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