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

Summary 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 men­ tal 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 'cere­ broactive' 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, pirace­ tam 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 fering levels or mechanisms of action are claimed chosen to describe the large group of compounds (table III), the old cornerstone of vasodilatation considered in this review (table I) give possibly the (tables IV and V) being transformed into thera­ most appropriate key for approaching this topic. peutic indications which cannot be viewed without These substances constitute a large proportion of some hesitation or scepticism (tables VI and VII). the total prescribed drugs in many countries but Are these compounds looking for a therapeutic they are hardly used at all in others (table II). They role or have they already found one? What is their do elicit pharmacological effects, but widely dif- role, for what pathology, and on what basis? The 'Cerebroactive' Drugs 45

Table I. Some 'cerebroactive' drugs Techniques now available to measure baseline data and drug effects (table VIII) should be con­ Bamethan sidered with particular care. Progress has been made Bencyclane Betahistine in assessing cerebral blood flow and its interaction Cyclandelate with basic metabolic events, and in the study of Cinnarizine the brain's electrical activity and its morphological Citicoline aspects (extremely useful for precise diagnosis). On Co-dergocrine (dihydroergotoxine) the other hand, the whole field of behavioural and Dihydroergocristine Eburnamonine psychometric assessment must be regarded with Flunarizine extreme caution because of the lack of satisfactory Isoxsuprine baseline data and comparative criteria for assess­ Naftidrofuryl ment of outcome. Nicergoline Nicotinic acid derivatives Nylidrin Oxpentifylline (pentoxifylline) Papaverine Table II. Usage patterns for available 'cerebroactive' drugs in Piracetam various countries Piribedil Country Usage patterns Raubasine Suloctidil Vincamine England 0.2% of all drugs prescribed by general practitioners (Skegg. 1979) 0.6% of all drugs prescribed nationally for following two quotations summarise the dilemma: people of all ages in 1975 (Department of Health and Social Security. England. 1977) 1. 'The haemodynamic disturbances are ap­ 5.4% of hospital patients with stroke. TIA or proached with vasodilating substances, which spe­ multi-infarct dementia (Spagnoli et al .• cifically assume the functional improvement of 1982) cortical arterial anastomoses allowing for the de­ velopment of substitutive circulation. Our phar­ Italy 32.0% of elderly community residents (Colombo et al.. 1979) macological armamentarium is rich with such sub­ 48.5% of hospital patients with stroke. TIA or stances, which include papaverine and ergot multi-infarct dementia (Spagnoli et al.. derivatives, raubasine and other synthetic mole­ 1982) cules such as cetiedil, piribedil, naftidrofuryl. It has been possible to quantify their haemodyamic ac­ Spain 4.5% of total drug expenditure in 1978 (Laporte et al.. 1979) tivity by direct measurement of cerebral blood flow' 33.6% of elderly community residents (Mas et (Goutelle et al., 1980). al .• 1983) 2. ' . . . the utility of vasodilators in reversing or delaying the deleterious effects of acute or chronic Germany 5.0% of total drug expenditure for ambulatory cerebrovascular insufficiency is controversial, and medical care in 1976 (Kimbel. 1979) the case for clinical efficacy is unimpressive' Yugoslavia 71.8% of hospital patients with stroke. TIA or (Needleman and Johnson, 1980). multi-infarct dementia (Spagnoli et al.. The fact that the accent is no longer on vaso­ 1982) dilatation but on subtler, less clearly defined mech­ anisms does not substantially alter the situation. Indonesia 50.0% of hospital patients with stroke. TIA or multi-infarct dementia (Spagnoli et al .• The question is whether or not there is docu­ 1982) mented evidence of clinical benefit, and it could not be more open. 'Cerebroactive' Drugs 46

1. Background Pharmacological chronically modified by drugs. Metabolic or neu­ Considerations ronal activation, increased energy utilisation, neurotransmitter modulation or substitution, and Most of the compounds listed in table I were membrane modification are among the more fash­ introduced and first tested as 'vasodilators' for ionable hypotheses which certainly define chal­ peripheral circulatory disorders and for cerebro­ lenging areas of research, but for which hard data vascular pathology. The basic assumption was that are scarce and fragmentary (even in laboratory ani­ an improvement of the circulation through various mals), and the search for protocols to provide re­ mechanisms was possible, real and therapeutically liable quantitative information in man is still in a useful (table IV). pioneer phase. The availability of more precise assessment As a general point, to which we shall come back, methods quickly showed that such claims were this change of direction in pharmacological re­ merely wishful thinking (see the 'model case' of co­ search points more and more to phenomena arid dergocrine, table V). At the same time, increased models bordering on psychopharmacology. The understanding of the aetiology and pathogenesis of switch is not marginal, as it foresees the use of these impairment of cerebral function made it evident drugs for symptoms and problems whose relation­ that neuronal metabolism, the microcirculation and ship with specific functional and/or organic dis­ neurotransmitters might playa more important role turbances is somewhat tenuous (see table VII). than blood flow per se. However, there is no sat­ It is easy to forecast a long period during which isfactory representation either of interactions among planning and evaluation of clinical trials will be various factors or of how they are acutely and/or 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 Co-dergocrineb, dihydroergocristineb , nicergoline

{3 -adrenoceptor stimulation 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, I 979b). This points firstly to the need for increased biochemical, functional, etc), and of assessing the attention to risk factors [hypertension, diet, smok­ clinical importance of even 'significant' changes in ing, transient ischaemic attacks (TIAs), atrial fi­ symptomatic and behavioural scales or psycho­ brillation, etc.], and secondly for appropriate anti­ metric tests. hypertensive treatment (Kagan et aI., 1980; Kannel et aI. , 1970; Mohr et aI., 1978; Rabkin et aI., 1978; 2. The Need for 'Cerebroactive' Drugs Veterans Administration Cooperative Study Group on Antihypertensive Agents, 1970). Is there a therapeutic need for 'cerebroactive' or The control of the main causes of mortality and 'vasodilator' drugs in the 3 main areas of patho­ morbidity among stroke survivors still poses com­ logy: (a) stroke patients; (b) dementia; and (c) the plex and controversial therapeutic problems both so-called 'common symptoms' of the elderly? for the acute events (brain oedema, cardiac abnor­ All these situations are directly or indirectly en­ malities, pulmonary emboli, pneumonia) [Milli­ visaged in the promotional claims for most of the kan, 1979] and for the chronic phase (coronary ar­ drugs discussed here (see table VI for a model case) tery disease, poor autonomy) [Cartlidge et ai, 1977; but this should not obscure the fact that these sit­ Furlan et aI., 1980; Greshan et aI., 1975; Toole et uations are not related, either in their aetiology or, aI., 1978]. above all, in their natural history, and therefore the prospects for their therapeutic control. 2.1 .2 The Role of 'Cerebroactive' Drugs A 'vasodilator' effect has been advocated in 2.1 Stroke stroke therapy to improve cerebral blood flow (CBF) in the ischaemic and perilesional area; the 2.1 .1 Epidemiology and Therapeutic Needs 'activator' effect has been claimed to help the me­ The decreasing mortality and morbidity rates tabolism of surviving neurons. for stroke (Garraway et aI., 1979a; Guberan, 1979; There is no doubt that at least some of the drugs Kuller, 1978; Levy, 1979), which have been clearly listed in table I are capable of modifying CBF over documented for some industrialised (Guberan, a short period when given at sufficiently high dos­ 1979; Kuller, 1978) but not all countries (Cooper, ages, though it is accepted that the most powerful 1981), is attributable more to a decrease in the in­ vasodilator is CO2 (Cook and James, 1981 ; Edit­ cidence of cerebral infarct (first episode) than to an orial, 1979; Heiss and Podreka, 1978; McHenry et increase in stroke survivors (Garraway et ai., ai, 1970; Meyer et aI., 1974). While this pharma- Table V. The 'evolution' of co-dergocrine (dihydroergotoxine): critical studies

Level of action Mechanism of action Experimental findings Reference

animals man

t~. 1. Vascular system Central depression of vasomotor nerve activity CBF t Rothlin (1946/47) Peripheral a-adrenoceptor blockade CBF - Rothlin and Taeschler (1951) Direct stimulation of smooth muscle CBF t Geraud et al. (1963) g CBF- Gottstein (1965) CBF. rCBF­ McHenry et ai, (1971)

rCBF (iv) ~. Olesen and Skinh0j (1972) rCBF (ic)-

2. Metabolism and Inhibition of low cyclic AMP Km­ Lactate/glucose metabolism t Meier-Ruge et a\. (1975) neurotransmitters phosphodiesterase Inhibition of phosphokinase activity Dimension of brain cortex capillaries t Inhibition of catecholamine stimulated EEC activity t ATP-ase and adenyl cyclase Inhibition of catecholamine reuptake Classical and paradoxical Loew et a\. (1976) sleep l Dopamine agonism at ponto-medullary Wakefulness t reticular formation Accumulation in the synapses Antinociceptive effects of morphine l

Abbreviations: CBF = cerebral blood flow; rCBF = regional cerebral blood flow; - = not modified; t = increased; l = decreased, a CBF reduced in areas with impaired autoregulation secondary to a reduction in arterial blood pressure. ~ 00 'Cerebroactive' Drugs 49

cological effect has never been associated with con­ Table VI. Suggested indications for piracetam found in the vincingly documented clinical efficacy, a consen­ literature sus seems to have been reached that vasodilatation Stroke patients may be dangerous because of the risk of a possible 'Common symptoms' of the elderly rise in intracranial pressure, the occurrence of 'steal' Senile dementia phenomena, and reduced perfusion pressure in the Dizziness lesional and perilesional areas consequent to a Memory disturbances Chronic schizophrenia broader vasodilatation. Head injuries ('mild and severe') The trend today as regards pharmacological reg­ Comatose patients ulation of metabolic activation points in the op­ Chronic and acute alcoholism posite direction, as research seems more interested Drug dependence in therapies to reduce the rate of brain metabolism CNS adverse effects of drugs Cerebral palsy (e.g. barbiturate therapy, therapeutic hypothermia) Language disturbances during development age [Safar, 1980]. The rather weak rationale, if any, for Adolescents with poor school results a therapeutic role of 'cerebroactive' drugs in stroke Neurogenic bladder patients is adequately defined in the following Sickle-cell disease statement, which summarises current knowledge derived from studies of local CBF and oxygen me­ tabolism (emission tomography with the ISO-in­ cerebrovascular disorders, cerebral insufficiency, or halation technique): 'The post-ischemic brain is a 'common symptoms' of the elderly, seem to be the complex mosaic of very different metabolic and most successful and practicable, and find scientific hemodynamic focal situations which tend to vary support in the literature dealing with 'specific' drug considerably within the first few days. An ischemic treatment for the 'demented' or 'cerebrally im­ lesion may show different perfusion patterns, any­ paired' elderly. It is easy to imagine that any such thing from persisting severe ischemia to complete dissociation is not without consequences, as both restoration of the circulation with luxury perfusion the definition of need and the assessment of bene­ and vasoparalysis' (Fieschi, 1980). fits of drug and other treatments will necessarily be biased by important confounding factors. 2.2 Dementia and the 'Common Symptoms' of the Elderly 2.2.2 A 'Rational' Approach to Pharmacological Treatment of Dementia? 2.2.1 Definitions A simple but important distinction should first The main questions, which cannot be avoided, be made between symptomatic control of specific could be formulated as follows: What is the degree manifestations such as insomnia, psychomotor ag­ of continuity between ageing of the brain and iis itation (for which nonspecific sedatives are used, most pathological expression, dementia? Is there mainly benzodiazepines and antipsychotic drugs), any continuity at all? Or should dementia be con­ and treatment aiming at interfering with the patho- sidered a completely separate issue for which old age is but one of the important risk factors? (Alex­ ander, 1972; Bowen et aI., 1979; Editorial, 1978a,b; Table VII. Some claimed indications for co-dergocrine

Fries, 1980; Gruenberg, 1978; Plum, 1979; Smith Improvement of 5 selected symptoms of the elderly: and Kiloh, 1981). mood depression The currently preferred attitude undoubtedly lack of self-care seems in favour of the second line of reasoning, dizziness but the picture changes if we look at medical prac­ confusion unsociability tice and public opinion. Basket definitions such as 'Cerebroactive' Drugs 50

genetic mechanisms of the disease. Only the latter haviour modification and control. The documen­ approach is considered here. With the rise and fall ted deficit of the cholinergic system in patients with of pathogenetic hypotheses, 3 main objectives have Alzheimer dementia (Bowen et aI., 1979; Davies been investigated and pursued: and Maloney, 1976; Perry et aI., 1977) has opened a) An increase in cerebral blood flow via vaso­ up much active research on the possibility of res­ dilatation of the arterial blood supply to favour toring central cholinergic pathways via the precur­ neuronal metabolism sors choline or lecithin (Barbeau et aI., 1979), with b) Direct support of the neuronal metabolism via the specific aim of improving at least one key nonspecific cerebral activation symptom of dementia, memory. Published data are c) Improvement of discrete cerebral functions (e.g. preliminary and results, while not yet exciting, are memory) via modification of specific neuronal not exactly negative (see section 4.1). circuits (e.g. the cholinergic system). However, the focus on this approach is meth­ With regard to (a), the critical points made in odologically interesting. Its restricted attention to section 2.1.2 concerning the possible utility of one key symptom can be seen in fact as the 'other vasodilatation in acute situations can be made even side' of the expectations from pharmacological more strongly when vasodilator treatment is ad­ control of the demented patient. It does not seek vocated for chronic conditions. Furthermore, in 50 global 'activation', but tries to see whether and to to 60% of cases, dementia is associated with a what extent the largely unknown and certainly primary neuronal deficit, a cause - not a conse­ complex puzzle of dementia can be elucidated by quence - of reduced blood flow (Strub, 1980; Wells, interfering with discrete functions. In this way, 1977). While their aetiology remains unknown, drugs are more likely to be used as investigative these forms are grouped under the common label tools rather than as therapeutic measures. of dementia of the Alzheimer type (DAT). Vas­ cular factors play a causative role only in the 3. Clinical and Pharmacological subgroup of multi-infarct dementia (MID), which Profiles of 'Cerebroactive' Drugs refers mainly not to atherosclerosis causing a re­ lentless strangulation of the brain's blood supply, Only drugs for which adequate information is but to multiple small or large cerebral infarcts from available and on which active research is in pro­ extracranial arteries and the heart (Hachinski et aI., gress will be discussed in detail in this section. After 1974). a brief pharmacological profile, the discussion will The more recent hypothesis recalled under (b) focus on the results and problems of controlled has received widespread attention and is at present trials dealing with their use in treatment of disor­ the object of research with almost all drugs for­ ders linked with CNS impairment. merly proposed primarily as vasodilators. Though apparently fascinating, such research is facing dif­ 3.1 Ergot Derivatives: Co-dergocrine, ficulties as the target of activation is not clear Dihydroergocristine and Nicergoline (membrane composition or activity? increased availability of energy and/or neurotransmitters? 3.1.1 Pharmacology expansion of neuronal networks?). Likewise, mark­ The pharmacological profiles and suggested uses ers of increased cerebral activity (as measurable of the most representative compounds of this group events in quantified EEG) are not directly inter­ have been partially delineated in tables III, V and pretable as proof of therapeutic effect. VII. Co-dergocrine (dihydroergotoxine; Hyder­ Hypothesis (c) can be seen as a special case of gine@) consists of 4 ergopeptine derivatives, dihy­ the broader neurotransmitter hypothesis which, droergocornine, dihydroergocristine, dihydro-a­ since the discovery of psychotropic drugs, has ergocryptine and dihydro-i3-ergocryptine, in a ratio formed the cornerstone of all research aimed at be- of 3 : 3: 2 : I (fig. 1). One component (dihydroer- 'Cerebroactive' Drugs 51

gocristine) is also marketed as a separate active Similar EEG results have been obtained with co­ principle, and in addition to its properties as an dergocrine, dihydroergocristine and bromocriptine ergot compound, an antiplatelet action has also (Agnoli et aI., 1981 ; Venn, 1980). been suggested (Gamba et aI. , 1978; Tomasi et aI., Among the various hypotheses of the mechan­ 1976). Nicergoline is the bromonicotinate of an er­ ism of action of these compounds (reference is spe­ goline derivative which in man lowers blood pres­ cifically made to co-dergocrine as data for dihy­ sure and has an anti platelet action (Bogaert, 1979a). droergocristine and nicergoline are lacking), the The relationship of these actions to the proposed interaction with neurotransmitters is at present definition (Saletu et aI., 1979) of an 'antihypoxi­ being widely investigated (Berde and Schild, 1978), dotic vasoactive ergot alkaloid' is by no means although the door is open to other possible activ­ straightforward. ities (see table V). The suggested stimulatory action In a study in 10 elderly patients utilising quan­ on dopamine receptors is not supported by in vitro titative EEG, nicergoline reduced delta and theta studies of the effect on dopamine-stimulated adenyl activity and increased alpha and beta activity, with cylase, though a possible agonist action at dopa­ an increase of the dominant frequency suggesting mine receptors not coupled to adenyl cyclase ac­ an improvement of , vigilance' (Saletu et aI., 1979). tivity (D2 receptors) has been proposed (Interna-

Dihydroergocristine Dihydroergocornine

Dihydro-a-ergocryptine Dihydro-/3-ergocryptine

Fig. 1. Co-dergocrine (dihydroergotoxine): chemical structures of the component alkaloids. 'Cerebroactive' Drugs 52

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

Cerebral blood flow (CBF) Invasive quantitative techniques for measurement of global CBF (nitrous (Fieschi and Des Rosiers, 1976; Fieschi. 1980) 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 3.1.2 Clinical Studies Alkaloids, Rome, October 28-30, 1981). Restricting the discussion to co-dergocrine seems The following quotation summarises the pres­ justified because clinical data on the other ergot ent status of the drug(s), and is reported here with­ alkaloids are too limited for any comprehensive out qualification, as it adequately reflects the rather evaluation, and the current revival of interest in uncertain state of knowledge: '[these compounds] this class of drugs has not included them. For the are unusual in the diversity of their pharmaco­ purpose of this review it is useful to distinguish logical actions... The structure of the ergot two 'generations' of clinical studies. molecule contains the essential features of four neurotransmitters: dopamine, norepinephrine, epi­ First 'Generation' Studies nephrine, and serotonin, which probably accounts Co-dergocrine has been compared mainly with for their capacity to interact with several neuro­ placebo and with papaverine (6 studies) in patients transmitter receptors ... and to restore the altered with 'senile cerebral insufficiency' (Fanchamps, neuronal balance [that accounts for] the neuro­ 1979). In 3 of these 6 studies the difference was psychiatric disturbances in aging' (Goldstein, 1980). statistically significant in favour of co-dergocrine The pharmacokinetics of co-dergocrine have with the other 3 suggesting an 'overall impression' been studied using a tritium-labelled preparation. in the same direction. When the drug was com­ Available information suggests poor absorption (20 pared with placebo, significant improvement was to 25% of the administered dose after sublingual reported by at least I investigator for each of the or oral administration) and describes only very ap­ 19 items on the Sandoz Clinical Assessment Geri­ proximately the pattern of elimination. It must, atric (SCAG) scale (the most widely used rating however, be qualified at best as preliminary and scale in these trials) [see table IX], but with no def­ with no clinical correlates (Spagnoli and Tognoni, inite pattern of symptom improvement. 1979). Co-dergocrine is generally well tolerated, the The careful review by Hughes et al. (1976) can only relevant side effect being sinus bradycardia be taken as the most reliable summary of these 'first which was reported to be associated with severe generation' trials. These authors stated that co-der­ deterioration of the general condition in 3 elderly gocrine 'consistently produced statistically signifi­ patients with multi-infarct dementia after doses of cant improvement in 13 symptoms associated with l.5mg tid orally (Dcayley et aI., 1975). dementia (mental alertness, orientation, confusion, 'Cerebroactive' Drugs 53

recent memory, depression, emotional lability, an­ Second 'Generation' Studies xiety /fears, motivation/initiative, agitation, dizzi­ Among the 'second generation' of trials, the 2 ness/vertigo, walking/mobility, locomotion, over­ main, best 'controlled' studies are examined as ex­ all impression, global therapeutic change). However, amples. Gaitz et al. (1977) evaluated the effect of because of the small magnitude of the improve­ co-dergocrine (sublingual tablets I.Omg thrice daily) ment and the absence of indications of long term in 54 nursing home residents with 'organic brain benefit, [co-dergocrine] would seem to be of minor syndrome' and the main reason stated for adding value in dementia therapy. Further research with this report to the literature was that patients were better methodology and design might lead to a dif­ followed up during a 24-week period. On the SCAG ferent conclusion.' scale a significant (p < 0.05) improvement was The US Food and Drugs Administration inter­ shown in 16 of the 19 items in the co-dergocrine pretation of these data was surprisingly different: group and in II in the placebo group at 12 weeks. co-dergocrine was declared effective for 5 'selected At 24 weeks, significant improvement was still ob­ symptoms of the elderly' (see table VII). Note that served in 15 items in the active drug group and 2 the indication is not for a disease state (e.g. de­ items in the placebo group. The authors concluded mentia) but for symptoms of a life period (ageing). that follow-up of patients beyond the usual 3-month What mechanism of action might underlie an im­ period showed greater effectiveness of co-dergo­ provement both in dizziness and lack of self-care? crine compared with placebo. What is dizziness in the elderly? Is it true vertigo This study suffered, however, from great vague­ or something else? Should the doctor prescribe co­ ness in the diagnostic and admission criteria of the dergocrine for mood depression in a 67-year-old patients; age and duration of illness are not spec­ and imipramine for a 37-year-old patient? ified, 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 Table IX. The Sandoz Clinical Assessment Geriatric (SCAG) reported in detail, the only information given was Scale. Rating key: 1 = not present; 2 = very mild; 3 = mild; that the MSCL showed no statistically significant 4 = mild to moderate; 5 = moderate; 6 = moderately differences, but the trend was toward more im­ severe; 7 = severe provement by the co-dergocrine-treated group than 1. Confusion the placebo group. Of the 54 heterogeneous patients 2. Mental alertness who entered the trial, only 35 completed the 24- 3. Impairment of recent memory week follow-up period but nothing is said about 4. Disorientation 5. Mood depreSSion drop-outs. 6. Emotional lability The mean value of the SCAG 'overall impres­ 7. Self-care sion' score is reported as indicating statistically sig­ 8. Anxiety nificant (p < 0.01) improvement from baseline to 9. Motivation, initiative the 24-week score in the co-dergocrine group but 10. Irritability 11. Hostility not in the placebo group. The degree of improve­ 12. Bothersome ment, however, on a 7-point scale, was 4.91 for the 13. Indifference to surroundings active drug group at base-line and 4.04 at the end 14. Unsociability of the trial, while for placebo group the respective 15. Uncooperativeness scores were 4.42 and 4.25. 16. Fatigue 17. Appetite Kugler et al. (1978) compared co-dergocrine and 18. Dizziness placebo in a controlled trial on 274 patients with 19. Overall impression 'senile cerebral insufficiency' followed up for 15 months. About two-thirds of the patients admitted 'Cerebroactive' Drugs 54

did not complete the study and scores (psycho­ eye reflexes induced by caloric stimulation of the metric tests) on which improvement was measured labyrinth, and other antihistamine properties (pro­ were distributed among those for which opposite tection against histamine-induced bronchospasm results have been documented in other studies. and increase in capillary permeability) [Laporte, Other recent studies with co-dergocrine (Biel et 1979]. Plasma elimination half-lives of 64 hours aI., 1976; Dennler and Bachmann, 1979; Junod, and from 3 to 24 hours have been reported in 2 1978; Matejcek et aI., 1979; Yesavage et aI., 1979) pharmacokinetic studies based on use of a 14C_ do not help clarify the problems pointed out by labelled compound (Janssen Pharmaceutica, un­ Hughes et ai. (1976) in their review or some ofthe published report, 1969) and on a GLC method other questions outlined above. In one of these (Morrison et aI., 1979) respectively, and conducted trials (Yesavage et aI., 1979) comparison of 3mg in young healthy volunteers. Side effects attribut­ versus 6mg daily doses of co-dergocrine for 12 weeks able to cinnarizine at the usual dosage (15 to 50mg (crossover design) in 11 inpatients with 'degener­ daily) are reportedly occasional and reversible, and ative or atherosclerotic chronic organic brain dis­ include asthenia, nausea, vomiting and drowsiness. ease' failed to show any significant difference in Flunarizine has been shown to prolong reactive favour of the 6mg dosage. hyperaemia after temporary arterial occlusion (thumb and leg) in healthy volunteers. This effect 3.2 Cinnarizine and Flunarizine of flunarizine (lOOmg orally) is twice that of cin­ narizine (200mg orally) [Jageneau et aI., 1974]. 3.2.1 Pharmacology Cinnarizine is an antihistamine of the pipera­ 3.2.2 Clinical Studies zine group (fig. 2). The drug antagonises smooth Between 1966 and 1972, 4 placebo-controlled muscle contraction induced by various agents clinical trials on cinnarizine were published (Beh­ (Godfraind and Kaba, 1969; Van Nueten, 1969; rens, 1966; Bernard and Goffart, 1968; Toledo et Van Nueten and Janssen, 1972) and both the par­ aI., 1972; Van der Meer-Van Manen, 1967). Cin­ ent drug and its difluoro derivative, flunarizine, in­ narizine was administered in daily doses from 25 hibit calcium-induced contraction of depolarised to 50mg, the mean number of patients was 26 arid arteries by reducing calcium transfer to depolarised the follow-up usually 8 weeks. These facts and the vascular smooth muscle (Godfraind and Polster, ill-defined diagnosis of admission (mainly 'cerebral 1968; Godfraind et aI., 1968; Van Nueten and arteriosclerosis') do not confirm the authors' fre­ Janssen, 1973). quent suggestions of positive results for a wide range In addition, cinnarizine has other pharmaco­ of clinical symptoms (Laporte, 1979). logical properties such as depression of vestibular 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 improve­ ment of physical symptoms such as headache, ver­ Cinnarizine tigo, tinnitus and sleep disturbances. A comparison was made between pre-trial and post-trial findings but not between the drug and placebo groups. Fig. 2. Chemical structure of cinnarizine. Nothing was said about 2 patients in the flunari- 'Cerebroactive' Drugs 55

placebo. It has been suggested that at a dosage of 30mg intravenously, vincamine increases the cere­ bral metabolic rate of oxygen (Heiss, 1979). The intravenous route should be avoided in car­ diac patients (Dekoninck et aI., 1978; Pirani et aI., 1978) as the drug has potential cardiac toxicity re­ lated 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 de­ Vincamine rivative of vincamine. The drug is said to be a 'cerebral oxygenator' with 'antihypoxic properties' which appear more pronounced than those of vin­ Fig. 3. Chemical structure of vincamine. carnine (Linee et aI., 1978) and with a more pro­ tracted 'vasoactive effect'. zine group who died after inclusion in the trial and 'were not considered for evaluation'. 3.3.2 Clinical Studies In a single-blind study (Dringoli et aI., 1975) in 3.3 Vincamine and Eburnamonine 32 patients with 'initial physical and mental in­ volution probably related to chronic cerebrovas­ 3.3.1 Pharmacology cular insufficiency', vincamine (60 mg/day orally) The profile of activity of these 2 drugs is some­ was evaluated against placebo. After a 4-month what ill-defined. Vincamine is an indolyl-alkaloid follow-up, the active group showed significant im­ isolated from Vinca minor (not to be confused with provement of subjective symptoms (headache, diz­ the cytotoxic substances derived from Vinca rosea) ziness, unsteadiness, tinnitus, insomnia and poor [fig. 3]. The drug is claimed to improve hemi­ vision) and in two psychometric tests (Raven Test, spheric as well as regional CBF. Effects on the CBF Associated Learning Test). 'Psychic' symptoms are claimed to be associated with plasma concen­ (poor memory, lack of attention, mood disorders) trations of the drug between 500 and 1000 ng/ml, showed no noteworthy modification. which are reached with infusions of 30mg over 20 In a double-blind study in 20 patients (aged 38 minutes or 40mg over 40 minutes, but not after to 88 years) with acute stroke (Dekoninck et aI., 20mg over 20 minutes or 30mg over 40 minutes. 1978) vincamine (60mg by intravenous infusion) The effect on CBF disappears, however, 15 min­ plus glycerol were compared with placebo plus utes after the end of the infusion (Heiss, 1979). A glycerol. After a 5-day follow-up period there was crossover study of the effect on CBF of a single stated to be a greater improvement of the neuro­ infusion of either vincamine (40mg over 20 min), logical status (homonymous hemianopsia, conju­ the ester derivative ethyl apovincaminate (20mg gated deviation of eyes, motor activity and sphinc­ over 20 min), or placebo, failed to show any sig­ ter control) with vincamine than with placebo. In nificant change of mean CBF values (Lim et aI., 2 of 11 patients on vincamine, cardiac disturb­ 1980). In this study 5 of the 6 healthy male volun­ ances occurred during treatment (ventricular extra­ teers complained of side effects during or after drug systoles and sinusal bradycardia with first-degree infusion (tinnitus, dizziness and faintness on atrioventricular block). standing, mild facial flushing and thrombosis of an In a multicentre double-blind study (Passeri, arm vein) while none developed symptoms with 1978) in 106 elderly patients suffering from 'estab- 'Cerebroactive'Drugs 56

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 Naftidrofuryl 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 Fig. 4. Chemical structure of naftidrofuryl. 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 in comparison with a control observation (Shaw ischaemia', eburnamonine (60 to 80 mgfday orally) and Johnson, 1975). In a randomised study of 34 was compared with nicergoline (15 to 20 mgfday subjects undergoing operations of moderate sever­ orally). The follow-up was stated by the authors to ity (Burns et ai., 1981), naftidrofuryl infusion be 'protracted for at least 20 days' and eburna­ (200mg twice daily for 3 days) was associated with monine induced an improvement of some symp­ a significant decrease of urinary excretion of nitro­ toms (insomnia, headache and dizziness) 'more gen attributed to drug-induced stimulation of fat rapidly and significantly than nicergoline'. and carbohydrate metabolism, leading to a reduc­ tion of amino acid oxidation which usually is in­ 3.4 Naftidrofuryl creased after injury. The only available pharmacokinetic studies with 3.4.1 Pharmacology naftidrofuryl (Fontaine et aI., 1969; Royer et aI., The spectrum of activity proposed for this drug 1975) have reported a mean plasma half-life of 1 (fig. 4) ranges from CBF increase (via a spasmo­ hour after oral administration. lytic effect on smooth muscle fibre) to metabolic 'activation' (enhancement of glucose entry and/or 3.4.2 Clinical Studies consumption in the brain) leading to nonspecific From 1972 to 1978, at least 11 randomised EEG 'activation' (Beghi, 1979; Bouchard and Ri­ double-blind clinical trials have been published. Of gal, 1970), to the recently suggested 'metabolic pro­ these, 10 have been concerned with 'chronic cere­ tection' of cells against ischaemia (Meynaud et aI., bral insufficiency', and the most recent one with 1975). 133Xe inhalation techniques however, failed stroke patients. to substantiate any significant effect on CBF, either The clinical trials in chronic cerebral insuffi­ after single intravenous infusions (120mg) or after ciency (Adriaensen, 1974; Bargheon, 1975; Bou­ long term oral administration (200mg 3 times a wier et aI., 1974; Branconnier and Cole, 1977; Bro­ day for 6 weeks) in 11 elderly patients with chronic die, 1977; Cox, 1975; Gerin, 1974; Judge and cerebrovascular disorders and/or senile dementia Urquhart, 1972; Robinson, 1972; Trouillas, 1977) (James et aI., 1978). were based on a mean sample size of 52 subjects The direct effect on tissue oxidative metabolism and a follow-up period of 2 to 3 months, with a via activation of succinic dehydrogenase (an en­ mean dosage of 300mg tid. The diagnostic and ad­ zyme of the tricarboxylic acid cycle) [Meynaud et mission criteria were invariably iII-defined, and ai., 1973] was tested in 5 young volunteers, where drop-outs were as high as 1 in 3 in 2 studies (Ad­ the post-exercise lactate-pyruvate ratio was signifi­ riaensen, 1974; Judge and Urquhart, 1972). Daily cantly reduced after naftidrofuryl (300mg orally), living activities were improved (Adriaensen, 1974; 'Cerebroactive' Drugs 57

Brodie, 1977) or unchanged (Judge and Urquhart, creased with the severity of the clinical situation; 1972); and the same was true for 'cognitive' func­ Ehrly and Kohler, 1976) in the same patients are tions which were either improved (Adriaensen, the main effects of the drug. These evidently occur 1974; Bouwier et aI., 1974; Cox, 1975; Judge and via an increase of ATP levels in red blood cells, an Urquhart, 1972; Trouillas, 1977) or unimproved increase in fibrinolytic activity, a decrease in plasma (Brodie, 1977; Judge and Urquhart, 1972). fibrinogen and inhibition of platelet aggregation. The study in stroke patients (Admani, 1978) was A significant increase in the erythrocyte filtra­ a double-blind placebo-controlled trial involving tion rate (a technique for the evaluation of red cell 91 patients with stroke due to recent ischaemic flexibility) and a decrease in whole blood viscosity cerebral infarction (mean interval ± SO between after oral and intravenous oxpentifylline have been stroke and treatment 5.04 ± 5.30 days for the naf­ reported in healthy volunteers (Grigoleit et aI., tidrofuryl group and 5.88 ± 6.10 days for the pla­ 1976) and in patients with chronic vascular dis­ cebo group). The diagnostic criteria were not spec­ orders (Schubotz and MOhlfeliner, 1977; Smud et ified; exclusion criteria were previous history of aI., 1976). These effects (also seen with the slow­ stroke or dementia, or severe confusion, uncon­ release 400mg preparation) are no longer measur­ sciousness, and stroke of non-vascular causes. Oral able after 2 hours. Caution is necessary when in­ naftidrofuryl 200mg tid was given for 4 weeks fol­ terpreting data on red cell flexibility because of its lowed by 100mg tid for 8 weeks. A better overall important circadian variations (Grigoleit et aI., score (power, sensation, daily living activities, etc.) 1976). and a significantly shorter hospital stay were re­ Pharmacokinetic information on oxpentifylline ported for the treated than for the control group. is scarce. Administration of the drug to healthy No difference in overall mortality but a signifi­ adult volunteers gave a peak plasma concentration cantly (p < 0.05) lower stroke mortality was docu­ at 2 to 3 hours; the plasma profile of a metabo­ mented in the naftidrofuryl group. lite [1-( 5-hydroxyhexyl)-3, 7-dimethylxanthine] fol­ In a timely comment on this study, Steiner et lowed the same pattern as the parent compound, al. (1979) pointed out the many weak points: a at concentrations 2 to 4 times higher (Hinze et aI., purely clinical diagnosis of recent ischaemic in­ 1976). farction, the skewed distribution of the interval be­ Side effects of oral oxpentifylline are reported tween stroke and treatment, low comparability of to be rare and include dose-dependent chest pain the 2 groups when subscores for neurological and and mild digestive discomfort (Feine-Haake, 1977; neurophysical variables are added. Their conclu­ Muggeo et aI., 1981). sion that a definite benefit in stroke from naftid­ rofuryl cannot be claimed (Steiner et aI., 1979) ap­ pears 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; Oxpentifylline Ointenfass, 1969; Oormandy, 1970) and improve­ ment of red cell flexibility (proportionately de- Fig. 5. Chemical structure of oxpentifylline (pentoxifylline). 'Cerebroactive' Drugs 58

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

Reference Population studied Variables observed Results

Hawart 60 patients with 14 'cerebral symptoms' (poor memory, Significant improvement for some clinical (1979) 'signs of cerebral headache, incontinence, etc.) symptoms, some PGRS items and insufficiency due to 'Peripheral' symptoms (paraesthesia, psychometric tests over a 2-month period old age' claudication, etc.) Plutchik Geriatric Rating Scale (PGRS) Psychometric tests (memory and psychomotor performance)

Pricladnitzki 40 'geriatric patients Clinical symptoms Significant improvement for headache, social (1979) with cerebrovascular isolation, poor memory and impaired insufficiency' concentration over an a-week period

Dominguez 40 patients with Clinical symptoms and psychometric tests Significant improvement for subjective et al. (1977) 'chronic complaints, practical abilities and anxiety cerebrovascular over a 4-month period. Anxiety, recorded in 2 insufficiency' different ways, showed contradictory evolution. One drop-out (oxpentifylline group) because of severe digestive side effects

3.5.2 Clinical Studies tween the 2 groups being not significant (Warlow Three double-blind placebo-controlled trials in and Peto, 1981). elderly patients have been published using a dosage schedule of 400mg tid (Dominguez et aI., 1977; 3.6 Piracetam Harwart, 1979) or bid (Pricladnitzki, 1979) [see table X]. 3.6.1 Pharmacology In a multicentre trial in TIA patients in Argen­ Piracetam (2-oxo-I-pyrrolidine-acetamide) [fig. tinian hospitals (Herskovits et aI., 1981), the effect 6], a cyclic derivative of GABA with no GABA­ of oxpentifylline (400mg tid orally) was assessed like properties, has been proposed as the prototype versus a fixed combination of aspirin and dipyri­ of the 'nootropic' drugs (Giurgea, 1973), a class of damole given tid (for a total daily dose of 1050mg psychoactive drugs selectively improving effi­ aspirin and 150mg dipyridamole). After a I-year ciency of 'higher telencephalic integrative activi­ follow-up there was a significant difference in mor­ ties' (Giurgea, 1978). Its therapeutic profile is bidity rate (new TIAs and stroke) in favour of ox­ claimed to include: (1) enhancement of learning pentifylline. The vague inclusion criteria (TIA of acquisition and resistance to agents impairing ac­ every type, age between 38 and 86 years), the small quisition (e.g. hypoxia, electroconvulsive shocks); number of patients (63) who completed the trial (2) facilitation of interhemispheric transfer of and hence the small number of observed events (3 information; (3) enhanced resistance to brain strokes and 13 patients with continuing TIAs) in 'aggressions'; (4) increased tonic, cortico-subcort­ addition to the absence of a placebo-controlled ical control; and (5) absence of sedation or stimu­ group leave these findings open to criticism (Gawel lation and virtually no toxicity (Giurgea, 1978). Se­ et aI., 1981; Warlow and Peto, 1981). There is also lective amelioration of the ATP/ADP ratio in the an error in the calculation of statistical signifi­ telencephalon (Giurgea, 1973), stimulation of syn­ cance, the difference in cumulative morbidity be- aptic transmission via enhancement of neuronal 'Cerebroactive' Drugs 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, in­

Piracetam cluding in the final analysis a mean of 28 geriatric patients with senile dementia, chronic or acute cerebral ischaemia and elderly patients with mild Fig. 6. Chemical structure of piracetam. deterioration of mental function (Abuzzahab et ai., 1978; Dencker and Lindberg, 1977; Diesfeldt et ai., 1978; Gedye et ai., 1978; Gustafson et ai., 1978; and synaptosomal phospholipase A activity (Woelk, Trabant et ai., 1977). 1979), and an antithrombotic (platelet-inhibiting) In 3 other double-blind studies, piracetam was activity (Bick, 1979) are proposed as the mechan­ found to be superior to placebo. These 3 positive isms underlying these effects. studies are summarised in table XI (Guilmot and Animal studies on learning, memory and global Van Ex, 1975; Macchione et ai., 1976; Stegink, performance however, give contradictory results 1972). (Bryant et ai., 1973; Means et ai., 1980; Oglesby Besides the usual criticism of vague criteria of and Winter, 1974; Sara and David-Remacle, 1974). patient selection and efficacy evaluation (Bogaert, Moreover, no significant effect has been found on 1979b), some specific points are worth emphasis­ regional CBF by the 133Xe inhalation technique in ing, mainly in the second and third studies: (1) the moderately demented patients (Gustafson et ai., poor matching of treated (112) versus placebo (70) 1978); whole EEG activation measured by power patients and the reported 'remission' of the psycho­ spectral analysis has been reported in hospitalised organic syndrome in 73.3% of treated patients and 'gerontopsychiatric' patients (Bente et ai., 1978); in 55.7% of placebo patients, which casts many and verbal, but not non-verbal learning was im­ doubts on the reliability of clinical criteria for ad­ proved in young healthy volunteers following 14 mission and clinical evaluation (Macchione et ai.,

Table XI. Results of double-blind trials with piracetam

Reference Population studied Variables observed Results

Guilmot and Van Ex 24 patients (final analysis) with Clinical symptoms Significant improvement for asthenia; but not (1975) 'involution depression' for anxiety, poor memory, psychomotor activity and consciousness disturbances over a 6-week period

Macchione et al. 182 patients with 'cerebral Clinical symptoms Significant improvement for asthenia, anxiety, (1976) psycho-organic syndrome' memory disturbances, psychomotor disturbances, failure to adapt to surroundings; but not for distraction and overall assessment over a 6- or a-week period

Stegink (1972) 191 patients with 'chronic Clinical symptoms Significant improvement for reduced alertness, irreversible deterioration of asthenia, psychomotor agitation and general intellectual function due to course of the syndrome over an 8-week period organic disorders of old age' 'Cerebroactive' Drugs 60

1976); and (2) the curious age range of 'elderly' 250 to 1000 mg/day intravenously) was given to patients, from 31 to 91 years (Stegink, 1972). 162 'post-stroke hemiplegic patients' participating in a functional rehabilitation programme. Signifi­ 3.7 Citicoline cantly better functional recovery measured on a 12- item scale (Hemiplegic Function test) was reported 3.7. J Pharmacology for upper but not for lower limbs; however, the As has been shown to be the case for other com­ study failed to document any positive result in the pounds, the pharmacological profile of citicoline physicians' overall judgement, subjective symp­ [or COP-choline (cytidine diphosphate choline), fig. toms and neurological signs. 7, the precursor of choline phosphoglyceride (or In the second study (Goas, 1979), 64 patients lecithin)] cannot claim consistency. The following with 'evident cerebrovascular accidents' (age range is a summary of the hypotheses put forward for 42 to 81 years) were followed for 90 days (daily justifying broad spectrum activity: dose of citicoline 250 or 750mg intravenously or a) Integration of the molecule into biological intramuscularly) and showed significant improve­ membranes to favour phospholipid synthesis and ment in motor and muscular tone disturbances, therefore to improve neurological deficits 'global clinical evolution', psychometric tests and b) Direct pharmacological effect on cerebral func­ EEG. tion possibly via interaction with transmitters and/ or receptors (data are particularly scanty in this re­ 4. New Hypotheses spect) [Nilsson, 1979] c) Specific activation of dopaminergic transmis­ The large amount of neurochemical data on the sion (Ishikawa et ai., 1973), possibly as the back­ ageing brain of 'normal' and Alzheimer subjects and ground for the suggested (Manaka et ai., 1970; Shi­ the evidence of a memory effect of the anti­ mamoto et ai., 1975) use of the drug concomitantly cholinergic drug hyoscine (scopolamine) have with levodopa in Parkinsonism drawn increasing attention to the role of neuro­ d) 'Vasoactive' and anti platelet activity leading to transmitters both in the 'normal' ageing process of improvement of the microcirculation (Tassi and the brain (where dopamine should be primarily in­ Perversi, 1978). volved) [Pradhan, 1980] and in pathological situ­ Parenteral administration is mandatory to avoid ations (where acetylcholine is to the fore) [see sec- intestinal hydrolysis. Less than 0.1 % of an intra­ venous 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 (Nils­ son, 1979). o 0 \I II 0 .(5N 3.7.2 Clinical Studies The few controlled studies available focus on (CH3hN+CH2CH20-P-0-P-0~C2 I I 0 the drug's ability to improve the long term prog­ 0- OH nosis of stroke patients (Boudouresques, 1979; H H Goas, 1979; Hazama et ai., 1980; Miyazaki, H H 1968a,b; Muramatsu et ai., 1971). Two double-blind Citicoline OH OH placebo controlled trials suggesting superiority of

the drug deserve more detailed analysis. Fig. 7. Chemical structure of citicoline (cytidine diphosphate In the first (Hazama et aI., 1980), citicoline (from choline). 'Cerebroactive' Drugs 61

tion 4.1). Overall, evaluation of current knowledge opened for testing the hypothesis of a 'replacement is clearly negative as regards any lasting sympto­ therapy' in Alzheimer dementia, where memory matic or (obviously) therapeutic role of the tested impairment is a principal and early symptom. In drugs (levodopa, choline, lecithin, arecoline, phy­ addition, a specific, significant reduction in the ac­ sostigmine) [International Study Group on the tivity of choline acetyltransferase, an enzyme in­ Pharmacology of Memory Disorders Associated volved in the synthesis of acetylcholine, has been with Aging, 1981). documented in the cerebral cortex and hippocam­ Some research leads, however, are worth men­ pus of patients with Alzheimer dementia (Bowen tioning, as the better controlled methodology and et ai., 1979; Davies and Maloney, 1976; Perry et orientation of the trials towards more specific tar­ ai., 1977). gets have resulted in better definition of the prob­ Oral choline is metabolised by intestinal bac­ lems, underlining the fallacy of looking for 'all­ teria to trimethylamine, a highly volatile amine encompassing' solutions and the limitations of which is excreted in urine, breath and sweat and available measuring tools (rating scales, psycho­ produces a disgusting fishy odour (Marks et al., metric tests). 1978). Lecithin should therefore be preferred, as it does not produce such an odour and gives higher, 4.1 Acetylcholine Precursors longer lasting levels of free choline in the serum (Wurtman et ai., 1977). Several reports have provided evidence that Reports have been published of at least 9 trials hyoscine and atropine, two anticholinergic drugs on mild to moderately demented patients treated with central activity, when given to normal hu­ with choline or lecithin. Of these, 5 were 'open' mans impair memory function via an effect on in­ trials (Boyd et ai., 1977; Christie et ai., 1979; Etienne formation storage (acquisition), rather than on et ai., 1978b; Friedman et ai., 1981; Signoret et al., retrieval (Drachman, 1977; Wetherell, 1980). 1978); the 4 placebo-controlled trials follow a However, the picture is by no means clear as only crossover design, 3 double- (Fovall et al., 1980; acute studies can be done, the duration of memory Peters and Levin, 1979; Smith et al., 1978) and 1 impairment varies widely and is largely dependent single-blind (Etienne et ai., 1978a). The mean on the dose and route of administration (Wether­ number of patients was 7 (range 3 to 11) with a ell, 1980). It is not known whether the same effects mean follow-up period of 8 weeks (range 1 to 20 could be produced by other drugs with anticholi­ weeks). Usually choline administration began at a nergic activity such as tricyclic antidepressants and daily dose of 1 to 5g and was gradually raised to some anti psychotics. 9 to 16g, while lecithin was administered at a daily Additional information has been gained from dose of 25 to 100g. Memory assessment was the studies where the anticholinesterase drug physo­ main target, but with attention to psychomotor stigmine has been shown to partially reverse the ability and behavioural variables. A very large in­ hyoscine effect; in contrast dextroamphetamine, ter- and intrasubject variability was evident and no whose nonspecific effect on memory occurs via in­ definite clinical benefit could be proved, though in creased alertness and attention, failed to antagon­ psychometric tests some patients showed signifi­ ise 'hyoscine dementia' (Drachman, 1977). Phy­ cant improvement of some aspects of memory sostigmine (lmg intravenously) also reportedly function (paired associate learning test, verbal enhanced long term memory (storage process) in memory retrieval, auditory and visual word rec­ normal volunteers, though the intersubject varia­ ognition) [Etienne et ai., 1978b; Fovall et ai., 1980; bility was considerable (Davis et al., 1978). As cho­ Friedman et ai., 1981; Peters and Levin, 1978). In line, a precursor of acetylcholine, and lecithin have 1 trial (Friedman et al., 1981), higher red cell cho­ been shown to raise choline levels in serum and line concentrations (before and during treatment) cerebrospinal fluid (Editorial, 1980), the way was were measured in 'responders'. 'Cerebroactive' Drugs 62

Side effects reported during treatment with cho­ creasing focus on elderly patients with Cl~S in­ line or lecithin were mainly 'digestive' (reduction volvement have created interest on a broader scale in appetite, nausea, abdominal bloating, diarrhoea) and under various labels (basic research, INDs, sci­ and 'behavioural' (depression, irritability, anxiety) entific meetings, large scale multicentre trials). [Boyd et ai., 1977; Christie et ai., 1979; Etienne et 'Cerebroactive' drugs are now a reality whose ai., 1978a; Fovall et ai., 1980; Smith et ai., 1978]. existence cannot be denied, neither in developed They were generally dose-dependent and tended to nor in developing countries, and many can claim subside when dosage was reduced. Faecal and urin­ some measure of support in the fact of their being ary incontinence and a small fall in blood pressure mentioned (not negatively) by leading authorities. were also reported (Boyd et ai., 1977; Christie et What then is behind this wave of interest? The ai., 1979; Etienne et ai., 1978a; Smith et ai., 1978). concluding remarks at the Milan meeting on In 4 patients, side effects caused the interruption 'cerebroactive' drugs, which has often been cited of drug treatment (I aggressive behaviour; I (Tognoni and Garattini, 1979), seem to hold true depression; I anxiety, fishy odour, nausea and for the majority of clinical trials (on which also this belching; I incontinence) [Christie et ai., 1979; review was based): Etienne et ai., 1978a; Fovall et ai., 1980; Smith et ' ... we heard, with growing horror the evidence ai., 1978]. about the efficacy of these drugs . . . I started being interested, then surprised, then shocked. Shocked 5. Other Drugs by the gross misuse of the double-blind random­ ized controlled trial ... In the USA and the UK Interest in the other drugs listed in table I as all protocols for research on patients have to be potential tools for the treatment of stroke patients, passed by ethical committees. It is becoming in­ dementia or the 'common symptoms' of the elderly creasingly accepted that it is unethical to allow has diminished in line with the falling credibility badly designed randomized controlled trials to be of the vasodilatation hypothesis as the basis for carried out ... Few, if any of the horrors we saw therapeutic effects. Even preliminary positive re­ . .. would be accepted by editors of respectable sults claimed for 'new' drugs such as hexobendine journals, but they would certainly welcome a witty and betahistine on CBF (McHenry et ai., 1972; monthly article summarising the publications in the Meyer et ai., 1971, 1974) and on the clinical status "free" press in a pithy way. We are a scientific and of patients with 'vertebrobasilar arterial insuffi­ caring profession and the solution is finally up to ciency with dementia' (Rivera et ai., 1974) or 'ar­ us. We can, in the first place, improve education, teriosclerotic dementia' (Seipel et ai., 1977) have by teaching students about methods of evaluation, remained isolated. and by encouraging them always to enquire of their elders and betters about the evidence that what they 6. Conclusions are doing is for the benefit of their patients. It is good for them and good for their elders' (Cochrane, When only a few years ago the request to crit­ 1979). ically review the activity profiles and use of this CNS problems of the elderly are, however, here class of drugs was forwarded to various experts in to stay, and will possibly increase, and increasing the field of cerebrovascular disorders, the first re­ cultural and industrial pressure to expand the mar­ action of many of them (in the UK, Scandinavia, ket must be expected, often with the justification Canada and USA) was to decline the invitation, as of extracting funds for badly needed basic and the topic appeared esoteric with no real basis in clinical research. The heart of the problem seems clinical practice and research. The scene has now to lie in this strained situation: the urgency to pro­ changed, as the aggressive attitudes of pharma­ duce positive results to support a market, and ceutical companies marketing the drugs and an in- awareness that the road to satisfactory integration 'Cerebroactive' Drugs 63

of the various areas of research in the field is by ate. Current Therapeutic Research 29: 321-326 (1981). no means easy nor short. Alexander, D.A.: "Senile dementia": A changing perspective. Important clarifications must certainly result British Journal of Psychiatry 121: 207-214 (1972). from the intensification of basic research by more Barbeau, A.: Growdon, J.H. and Wurtmap, RJ. (Eds): Nutrition and the Brain, Vol. 5: Choline and Lecithin in Brain Disor­ groups. A multiplication of clinical trials in differ­ ders (Raven Press, New York 1979). ent cultural settings and in well-defined subpopu­ Bargheon, J.: Essai en double aveugle du praxilene en geriatrie. lations will also enable us to orient ourselves more Gazette Medicale de France 82: 4755-4758 (1975). objectively among the presently contradictory re­ Beghi, E.: Naftidrofuryl; in Tognoni and Garattini (Eds) Drug sults, and to distinguish insignificant and relevant Treatment and Prevention in Cerebrovascular Disorders, pp.211-222 (Elsevier/North Holland Biomedical Press, Am­ symptomatic or therapeutic effects. sterdam 1979). While promising and possibly decisive steps Behrens, E.: Medikamentbse beeinflussung der hirndrchblutung have been made with respect to non-invasive durch stutgeron. Medizinische Welt 38: 2029-2031 (1966). methods for assessing brain functions, 2 critical Bente, D.: Glatthaar, G.; Ulrich, G. and Lewinsky, M.: Piracetam preliminary issues remain to be adequately solved: und vigilanz. Arzneimittel-Forschung 28: 1529-1530 (1978). Berde, B. and Schild, H.O. (Eds): Ergot Alkaloids and Related definition of the target population(s) with easily Compounds (Springer-Verlag, Berlin 1978). applicable and reliable psychometric tools; and the Bergmann, K.; Proctor, S. and Prudham, D.: Symptom profiles need for assessing drug effects together or inter­ in hospital and community resident elderly persons with de­ acting with other supportive or intervention meas­ mentia; in Hoffmeister and Miiller (Eds) Brain Function in ures known sometimes to playa major role in this Old Age. Evaluation of Changes and Disorders, pp.60-67 (Springer-Verlag, Berlin 1979). class of patients. Bernard. A. and Goffart, J.M.: A double-blind cross-over clinical Methodological and epidemiological lessons evaluation of cinnarizine. Clinical Trials Journal 5: 945-948 learned over the last few years for psychiatric dis­ (1968). eases could be of great help (Tognoni et aI., 1981) Bick. R.L.: In-vivo platelet inhibition by piracetam. Lancet 2: 752- in accepting the limits of what has been achieved 753 (1979). Biel. M.L.: Seus. R. and Struppler, A.: Medikamentbse therapie and in recognising the potential of new approaches. des hirnorganischen psychosyndroms im alter. Eine doppel­ blindstudie mit hydergin. Medizinische K1inik 71: 2177-2184 (1976). Acknowledgements Bogaert, M.: Nicergoline; in Tognoni and Garattini (Eds) Drug Treatment and Prevention in Cerebrovascular Disorders, pp .. This work was partially funded by the CNR (National 241-243 (Elsevier/North Holland Biomedical Press. Amster­ Research Council, Rome, Italy) program on Clinical dam I 979a). Pharmacology and Rare Diseases and by the generous Bogaert, M.: Piracetam; in Tognoni and Garattini (Eds) Drug contribution of the Fondazione Angelo e Angela Valenti, Treatment and Prevention in Cerebrovascular Disorders, Milan, Italy. pp.235-239 (Elsevier/North Holland Biomedical Press, Am· sterdam 1979b). Bouchard, Ch. and Rigal, J.: Contribution au traitement des in­ suffisances circulatoires cerebrales. Gazette Medicale de France References 77: 5582-5589 (1970). Boudouresques. J.: Valutazione clinica della citicolina (Rexort®) Abuzzahab, F.S. Sr.; Merwin, G.E.; Zimmermann, R.L. and Sher­ nel trattamento dell'insufficienza circolatoria cerebrale scorn· man, M.e.: A double-blind investigation of piracetam (Noo­ pensata. TB.Today 6: 7·16 (1979). tropil) versus placebo in the memory of geriatric inpatients. Bouwier, J.B.; Passeron, O. and Chupin, M.P.: Psychometric study Psychopharmacology Bulletin 14: 23-25 (1978). of praxilene. Journal ofinternational Medical Research 2: 59· Admani, A.K.: New approach to treatment of recent stroke. Brit­ 65 (1974). ish Medical Journal 2: 1678-1679 (1978). Bowen, D.M.: White, P.; Spillane, J.A.; Goodhardt, MJ.; Curzon, Adriaensen, H.: Le naftidrofuryl dans I'insuffisance cerebrale du G.; Iwangoff, P.; Meier-Ruge, W. and Davison, A.N.: Accel­ sujet age. Personal communication (1974). erated ageing or selective neuronal loss as an important cause Agnoli. A.; Manna, V.; Bocola, V. and Martucci, N.: Chronic cer­ of dementia? Lancet I: 11·14 (1979). ebro-vascular disorders: Modification of the EEG spectral Boyd. W.D.: Graham·White, J.; Blackwood, G.; Glen, I. and analysis determined by dihydroegrocristine methanesulfon- McQueen, J.: Clinical effects of choline in Alzheimer senile 'Cerebroactive' Drugs 64

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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]

• Under the auspices of the Italian Society of Endocrinology