroergocristineb , nicergoline

Isoxsuprineb , nylidrin

CNS' Co-dergocrineb , dihydroergocristineb

a Central depression of vasomotor nerve activity. b More than one level of action is suggested for these drugs' vasodilator effect.

expected or purported effect (electrophysiological, biochemical, functional, etc), and of assessing the clinical importance of even 'significant' changes in symptomatic and behavioural scales or psychometric tests.

2. The Need for 'Cerebroactive' Drugs

Is there a therapeutic need for 'cerebroactive' or 'vasodilator' drugs in the 3 main areas of pathology: (a) stroke patients; (b) dementia; and (c) the so-called 'common symptoms' of the elderly?

All these situations are directly or indirectly envisaged in the promotional claims for most of the drugs discussed here (see table VI for a model case) but this should not obscure the fact that these situations are not related, either in their aetiology or, above all, in their natural history, and therefore the prospects for their therapeutic control.

2.1 Stroke

2.1 .1 Epidemiology and Therapeutic Needs The decreasing mortality and morbidity rates

for stroke (Garraway et aI., 1979a; Guberan, 1979; Kuller, 1978; Levy, 1979), which have been clearly documented for some industrialised (Guberan, 1979; Kuller, 1978) but not all countries (Cooper, 1981), is attributable more to a decrease in the incidence of cerebral infarct (first episode) than to an increase in stroke survivors (Garraway et ai.,

I 979b). This points firstly to the need for increased attention to risk factors [hypertension, diet, smoking, transient ischaemic attacks (TIAs), atrial fibrillation, etc.], and secondly for appropriate antihypertensive treatment (Kagan et aI. , 1980; Kannel et aI. , 1970; Mohr et aI. , 1978; Rabkin et aI., 1978; Veterans Administration Cooperative Study Group on Antihypertensive Agents, 1970).

The control of the main causes of mortality and morbidity among stroke survivors still poses complex and controversial therapeutic problems both for the acute events (brain oedema, cardiac abnormalities, pulmonary emboli, pneumonia) [Millikan, 1979] and for the chronic phase (coronary artery disease, poor autonomy) [Cartlidge et ai, 1977; Furlan et aI., 1980; Greshan et aI., 1975; Toole et aI., 1978].

2.1 .2 The Role of 'Cerebroactive' Drugs A 'vasodilator' effect has been advocated in

stroke therapy to improve cerebral blood flow (CBF) in the ischaemic and perilesional area; the 'activator' effect has been claimed to help the metabolism of surviving neurons.

There is no doubt that at least some of the drugs listed in table I are capable of modifying CBF over a short period when given at sufficiently high dosages, though it is accepted that the most powerful vasodilator is CO2 (Cook and James, 1981 ; Editorial, 1979; Heiss and Podreka, 1978; McHenry et ai, 1970; Meyer et aI., 1974). While this pharma-

Tab

le V

. T

he '

evol

utio

n' o

f co

-der

gocr

ine

(dih

ydro

ergo

toxi

ne):

crit

ical

stu

dies

Leve

l of

act

ion

1.

Vas

cula

r sy

stem

2. M

etab

olis

m a

nd

neur

otra

nsm

itter

s

Mec

hani

sm o

f ac

tion

Exp

erim

enta

l fin

ding

s

anim

als

Cen

tral

dep

ress

ion

of

vaso

mot

or n

erve

act

ivity

C

BF

t P

erip

hera

l a

-ad

ren

oce

pto

r bl

ocka

de

CB

F -

Dir

ect

stim

ulat

ion

of

smoo

th m

uscl

e

Inhi

bitio

n o

f lo

w c

yclic

AM

P K

m

phos

phod

iest

eras

e In

hibi

tion

of

phos

phok

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e ac

tivity

Inhi

bitio

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f ca

tech

olam

ine

stim

ulat

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A T

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tion

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upta

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Acc

umul

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apse

s

Lact

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ose

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abol

ism

t

Dim

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ain

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llarie

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p l

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eful

ness

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ect

s o

f m

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man

CB

F t

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F-

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BF

rC

BF

(iv

) ~.

rCB

F (

ic)-

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revi

atio

ns:

CB

F =

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ebra

l bl

ood

flow

; rC

BF

= r

egio

nal

cere

bral

blo

od f

low

; -

= n

ot

mod

ified

; t

= i

ncre

ased

; l =

dec

reas

ed,

a C

BF

redu

ced

in a

reas

with

im

pair

ed a

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egul

atio

n se

cond

ary

to a

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uctio

n in

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eria

l bl

ood

pres

sure

.

Ref

eren

ce

Rot

hlin

(19

46/4

7)

Rot

hlin

and

Tae

schl

er (

1951

) G

erau

d et

al.

(196

3)

Got

tste

in (

1965

) M

cHen

ry e

t ai

, (1

971)

O

lese

n an

d S

kinh

0j (

1972

)

Mei

er-R

uge

et a

\. (1

975)

Loew

et

a\.

(197

6)

t ~. g ~

00


cological effect has never been associated with convincingly documented clinical efficacy, a consensus seems to have been reached that vasodilatation may be dangerous because of the risk of a possible rise in intracranial pressure, the occurrence of 'steal' phenomena, and reduced perfusion pressure in the lesional and perilesional areas consequent to a broader vasodilatation.

The trend today as regards pharmacological regulation of metabolic activation points in the opposite direction, as research seems more interested in therapies to reduce the rate of brain metabolism (e.g. barbiturate therapy, therapeutic hypothermia) [Safar, 1980]. The rather weak rationale, if any, for a therapeutic role of 'cerebroactive' drugs in stroke patients is adequately defined in the following statement, which summarises current knowledge derived from studies of local CBF and oxygen metabolism (emission tomography with the ISO-inhalation technique): 'The post-ischemic brain is a complex mosaic of very different metabolic and hemodynamic focal situations which tend to vary considerably within the first few days. An ischemic lesion may show different perfusion patterns, anything from persisting severe ischemia to complete restoration of the circulation with luxury perfusion and vasoparalysis' (Fieschi, 1980).

2.2 Dementia and the 'Common Symptoms' of the Elderly

2.2.1 Definitions The main questions, which cannot be avoided,

could be formulated as follows: What is the degree of continuity between ageing of the brain and iis most pathological expression, dementia? Is there any continuity at all? Or should dementia be considered a completely separate issue for which old age is but one of the important risk factors? (Alexander, 1972; Bowen et aI. , 1979; Editorial, 1978a,b; Fries, 1980; Gruenberg, 1978; Plum, 1979; Smith and Kiloh, 1981).

The currently preferred attitude undoubtedly seems in favour of the second line of reasoning, but the picture changes if we look at medical practice and public opinion. Basket definitions such as

49

Table VI. Suggested indications for piracetam found in the literature

Stroke patients

'Common symptoms' of the elderly

Senile dementia Dizziness

Memory disturbances Chronic schizophrenia

Head injuries ('mild and severe')

Comatose patients

Chronic and acute alcoholism

Drug dependence

CNS adverse effects of drugs Cerebral palsy

Language disturbances during development age Adolescents with poor school results

Neurogenic bladder

Sickle-cell disease

cerebrovascular disorders, cerebral insufficiency, or 'common symptoms' of the elderly, seem to be the most successful and practicable, and find scientific support in the literature dealing with 'specific' drug treatment for the 'demented' or 'cerebrally impaired' elderly. It is easy to imagine that any such dissociation is not without consequences, as both the definition of need and the assessment of benefits of drug and other treatments will necessarily be biased by important confounding factors.

2.2.2 A 'Rational' Approach to Pharmacological Treatment of Dementia? A simple but important distinction should first

be made between symptomatic control of specific manifestations such as insomnia, psychomotor agitation (for which nonspecific sedatives are used, mainly benzodiazepines and antipsychotic drugs), and treatment aiming at interfering with the patho-

Table VII. Some claimed indications for co-dergocrine

Improvement of 5 selected symptoms of the elderly:

mood depression

lack of self-care

dizziness

confusion unsociability


genetic mechanisms of the disease. Only the latter approach is considered here. With the rise and fall of pathogenetic hypotheses, 3 main objectives have been investigated and pursued: a) An increase in cerebral blood flow via vaso

dilatation of the arterial blood supply to favour neuronal metabolism

b) Direct support of the neuronal metabolism via nonspecific cerebral activation

c) Improvement of discrete cerebral functions (e.g. memory) via modification of specific neuronal circuits (e.g. the cholinergic system). With regard to (a), the critical points made in

section 2.1.2 concerning the possible utility of vasodilatation in acute situations can be made even more strongly when vasodilator treatment is advocated for chronic conditions. Furthermore, in 50 to 60% of cases, dementia is associated with a primary neuronal deficit, a cause - not a consequence - of reduced blood flow (Strub, 1980; Wells, 1977). While their aetiology remains unknown, these forms are grouped under the common label of dementia of the Alzheimer type (DAT). Vascular factors play a causative role only in the subgroup of multi-infarct dementia (MID), which refers mainly not to atherosclerosis causing a relentless strangulation of the brain's blood supply, but to multiple small or large cerebral infarcts from extracranial arteries and the heart (Hachinski et aI., 1974).

The more recent hypothesis recalled under (b) has received widespread attention and is at present the object of research with almost all drugs formerly proposed primarily as vasodilators. Though apparently fascinating, such research is facing difficulties as the target of activation is not clear (membrane composition or activity? increased availability of energy and/or neurotransmitters? expansion of neuronal networks?). Likewise, markers of increased cerebral activity (as measurable events in quantified EEG) are not directly interpretable as proof of therapeutic effect.

Hypothesis (c) can be seen as a special case of the broader neurotransmitter hypothesis which, since the discovery of psychotropic drugs, has formed the cornerstone of all research aimed at be-

50

haviour modification and control. The documented deficit of the cholinergic system in patients with Alzheimer dementia (Bowen et aI., 1979; Davies and Maloney, 1976; Perry et aI., 1977) has opened up much active research on the possibility of restoring central cholinergic pathways via the precursors choline or lecithin (Barbeau et aI. , 1979), with the specific aim of improving at least one key symptom of dementia, memory. Published data are preliminary and results, while not yet exciting, are not exactly negative (see section 4.1).

However, the focus on this approach is methodologically interesting. Its restricted attention to one key symptom can be seen in fact as the 'other side' of the expectations from pharmacological control of the demented patient. It does not seek global 'activation', but tries to see whether and to what extent the largely unknown and certainly complex puzzle of dementia can be elucidated by interfering with discrete functions. In this way, drugs are more likely to be used as investigative tools rather than as therapeutic measures.

3. Clinical and Pharmacological Profiles of 'Cerebroactive' Drugs

Only drugs for which adequate information is available and on which active research is in progress will be discussed in detail in this section. After a brief pharmacological profile, the discussion will focus on the results and problems of controlled trials dealing with their use in treatment of disorders linked with CNS impairment.

3.1 Ergot Derivatives: Co-dergocrine, Dihydroergocristine and Nicergoline

3.1.1 Pharmacology The pharmacological profiles and suggested uses

of the most representative compounds of this group have been partially delineated in tables III, V and VII. Co-dergocrine (dihydroergotoxine; Hydergine@) consists of 4 ergopeptine derivatives, dihydroergocornine, dihydroergocristine, dihydro-aergocryptine and dihydro-i3-ergocryptine, in a ratio of 3 : 3: 2 : I (fig. 1). One component (dihydroer-


gocristine) is also marketed as a separate active principle, and in addition to its properties as an ergot compound, an antiplatelet action has also been suggested (Gamba et aI. , 1978; Tomasi et aI. , 1976). Nicergoline is the bromonicotinate of an ergoline derivative which in man lowers blood pressure and has an anti platelet action (Bogaert, 1 979a). The relationship of these actions to the proposed definition (Saletu et aI. , 1979) of an 'antihypoxidotic vasoactive ergot alkaloid' is by no means straightforward.

In a study in 10 elderly patients utilising quantitative EEG, nicergoline reduced delta and theta activity and increased alpha and beta activity, with an increase of the dominant frequency suggesting an improvement of , vigilance' (Saletu et aI., 1979).

Dihydroergocristine

Dihydro-a-ergocryptine

51

Similar EEG results have been obtained with codergocrine, dihydroergocristine and bromocriptine (Agnoli et aI., 1981 ; Venn, 1980).

Among the various hypotheses of the mechanism of action of these compounds (reference is specifically made to co-dergocrine as data for dihydroergocristine and nicergoline are lacking), the interaction with neurotransmitters is at present being widely investigated (Berde and Schild, 1978), although the door is open to other possible activities (see table V). The suggested stimulatory action on dopamine receptors is not supported by in vitro studies of the effect on dopamine-stimulated adenyl cylase, though a possible agonist action at dopamine receptors not coupled to adenyl cyclase activity (D2 receptors) has been proposed (Interna-

Dihydroergocornine

Dihydro-/3-ergocryptine

Fig. 1. Co-dergocrine (dihydroergotoxine): chemical structures of the component alkaloids.


Table VIII. Principal techniques of investigation of 'cerebroactive' drugs and their progress

Cerebral blood flow (CBF)

(Fieschi and Des Rosiers, 1976; Fieschi. 1980)

Invasive quantitative techniques for measurement of global CBF (nitrous

oxide method. 1945) Invasive quantitative techniques for measurement of regional CBF

(intracarotid injection of radioactive inert gases. 1961)

Non-invasive quantitative techniques for measurement of regional CBF

(inhalation or intravenous injection of radioactive inert gases, 1967) Study of the local CBF and oxygen metabolism by emission tomography

with the oxygen-15 inhalation technique (1978)

EEG Computer techniques for quantification of the EEG (1963)

Morphological data Computerised axial tomography (1973)

Behavioural and psychometric quantification Rating scales, psychometric tests: nothing new but many problems (reliability, validity, overall judgment .. . )

tional Symposium on the Aging Brain and Ergot Alkaloids, Rome, October 28-30, 1981).

The following quotation summarises the present status of the drug(s), and is reported here without qualification, as it adequately reflects the rather uncertain state of knowledge: '[these compounds] are unusual in the diversity of their pharmacological actions... The structure of the ergot molecule contains the essential features of four neurotransmitters: dopamine, norepinephrine, epinephrine, and serotonin, which probably accounts for their capacity to interact with several neurotransmitter receptors ... and to restore the altered neuronal balance [that accounts for] the neuropsychiatric disturbances in aging' (Goldstein, 1980).

The pharmacokinetics of co-dergocrine have been studied using a tritium-labelled preparation. Available information suggests poor absorption (20 to 25% of the administered dose after sublingual or oral administration) and describes only very approximately the pattern of elimination. It must, however, be qualified at best as preliminary and with no clinical correlates (Spagnoli and Tognoni, 1979). Co-dergocrine is generally well tolerated, the only relevant side effect being sinus bradycardia which was reported to be associated with severe deterioration of the general condition in 3 elderly patients with multi-infarct dementia after doses of l.5mg tid orally (Dcayley et aI., 1975).

3.1.2 Clinical Studies Restricting the discussion to co-dergocrine seems

justified because clinical data on the other ergot alkaloids are too limited for any comprehensive evaluation, and the current revival of interest in this class of drugs has not included them. For the purpose of this review it is useful to distinguish two 'generations' of clinical studies.

First 'Generation' Studies Co-dergocrine has been compared mainly with

placebo and with papaverine (6 studies) in patients with 'senile cerebral insufficiency' (Fanchamps, 1979). In 3 of these 6 studies the difference was statistically significant in favour of co-dergocrine with the other 3 suggesting an 'overall impression' in the same direction. When the drug was compared with placebo, significant improvement was reported by at least I investigator for each of the 19 items on the Sandoz Clinical Assessment Geriatric (SCAG) scale (the most widely used rating scale in these trials) [see table IX], but with no definite pattern of symptom improvement.

The careful review by Hughes et al. (1976) can be taken as the most reliable summary of these 'first generation' trials. These authors stated that co-dergocrine 'consistently produced statistically significant improvement in 13 symptoms associated with dementia (mental alertness, orientation, confusion,


recent memory, depression, emotional lability, anxiety /fears, motivation/initiative, agitation, dizziness/vertigo, walking/mobility, locomotion, overall impression, global therapeutic change). However, because of the small magnitude of the improvement and the absence of indications of long term benefit, [co-dergocrine] would seem to be of minor value in dementia therapy. Further research with better methodology and design might lead to a different conclusion.'

The US Food and Drugs Administration interpretation of these data was surprisingly different: co-dergocrine was declared effective for 5 'selected symptoms of the elderly' (see table VII). Note that the indication is not for a disease state (e.g. dementia) but for symptoms of a life period (ageing). What mechanism of action might underlie an improvement both in dizziness and lack of self-care? What is dizziness in the elderly? Is it true vertigo or something else? Should the doctor prescribe codergocrine for mood depression in a 67-year-old and imipramine for a 37-year-old patient?

Table IX. The Sandoz Clinical Assessment Geriatric (SCAG)

Scale. Rating key: 1 = not present; 2 = very mild; 3 = mild; 4 = mild to moderate; 5 = moderate; 6 = moderately severe; 7 = severe

1. Confusion

2. Mental alertness 3. Impairment of recent memory 4. Disorientation 5. Mood depreSSion 6. Emotional lability 7. Self-care 8. Anxiety

9. Motivation, initiative

10. Irritability

11. Hostility

12. Bothersome

13. Indifference to surroundings

14. Unsociability

15. Uncooperativeness

16. Fatigue 17. Appetite

18. Dizziness

19. Overall impression

53

Second 'Generation' Studies Among the 'second generation' of trials, the 2

main, best 'controlled' studies are examined as examples. Gaitz et al. (1977) evaluated the effect of co-dergocrine (sublingual tablets I.Omg thrice daily) in 54 nursing home residents with 'organic brain syndrome' and the main reason stated for adding this report to the literature was that patients were followed up during a 24-week period. On the SCAG scale a significant (p < 0.05) improvement was shown in 16 of the 19 items in the co-dergocrine group and in II in the placebo group at 12 weeks. At 24 weeks, significant improvement was still observed in 15 items in the active drug group and 2 items in the placebo group. The authors concluded that follow-up of patients beyond the usual 3-month period showed greater effectiveness of co-dergocrine compared with placebo.

This study suffered, however, from great vagueness in the diagnostic and admission criteria of the patients; age and duration of illness are not specified, and no information is given to distinguish between 'vascular' and 'degenerative' dementia. The results of parallel assessment of clinical evolution with the Mental Status Check List (MSCL) are not reported in detail, the only information given was that the MSCL showed no statistically significant differences, but the trend was toward more improvement by the co-dergocrine-treated group than the placebo group. Of the 54 heterogeneous patients who entered the trial, only 35 completed the 24-week follow-up period but nothing is said about drop-outs.

The mean value of the SCAG 'overall impression' score is reported as indicating statistically significant (p < 0.01) improvement from baseline to the 24-week score in the co-dergocrine group but not in the placebo group. The degree of improvement, however, on a 7-point scale, was 4.91 for the active drug group at base-line and 4.04 at the end of the trial, while for placebo group the respective scores were 4.42 and 4.25.

Kugler et al. (1978) compared co-dergocrine and placebo in a controlled trial on 274 patients with 'senile cerebral insufficiency' followed up for 15 months. About two-thirds of the patients admitted


did not complete the study and scores (psychometric tests) on which improvement was measured were distributed among those for which opposite results have been documented in other studies.

Other recent studies with co-dergocrine (Biel et aI., 1976; Dennler and Bachmann, 1979; Junod, 1978; Matejcek et aI., 1979; Yesavage et aI., 1979) do not help clarify the problems pointed out by Hughes et ai. (1976) in their review or some ofthe other questions outlined above. In one of these trials (Yesavage et aI., 1979) comparison of 3mg versus 6mg daily doses of co-dergocrine for 12 weeks (crossover design) in 11 inpatients with 'degenerative or atherosclerotic chronic organic brain disease' failed to show any significant difference in favour of the 6mg dosage.

3.2 Cinnarizine and Flunarizine

3.2.1 Pharmacology Cinnarizine is an antihistamine of the pipera

zine group (fig. 2). The drug antagonises smooth muscle contraction induced by various agents (Godfraind and Kaba, 1969; Van Nueten, 1969; Van Nueten and Janssen, 1972) and both the parent drug and its difluoro derivative, flunarizine, inhibit calcium-induced contraction of depolarised arteries by reducing calcium transfer to depolarised vascular smooth muscle (Godfraind and Polster, 1968; Godfraind et aI., 1968; Van Nueten and Janssen, 1973).

In addition, cinnarizine has other pharmacological properties such as depression of vestibular

Cinnarizine

Fig. 2. Chemical structure of cinnarizine.

54

eye reflexes induced by caloric stimulation of the labyrinth, and other antihistamine properties (protection against histamine-induced bronchospasm and increase in capillary permeability) [Laporte, 1979]. Plasma elimination half-lives of 64 hours and from 3 to 24 hours have been reported in 2 pharmacokinetic studies based on use of a 14C_ labelled compound (Janssen Pharmaceutica, unpublished report, 1969) and on a GLC method (Morrison et aI., 1979) respectively, and conducted in young healthy volunteers. Side effects attributable to cinnarizine at the usual dosage (15 to 50mg daily) are reportedly occasional and reversible, and include asthenia, nausea, vomiting and drowsiness.

Flunarizine has been shown to prolong reactive hyperaemia after temporary arterial occlusion (thumb and leg) in healthy volunteers. This effect of flunarizine (lOOmg orally) is twice that of cinnarizine (200mg orally) [Jageneau et aI., 1974].

3.2.2 Clinical Studies Between 1966 and 1972, 4 placebo-controlled

clinical trials on cinnarizine were published (Behrens, 1966; Bernard and Goffart, 1968; Toledo et aI., 1972; Van der Meer-Van Manen, 1967). Cinnarizine was administered in daily doses from 25 to 50mg, the mean number of patients was 26 arid the follow-up usually 8 weeks. These facts and the ill-defined diagnosis of admission (mainly 'cerebral arteriosclerosis') do not confirm the authors' frequent suggestions of positive results for a wide range of clinical symptoms (Laporte, 1979).

In a recent double-blind placebo-controlled clinical trial (Zissis et aI., 1981) in 28 demented patients treated with flunarizine (10 mg/day orally), clinical symptoms (rating scale), a mental capacity test and the investigator's overall impression were assessed. After a follow-up period of 12 weeks no significant modifications of overall impression and of mental capacity test findings were noted. The authors reported a statistically significant improvement of physical symptoms such as headache, vertigo, tinnitus and sleep disturbances. A comparison was made between pre-trial and post-trial findings but not between the drug and placebo groups. Nothing was said about 2 patients in the flunari-


Vincamine

Fig. 3. Chemical structure of vincamine.

zine group who died after inclusion in the trial and 'were not considered for evaluation'.

3.3 Vincamine and Eburnamonine

3.3.1 Pharmacology The profile of activity of these 2 drugs is some

what ill-defined. Vincamine is an indolyl-alkaloid isolated from Vinca minor (not to be confused with the cytotoxic substances derived from Vinca rosea) [fig. 3]. The drug is claimed to improve hemispheric as well as regional CBF. Effects on the CBF are claimed to be associated with plasma concentrations of the drug between 500 and 1000 ng/ml, which are reached with infusions of 30mg over 20 minutes or 40mg over 40 minutes, but not after 20mg over 20 minutes or 30mg over 40 minutes. The effect on CBF disappears, however, 15 minutes after the end of the infusion (Heiss, 1979). A crossover study of the effect on CBF of a single infusion of either vincamine (40mg over 20 min), the ester derivative ethyl apovincaminate (20mg over 20 min), or placebo, failed to show any significant change of mean CBF values (Lim et aI., 1980). In this study 5 of the 6 healthy male volunteers complained of side effects during or after drug infusion (tinnitus, dizziness and faintness on standing, mild facial flushing and thrombosis of an arm vein) while none developed symptoms with

55

placebo. It has been suggested that at a dosage of 30mg intravenously, vincamine increases the cerebral metabolic rate of oxygen (Heiss, 1979).

The intravenous route should be avoided in cardiac patients (Dekoninck et aI., 1978; Pirani et aI., 1978) as the drug has potential cardiac toxicity related to arrhythmias and ventricular fibrillation (Nunziata et aI., 1978), possibly as a consequence of its effect on smooth muscle contraction (Spina et aI., 1977). However, data on vincamine cardiac toxicity need further study.

Eburnamonine is a semi-synthetic alkaloid derivative of vincamine. The drug is said to be a 'cerebral oxygenator' with 'antihypoxic properties' which appear more pronounced than those of vincarnine (Linee et aI., 1978) and with a more protracted 'vasoactive effect'.

3.3.2 Clinical Studies In a single-blind study (Dringoli et aI., 1975) in

32 patients with 'initial physical and mental involution probably related to chronic cerebrovascular insufficiency', vincamine (60 mg/day orally) was evaluated against placebo. After a 4-month follow-up, the active group showed significant improvement of subjective symptoms (headache, dizziness, unsteadiness, tinnitus, insomnia and poor vision) and in two psychometric tests (Raven Test, Associated Learning Test). 'Psychic' symptoms (poor memory, lack of attention, mood disorders) showed no noteworthy modification.

In a double-blind study in 20 patients (aged 38 to 88 years) with acute stroke (Dekoninck et aI., 1978) vincamine (60mg by intravenous infusion) plus glycerol were compared with placebo plus glycerol. After a 5-day follow-up period there was stated to be a greater improvement of the neurological status (homonymous hemianopsia, conjugated deviation of eyes, motor activity and sphincter control) with vincamine than with placebo. In 2 of 11 patients on vincamine, cardiac disturbances occurred during treatment (ventricular extrasystoles and sinusal bradycardia with first-degree atrioventricular block).

In a multicentre double-blind study (Passeri, 1978) in 106 elderly patients suffering from 'estab-

'Cerebroactive'Drugs

lished chronic brain ischaemia', eburnamonine (60 mgfday orally) and cinnarizine (190 mgfday orally) were compared. The vague admission criteria, the absence of randomisation, the lack of a placebo group and the short follow-up (I month) for patients with 'chronic ischaemia' make the results of this trial unreliable. The authors stated that both drugs improved psychic disturbances and the overall clinical picture, and that in order not to complicate the trial and for ethical reasons they did not set up a control group to be treated with a placebo, a method which they (the authors) oppose. In a double-blind study (Marolda et aI., 1978) carried out on a group of 28 patients with 'chronic brain ischaemia', eburnamonine (60 to 80 mgfday orally) was compared with nicergoline (15 to 20 mgfday orally). The follow-up was stated by the authors to be 'protracted for at least 20 days' and eburnamonine induced an improvement of some symptoms (insomnia, headache and dizziness) 'more rapidly and significantly than nicergoline'.

3.4 Naftidrofuryl

3.4.1 Pharmacology The spectrum of activity proposed for this drug

(fig. 4) ranges from CBF increase (via a spasmolytic effect on smooth muscle fibre) to metabolic 'activation' (enhancement of glucose entry and/or consumption in the brain) leading to nonspecific EEG 'activation' (Beghi, 1979; Bouchard and Rigal, 1970), to the recently suggested 'metabolic protection' of cells against ischaemia (Meynaud et aI., 1975). 133Xe inhalation techniques however, failed to substantiate any significant effect on CBF, either after single intravenous infusions (120mg) or after long term oral administration (200mg 3 times a day for 6 weeks) in 11 elderly patients with chronic cerebrovascular disorders and/or senile dementia (James et aI., 1978).

The direct effect on tissue oxidative metabolism via activation of succinic dehydrogenase (an enzyme of the tricarboxylic acid cycle) [Meynaud et ai., 1973] was tested in 5 young volunteers, where the post-exercise lactate-pyruvate ratio was significantly reduced after naftidrofuryl (300mg orally),

56

Naftidrofuryl

Fig. 4. Chemical structure of naftidrofuryl.

in comparison with a control observation (Shaw and Johnson, 1975). In a randomised study of 34 subjects undergoing operations of moderate severity (Burns et ai., 1981), naftidrofuryl infusion (200mg twice daily for 3 days) was associated with a significant decrease of urinary excretion of nitrogen attributed to drug-induced stimulation of fat and carbohydrate metabolism, leading to a reduction of amino acid oxidation which usually is increased after injury.

The only available pharmacokinetic studies with naftidrofuryl (Fontaine et aI., 1969; Royer et aI., 1975) have reported a mean plasma half-life of 1 hour after oral administration.

3.4.2 Clinical Studies From 1972 to 1978, at least 11 randomised

double-blind clinical trials have been published. Of these, 10 have been concerned with 'chronic cerebral insufficiency', and the most recent one with stroke patients.

The clinical trials in chronic cerebral insufficiency (Adriaensen, 1974; Bargheon, 1975; Bouwier et aI., 1974; Branconnier and Cole, 1977; Brodie, 1977; Cox, 1975; Gerin, 1974; Judge and Urquhart, 1972; Robinson, 1972; Trouillas, 1977) were based on a mean sample size of 52 subjects and a follow-up period of 2 to 3 months, with a mean dosage of 300mg tid. The diagnostic and admission criteria were invariably iII-defined, and drop-outs were as high as 1 in 3 in 2 studies (Adriaensen, 1974; Judge and Urquhart, 1972). Daily living activities were improved (Adriaensen, 1974;


Brodie, 1977) or unchanged (Judge and Urquhart, 1972); and the same was true for 'cognitive' functions which were either improved (Adriaensen, 1974; Bouwier et aI., 1974; Cox, 1975; Judge and Urquhart, 1972; Trouillas, 1977) or unimproved (Brodie, 1977; Judge and Urquhart, 1972).

The study in stroke patients (Admani, 1978) was a double-blind placebo-controlled trial involving 91 patients with stroke due to recent ischaemic cerebral infarction (mean interval ± SO between stroke and treatment 5.04 ± 5.30 days for the naftidrofuryl group and 5.88 ± 6.10 days for the placebo group). The diagnostic criteria were not specified; exclusion criteria were previous history of stroke or dementia, or severe confusion, unconsciousness, and stroke of non-vascular causes. Oral naftidrofuryl 200mg tid was given for 4 weeks followed by 100mg tid for 8 weeks. A better overall score (power, sensation, daily living activities, etc.) and a significantly shorter hospital stay were reported for the treated than for the control group. No difference in overall mortality but a significantly (p < 0.05) lower stroke mortality was documented in the naftidrofuryl group.

In a timely comment on this study, Steiner et al. (1979) pointed out the many weak points: a purely clinical diagnosis of recent ischaemic infarction, the skewed distribution of the interval between stroke and treatment, low comparability of the 2 groups when subscores for neurological and neurophysical variables are added. Their conclusion that a definite benefit in stroke from naftidrofuryl cannot be claimed (Steiner et aI., 1979) appears largely justified.

3.5 Oxpentifylline (Pentoxifylline)

3.5.1 Pharmacology Oxpentifylline (fig. 5) is a xanthine derivative

with an inhibitory effect on phosphodiesterase and it is said to be a 'blood flow-promoting' agent with no distinct action on blood pressure (MOller, 1978). Reduction of whole blood viscosity (reportedly greater in patients with chronic vascular diseases; Ointenfass, 1969; Oormandy, 1970) and improvement of red cell flexibility (proportionately de-

57

creased with the severity of the clinical situation; Ehrly and Kohler, 1976) in the same patients are the main effects of the drug. These evidently occur via an increase of A TP levels in red blood cells, an increase in fibrinolytic activity, a decrease in plasma fibrinogen and inhibition of platelet aggregation.

A significant increase in the erythrocyte filtration rate (a technique for the evaluation of red cell flexibility) and a decrease in whole blood viscosity after oral and intravenous oxpentifylline have been reported in healthy volunteers (Grigoleit et aI., 1976) and in patients with chronic vascular disorders (Schubotz and MOhlfeliner, 1977; Smud et aI., 1976). These effects (also seen with the slowrelease 400mg preparation) are no longer measurable after 2 hours. Caution is necessary when interpreting data on red cell flexibility because of its important circadian variations (Grigoleit et aI., 1976).

Pharmacokinetic information on oxpentifylline is scarce. Administration of the drug to healthy adult volunteers gave a peak plasma concentration at 2 to 3 hours; the plasma profile of a metabolite [1-( 5-hydroxyhexyl)-3, 7 -dimethylxanthine] followed the same pattern as the parent compound, at concentrations 2 to 4 times higher (Hinze et aI., 1976).

Side effects of oral oxpentifylline are reported to be rare and include dose-dependent chest pain and mild digestive discomfort (Feine-Haake, 1977; Muggeo et aI., 1981).

Oxpentifylline

Fig. 5. Chemical structure of oxpentifylline (pentoxifylline).


Table X. Results of double-blind trials with oxpentifylline (pentoxifylline)

Reference Population studied Variables observed Results

Hawart (1979)

60 patients with 'signs of cerebral insufficiency due to old age'

14 'cerebral symptoms' (poor memory, headache, incontinence, etc.) 'Peripheral' symptoms (paraesthesia, claudication, etc.)

Significant improvement for some clinical symptoms, some PGRS items and psychometric tests over a 2-month period

Plutchik Geriatric Rating Scale (PGRS) Psychometric tests (memory and psychomotor performance)

Pricladnitzki 40 'geriatric patients Clinical symptoms (1979) with cerebrovascular

insufficiency'

Significant improvement for headache, social isolation, poor memory and impaired concentration over an a-week period

Dominguez 40 patients with et al. (1977) 'chronic

Clinical symptoms and psychometric tests Significant improvement for subjective complaints, practical abilities and anxiety

cerebrovascular insufficiency'

3.5.2 Clinical Studies Three double-blind placebo-controlled trials in

elderly patients have been published using a dosage schedule of 400mg tid (Dominguez et aI., 1977; Harwart, 1979) or bid (Pricladnitzki, 1979) [see table X].

In a multicentre trial in TIA patients in Argentinian hospitals (Herskovits et aI., 1981), the effect of oxpentifylline (400mg tid orally) was assessed versus a fixed combination of aspirin and dipyridamole given tid (for a total daily dose of 1050mg aspirin and 150mg dipyridamole). After a I-year follow-up there was a significant difference in morbidity rate (new TIAs and stroke) in favour of oxpentifylline. The vague inclusion criteria (TIA of every type, age between 38 and 86 years), the small number of patients (63) who completed the trial and hence the small number of observed events (3 strokes and 13 patients with continuing TIAs) in addition to the absence of a placebo-controlled group leave these findings open to criticism (Gawel et aI., 1981; Warlow and Peto, 1981). There is also an error in the calculation of statistical significance, the difference in cumulative morbidity be-

over a 4-month period. Anxiety, recorded in 2 different ways, showed contradictory evolution. One drop-out (oxpentifylline group) because of severe digestive side effects

tween the 2 groups being not significant (Warlow and Peto, 1981).

3.6 Piracetam

3.6.1 Pharmacology Piracetam (2-oxo-I-pyrrolidine-acetamide) [fig.

6], a cyclic derivative of GABA with no GABAlike properties, has been proposed as the prototype of the 'nootropic' drugs (Giurgea, 1973), a class of psychoactive drugs selectively improving efficiency of 'higher telencephalic integrative activities' (Giurgea, 1978). Its therapeutic profile is claimed to include: (1) enhancement of learning acquisition and resistance to agents impairing acquisition (e.g. hypoxia, electroconvulsive shocks); (2) facilitation of interhemispheric transfer of information; (3) enhanced resistance to brain 'aggressions'; (4) increased tonic, cortico-subcortical control; and (5) absence of sedation or stimulation and virtually no toxicity (Giurgea, 1978). Selective amelioration of the ATP/ADP ratio in the telencephalon (Giurgea, 1973), stimulation of synaptic transmission via enhancement of neuronal


Piracetam

Fig. 6. Chemical structure of piracetam.

and synaptosomal phospholipase A activity (Woelk, 1979), and an antithrombotic (platelet-inhibiting) activity (Bick, 1979) are proposed as the mechanisms underlying these effects.

Animal studies on learning, memory and global performance however, give contradictory results (Bryant et ai., 1973; Means et ai., 1980; Oglesby and Winter, 1974; Sara and David-Remacle, 1974). Moreover, no significant effect has been found on regional CBF by the 133Xe inhalation technique in moderately demented patients (Gustafson et ai., 1978); whole EEG activation measured by power spectral analysis has been reported in hospitalised 'gerontopsychiatric' patients (Bente et ai., 1978); and verbal, but not non-verbal learning was improved in young healthy volunteers following 14

Table XI. Results of double-blind trials with piracetam

59

days of 1.6g daily administration of piracetam (no effect on day 7) [Dimond and Brouwers, 1976].

3.6.2 Clinical Studies Piracetam (2.4 to 9.5 g/day) did not signifi

cantly differ from placebo in 6 controlled trials, including in the final analysis a mean of 28 geriatric patients with senile dementia, chronic or acute cerebral ischaemia and elderly patients with mild deterioration of mental function (Abuzzahab et ai., 1978; Dencker and Lindberg, 1977; Diesfeldt et ai., 1978; Gedye et ai., 1978; Gustafson et ai., 1978; Trabant et ai., 1977).

In 3 other double-blind studies, piracetam was found to be superior to placebo. These 3 positive studies are summarised in table XI (Guilmot and Van Ex, 1975; Macchione et ai., 1976; Stegink, 1972).

Besides the usual criticism of vague criteria of patient selection and efficacy evaluation (Bogaert, 1979b), some specific points are worth emphasising, mainly in the second and third studies: (1) the poor matching of treated (112) versus placebo (70) patients and the reported 'remission' of the psychoorganic syndrome in 73.3% of treated patients and in 55.7% of placebo patients, which casts many doubts on the reliability of clinical criteria for admission and clinical evaluation (Macchione et ai.,

Reference Population studied Variables observed Results

Guilmot and Van Ex 24 patients (final analysis) with Clinical symptoms (1975) 'involution depression'

Macchione et al. (1976)

Stegink (1972)

182 patients with 'cerebral psycho-organic syndrome'

191 patients with 'chronic irreversible deterioration of

intellectual function due to organic disorders of old age'

Clinical symptoms

Clinical symptoms

Significant improvement for asthenia; but not for anxiety, poor memory, psychomotor activity and consciousness disturbances over a 6-week period

Significant improvement for asthenia, anxiety, memory disturbances, psychomotor disturbances, failure to adapt to surroundings;

but not for distraction and overall assessment over a 6- or a-week period

Significant improvement for reduced alertness, asthenia, psychomotor agitation and general course of the syndrome over an 8-week period


1976); and (2) the curious age range of 'elderly' patients, from 31 to 91 years (Stegink, 1972).

3.7 Citicoline

3.7. J Pharmacology As has been shown to be the case for other com

pounds, the pharmacological profile of citicoline [or COP-choline (cytidine diphosphate choline), fig. 7, the precursor of choline phosphoglyceride (or lecithin)] cannot claim consistency. The following is a summary of the hypotheses put forward for justifying broad spectrum activity: a) Integration of the molecule into biological membranes to favour phospholipid synthesis and therefore to improve neurological deficits b) Direct pharmacological effect on cerebral function possibly via interaction with transmitters and/ or receptors (data are particularly scanty in this respect) [Nilsson, 1979] c) Specific activation of dopaminergic transmission (Ishikawa et ai., 1973), possibly as the background for the suggested (Manaka et ai., 1970; Shimamoto et ai., 1975) use of the drug concomitantly with levodopa in Parkinsonism d) 'Vasoactive' and anti platelet activity leading to improvement of the microcirculation (Tassi and Perversi, 1978).

Parenteral administration is mandatory to avoid intestinal hydrolysis. Less than 0.1 % of an intravenous dose is found in the rat brain, suggesting a very poor capacity to cross the blood-brain barrier to reach the presumed sites of action (Nilsson, 1979). Signs of cholinergic stimulation have been noticed in man only after very large doses (Nilsson, 1979).

3.7.2 Clinical Studies The few controlled studies available focus on

the drug's ability to improve the long term prognosis of stroke patients (Boudouresques, 1979; Goas, 1979; Hazama et ai., 1980; Miyazaki, 1 968a,b; Muramatsu et ai., 1971). Two double-blind placebo controlled trials suggesting superiority of the drug deserve more detailed analysis.

In the first (Hazama et aI., 1980), citicoline (from

60

250 to 1000 mg/day intravenously) was given to 162 'post-stroke hemiplegic patients' participating in a functional rehabilitation programme. Significantly better functional recovery measured on a 12-item scale (Hemiplegic Function test) was reported for upper but not for lower limbs; however, the study failed to document any positive result in the physicians' overall judgement, subjective symptoms and neurological signs.

In the second study (Goas, 1979), 64 patients with 'evident cerebrovascular accidents' (age range 42 to 81 years) were followed for 90 days (daily dose of citicoline 250 or 750mg intravenously or intramuscularly) and showed significant improvement in motor and muscular tone disturbances, 'global clinical evolution', psychometric tests and EEG.

4. New Hypotheses

The large amount of neurochemical data on the ageing brain of 'normal' and Alzheimer subjects and the evidence of a memory effect of the anticholinergic drug hyoscine (scopolamine) have drawn increasing attention to the role of neurotransmitters both in the 'normal' ageing process of the brain (where dopamine should be primarily involved) [Pradhan, 1980] and in pathological situations (where acetylcholine is to the fore) [see sec-

o 0 .(5 \I II 0 N

(CH3hN+CH2CH20-P-0-P-0~C2 I I 0 0- OH

H H

H H

Citicoline OH OH

Fig. 7. Chemical structure of citicoline (cytidine diphosphate choline).


tion 4.1). Overall, evaluation of current knowledge is clearly negative as regards any lasting symptomatic or (obviously) therapeutic role of the tested drugs (levodopa, choline, lecithin, arecoline, physostigmine) [International Study Group on the Pharmacology of Memory Disorders Associated with Aging, 1981).

Some research leads, however, are worth mentioning, as the better controlled methodology and orientation of the trials towards more specific targets have resulted in better definition of the problems, underlining the fallacy of looking for 'allencompassing' solutions and the limitations of available measuring tools (rating scales, psychometric tests).

4.1 Acetylcholine Precursors

Several reports have provided evidence that hyoscine and atropine, two anticholinergic drugs with central activity, when given to normal humans impair memory function via an effect on information storage (acquisition), rather than on retrieval (Drachman, 1977; Wetherell, 1980). However, the picture is by no means clear as only acute studies can be done, the duration of memory impairment varies widely and is largely dependent on the dose and route of administration (Wetherell, 1980). It is not known whether the same effects could be produced by other drugs with anticholinergic activity such as tricyclic antidepressants and some anti psychotics.

Additional information has been gained from studies where the anticholinesterase drug physostigmine has been shown to partially reverse the hyoscine effect; in contrast dextroamphetamine, whose nonspecific effect on memory occurs via increased alertness and attention, failed to antagonise 'hyoscine dementia' (Drachman, 1977). Physostigmine (lmg intravenously) also reportedly enhanced long term memory (storage process) in normal volunteers, though the intersubject variability was considerable (Davis et al., 1978). As choline, a precursor of acetylcholine, and lecithin have been shown to raise choline levels in serum and cerebrospinal fluid (Editorial, 1980), the way was

61

opened for testing the hypothesis of a 'replacement therapy' in Alzheimer dementia, where memory impairment is a principal and early symptom. In addition, a specific, significant reduction in the activity of choline acetyltransferase, an enzyme involved in the synthesis of acetylcholine, has been documented in the cerebral cortex and hippocampus of patients with Alzheimer dementia (Bowen et ai., 1979; Davies and Maloney, 1976; Perry et ai., 1977).

Oral choline is metabolised by intestinal bacteria to trimethylamine, a highly volatile amine which is excreted in urine, breath and sweat and produces a disgusting fishy odour (Marks et al., 1978). Lecithin should therefore be preferred, as it does not produce such an odour and gives higher, longer lasting levels of free choline in the serum (Wurtman et ai., 1977).

Reports have been published of at least 9 trials on mild to moderately demented patients treated with choline or lecithin. Of these, 5 were 'open' trials (Boyd et ai., 1977; Christie et ai., 1979; Etienne et ai., 1978b; Friedman et ai., 1981; Signoret et al., 1978); the 4 placebo-controlled trials follow a crossover design, 3 double- (Fovall et al., 1980; Peters and Levin, 1979; Smith et al., 1978) and 1 single-blind (Etienne et ai., 1978a). The mean number of patients was 7 (range 3 to 11) with a mean follow-up period of 8 weeks (range 1 to 20 weeks). Usually choline administration began at a daily dose of 1 to 5g and was gradually raised to 9 to 16g, while lecithin was administered at a daily dose of 25 to 100g. Memory assessment was the main target, but with attention to psychomotor ability and behavioural variables. A very large inter- and intrasubject variability was evident and no definite clinical benefit could be proved, though in psychometric tests some patients showed significant improvement of some aspects of memory function (paired associate learning test, verbal memory retrieval, auditory and visual word recognition) [Etienne et ai., 1978b; Fovall et ai., 1980; Friedman et ai., 1981; Peters and Levin, 1978). In 1 trial (Friedman et al., 1981), higher red cell choline concentrations (before and during treatment) were measured in 'responders'.


Side effects reported during treatment with choline or lecithin were mainly 'digestive' (reduction in appetite, nausea, abdominal bloating, diarrhoea) and 'behavioural' (depression, irritability, anxiety) [Boyd et ai., 1977; Christie et ai., 1979; Etienne et ai., 1978a; Fovall et ai., 1980; Smith et ai., 1978]. They were generally dose-dependent and tended to subside when dosage was reduced. Faecal and urinary incontinence and a small fall in blood pressure were also reported (Boyd et ai., 1977; Christie et ai., 1979; Etienne et ai., 1978a; Smith et ai., 1978). In 4 patients, side effects caused the interruption of drug treatment (I aggressive behaviour; I depression; I anxiety, fishy odour, nausea and belching; I incontinence) [Christie et ai., 1979; Etienne et ai., 1978a; Fovall et ai., 1980; Smith et ai., 1978].

5. Other Drugs

Interest in the other drugs listed in table I as potential tools for the treatment of stroke patients, dementia or the 'common symptoms' of the elderly has diminished in line with the falling credibility of the vasodilatation hypothesis as the basis for therapeutic effects. Even preliminary positive results claimed for 'new' drugs such as hexobendine and betahistine on CBF (McHenry et ai., 1972; Meyer et ai., 1971, 1974) and on the clinical status of patients with 'vertebrobasilar arterial insufficiency with dementia' (Rivera et ai., 1974) or 'arteriosclerotic dementia' (Seipel et ai., 1977) have remained isolated.

6. Conclusions

When only a few years ago the request to critically review the activity profiles and use of this class of drugs was forwarded to various experts in the field of cerebrovascular disorders, the first reaction of many of them (in the UK, Scandinavia, Canada and USA) was to decline the invitation, as the topic appeared esoteric with no real basis in clinical practice and research. The scene has now changed, as the aggressive attitudes of pharmaceutical companies marketing the drugs and an in-

62

creasing focus on elderly patients with Cl~S involvement have created interest on a broader scale and under various labels (basic research, INDs, scientific meetings, large scale multicentre trials).

'Cerebroactive' drugs are now a reality whose existence cannot be denied, neither in developed nor in developing countries, and many can claim some measure of support in the fact of their being mentioned (not negatively) by leading authorities.

What then is behind this wave of interest? The concluding remarks at the Milan meeting on 'cerebroactive' drugs, which has often been cited (Tognoni and Garattini, 1979), seem to hold true for the majority of clinical trials (on which also this review was based):

' ... we heard, with growing horror the evidence about the efficacy of these drugs . . . I started being interested, then surprised, then shocked. Shocked by the gross misuse of the double-blind randomized controlled trial ... In the USA and the UK all protocols for research on patients have to be passed by ethical committees. It is becoming increasingly accepted that it is unethical to allow badly designed randomized controlled trials to be carried out ... Few, if any of the horrors we saw . .. would be accepted by editors of respectable journals, but they would certainly welcome a witty monthly article summarising the publications in the "free" press in a pithy way. We are a scientific and caring profession and the solution is finally up to us. We can, in the first place, improve education, by teaching students about methods of evaluation, and by encouraging them always to enquire of their elders and betters about the evidence that what they are doing is for the benefit of their patients. It is good for them and good for their elders' (Cochrane, 1979).

CNS problems of the elderly are, however, here to stay, and will possibly increase, and increasing cultural and industrial pressure to expand the market must be expected, often with the justification of extracting funds for badly needed basic and clinical research. The heart of the problem seems to lie in this strained situation: the urgency to produce positive results to support a market, and awareness that the road to satisfactory integration


of the various areas of research in the field is by no means easy nor short.

Important clarifications must certainly result from the intensification of basic research by more groups. A multiplication of clinical trials in different cultural settings and in well-defined subpopulations will also enable us to orient ourselves more objectively among the presently contradictory results, and to distinguish insignificant and relevant symptomatic or therapeutic effects.

While promising and possibly decisive steps have been made with respect to non-invasive methods for assessing brain functions, 2 critical preliminary issues remain to be adequately solved: definition of the target population(s) with easily applicable and reliable psychometric tools; and the need for assessing drug effects together or interacting with other supportive or intervention measures known sometimes to playa major role in this class of patients.

Methodological and epidemiological lessons learned over the last few years for psychiatric diseases could be of great help (Tognoni et aI., 1981) in accepting the limits of what has been achieved and in recognising the potential of new approaches.

Acknowledgements

This work was partially funded by the CNR (National Research Council, Rome, Italy) program on Clinical Pharmacology and Rare Diseases and by the generous contribution of the Fondazione Angelo e Angela Valenti, Milan, Italy.

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Author's address: Dr A. Spagnoli, Regional Center for Drug Information, Laboratory of Clinical Pharmacology, Istituto di Ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, 20157 Milano (Italy).

International Symposium* on

Central and Peripheral Endorphins: Basic and Clinical Aspects

Date: October 6-8, 1983 Venue: Viareggio, Italy

For further information, contact the Scientific Secretaries: E.E. Muller and A.A. Genazzani, Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, ITALY. [Phone: (02) 717470]

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