Br J Gen Pract v55510 January 2005 PMC1266239 Br J Gen Pract 2005 Jan 1 55510 2631 PMCID PMC1266239 Religious beliefs about causes and treatment of epilepsy Hanif Ismail MSc Research Fellow John Wright MRCP Consultant in Clinical Epidemiology and Public Health and Penny Rhodes PhD Research Fellow Bradford Teaching Hospitals NHS Trust Bradford Royal Infirmary Bradford Neil Small PhD Professor of Community and Primary Care University of Bradford School of Health Studies Bradford Author information Article notes Copyright and License information This article has been cited by other articles in PMC Abstract Background It has been acknowledged that religious and complementary therapies are commonly used among South Asian communities in the UK However little is known about their religious beliefs in relation to epilepsy and the type of South Asian therapies that they use to treat the condition Aim To explore the influences of spiritual and religious beliefs on explanation of the cause of epilepsy and the choice of treatment in people of South Asian origin who have epilepsy Design of study Qualitative study using interviews with patients carers health professionals and focus groups of people from minority ethnic communities Setting Bradford and Leeds Method Semistructured individual interviews with 20 Muslims six Sikhs and four Hindus with epilepsy 16 nominated carers family members friends 10 health professionals specialist GPs neurologists specialists nurses social workers community GPs and two focus groups with a total of 16 South Asians without epilepsy Results It was found that over half of responders attributed their illness to fate and the will of God or as punishment for sins of a past life Some patients had experienced prejudice from people who believed that their epilepsy was contagious A strong network of traditional healers was found providing a parallel system of health care in the UK and on the Indian subcontinent People turned to religiospiritual treatments in desperation for a cure often under the influence of their families after the perceived failure of Western medicine Such treatments were viewed as complementary rather than as an alternative to Conclusions In this studys South Asian sample patients commonly turned to traditional healers in search of better health Health professionals should be aware of the belief systems of these patients and understand the types of treatments in common use Although these treatments might potentially compete with Western health care they are used as an adjunct rather than a substitute Patients have a healthy scepticism about the effectiveness of such treatments and adherence to medical therapy does not appear to be affected Keywords beliefs epilepsy medicine traditional Southern Asia spirituality INTRODUCTION There is a wide variety of influences on peoples beliefs about illness and treatments including culture and religion Religious beliefs can exert positive influences on health by acting as a source of inspiration 1 or negative influences when they are linked with guilt and punishment 2 Religious beliefs can also engender a sense of fatalism a belief that someone or something is in control 3 This identification of an external locus of control can impact on health behaviour 4 Beliefs about health and illness affect peoples decisions regarding their choice of treatments 5 Religious and complementary therapies are commonly used among South Asian communities in the UK 6 8 However details about the type of therapies and how they are used in relation to conventional medicine are scarce in particular little is known about alternative treatments for epilepsy It is important that health professionals are aware of their patients lay beliefs about illness and the alternative treatments that they may choose This article reports findings about beliefs and their impact on the choice of spiritual and traditional therapies from a study exploring health beliefs and experiences of people of South Asian origin who have epilepsy METHOD This was a study of the health beliefs and experiences of people living in Bradford and Leeds who are of South Asian origin and have epilepsy Individual indepth interviews were undertaken with 30 patients 16 carers and 10 health professionals In addition focus groups were conducted with 16 South Asians from local communities who did not have epilepsy The South Asian population is heterogeneous in terms of ethnicity religions and language Religious grouping provides a robust framework for reflecting some of this diversity 9 we chose to divide our sample into Muslim Sikh and Hindu patients A sampling frame of patients aged over 18 years who have epilepsy and live in Leeds and Bradford was compiled using data from epilepsy registers and hospital databases Using recorded information on ethnicity and religion together with an analysis of names these were categorised into the three religious groups The largest group was of Muslims 109 from which a random sample was selected All patients from the Sikh 17 and Hindu 13 categories were invited to participate in the study Patients were invited by letter and asked to indicate on a return slip whether or not they wished to take Characteristics of sample A total of 20 Muslims 10 male and 10 female six Sikhs two male and four female and four Hindus three male and one female accepted the invitation The age range was 1868 years with 18 responders aged below 35 years Five responders classified their occupation as professionalmanagerial six as skilled or unskilled manual nine as housewives eight as retired or unemployed and two as university students Each responder was asked to nominate their main carer Fourteen responders preferred not to nominate a carer for interview For the remaining 16 responders eight of the carers nominated were spouses three siblings four parents and one a friend Interviews and analysis Wideranging topic guides were used which included a section on health beliefs and practices in relation to epilepsy as well as questions about the impact of epilepsy on lifestyle and relationships understanding of seizures and treatment options These were informed by a literature review the research advisory group which included representatives from local communities and preliminary discussions with patients and health professionals Most of the interviews were conducted by a male researcher but five were undertaken by a trained female researcher at the request of patients Interviews took place in the patients or carers homes and lasted roughly 1 hour Two focus groups were held consisting of eight males and eight females recruited from community centres An unstructured topic guide was used to stimulate discussion How this fits in Religion plays an important role for many individuals from South Asian minority ethnic groups in coping with and understanding their illness Religious and traditional therapies are commonly used in South Asian communities Little is known about how these traditional and religious forms of therapy are used in relation to conventional medicine Although many people of South Asian origin attributed their illness to the will of God or saw it as punishment for sins of a past life this did not necessarily lead to resignation or passivity in respect of their illness There is a strong network of traditional South Asian All interviews were audiotaped translated if required and transcribed A framework approach was adopted to analyse the data A coding frame was applied to each transcript and relevant text was indexed whenever a particular theme appeared 10 Indexed data were transferred to a grid to compare cases and identify similarities and differences RESULTS We found that many of our responders believed that they had been fated by God to suffer from epilepsy This was particularly but not exclusively true for Muslim patients The following comments were typical Well everything comes from up there everythings from Allah and the one who fixes it is Allah as well You see thats our Muslim belief what do you think You see the doctors give you your medication but the cure comes from Allah 43yearold Muslim male If its written for you its written for you theres nothing you could do about it can you So when it comes to you it comes to you its in Gods hands so theres nothing you can do about it 25yearold Muslim male The belief that illness may be a punishment for sins committed in a past life is part of the doctrine of Hinduism and Sikhism We found some evidence of this belief in our sample They do say that you have to repent in this life for sins that youve maybe committed in your previous life but I dont know I mean illness is something thats fated to happen to you in life I dont know I mean I just cant understand that I think I was just fated to have it 46yearold Sikh female I remember them having a conversation with some guru of theirs and he was saying that in a previous life Id killed a snake or something thats why Im epileptic Thats kind of spooky actually But I dont really believe in this sort of thing 19yearold Sikh male Epilepsy has been associated with spirit possession in many cultures 11 Few of our responders gave credence to such beliefs however there was support for the belief of possession by spiritual beings jinns among some of our sample particularly older Muslims and those born or brought up in the Indian subcontinent A Sikh woman for example described how her nephew in India Went for ages without getting any medication The family in India said hes got this hes got that hes got some kind of spirit involved the winds affected that hes got jinn possession by spiritual beings But in our family weve never believed things like that you see I think these beliefs are more prevalent in India I think its more in the villages really you see because people dont have that much knowledge in the villages 46yearold Sikh female Similarly a 28yearold Muslim woman commented I think they think its something like an evil spirit I would say thats the elders no matter where they are Medical knowledge did not necessarily preclude belief in jinn as the following comments from a Hindu woman who had herself been medically trained demonstrate This is one of these things not like diabetes or coronary heart disease its one of the things that happened to me maybe the jinn jinn is a factor I dont know As far as Im concerned my knowledge medical I dont know anything 53yearold Hindu female Belief that epilepsy is a contagious disease was experienced by responders through the negative attitudes and actions of other community members as a 29yearold Muslim woman explained Other people sometimes you sense they just keep away because they dont want to get it epilepsy They think they might catch it Sometimes you shake hands with other women if youre greeting them but they dont want to put their hand forward they dont want to shake hands so I just think leave it I mean I know its not an infectious condition Our Asian women here the elderly ones in particular tend to think that if I mix with their children or sit with them then like I say the children will catch it Traditional South Asian therapies We found that the use of traditional South Asian therapies as outlined in Supplementary Appendix 1 was widespread in our sample although in all cases it was a secondline treatment rather than an alternative to antiepileptic drugs However as our sample was accessed through medical records we have no knowledge of the extent to which people with epilepsy may have been using traditional therapies without being in contact with medical services Sixteen of the 30 people from our sample who had epilepsy had sought help from traditional South Asian healers A common reason for using these therapies was desperation and each individuals hope that he or she might find a cure or effective treatment for their seizures I think it is desperation because you know youve been trying something for so long and its not getting you anywhere I suppose it is I dont care as long as it helps me Anything I was willing to do anything Id try anything to cure the problem but the only answer was these tablets No more 42yearold Hindu male I was really tired sick of it nothing was helping and Im suffering Ill do anything to get better They amulets helped me I believe in it they helped me but I think the medication the doctor writes you should always go for the medication 31yearold Muslim female W e must have tried nearly everything anybody that said you know try this for epilepsy its like go an Islamic way going beyond it Its like you know something you wouldnt do you know My family is quite religious and sometimes we actually went to this Hindu healer Theres nothing wrong with that but I suppose you know when youve got your child youre helpless you dont know what to do you run to everyone you dont care who youre going to and what religion they are 34yearold Muslim female All those who had used other therapies had experienced continued seizures despite compliance with medical regimens Some people were persuaded to use them by family or friends often when visiting India or Pakistan while others looked for alternative treatments as they were suspicious about the effects of longterm antiepileptic drugs on their physical or mental health Most of our sample irrespective of ethnicity used some form of religious healing For some this was a personal prayer or recitation from religious texts in private rather than seeking help from religious healers Others undertook pilgrimages to places of worship in order to seek forgiveness for their sins and alleviation of their illness Fourteen responders turned to religious healers usually under pressure from their families or in an attempt to placate them as illustrated in the following examples Pir came from Pakistan and he was 100 years old or something came with a long white beard He made me read something in Farsi Its like Arabic couldnt understand it I read it yeah He said to me Understand it I said Alright My dad read it and he said I understand it he gave me something told my mum downstairs Its like a sayaa influence of a evil spirit when he was born he said naraa veins in his head which collapses 32yearold Muslim male People pirs came from Pakistan here and I went there once I remember in Bradford and he said Im gonna do something I dont know what they were doing 39yearold Muslim male My parents sent this taweez amulet from Pakistan I had a couple sent a couple of years ago and theyve been helping as well Got it from pir in Pakistan I think it does work but when I have these attacks I just have these doubts again I had these taweez I had to wear them on my arm one on each one on my left and one on my right Then after 2 or 3 years I was in that previous state when I used to keep on having fits again and again I thought they werent working so I just took them off just stopped using them Yeah I told them family that I took them off but I have the arm ones Asked if the family objected No because I got some more taweez they said Here wear these new ones Wearing the taweez I think does help a lot not me myself personally but my family think thats one of the reasons thats helped me a lot 24yearold Muslim male Many of these consultations were with gurus Hindus and Sikhs or pirs Muslims visiting from the Indian subcontinent although some responders took advantage of trips abroad when visiting family to consult with local wellknown healers Others consulted religious healers established in the UK often affiliated to famous pirs from the Indian subcontinent Most of the Muslim sample who had consulted with pirs were instructed to wear some kind of amulet containing verses from the Koran taweez usually around the neck or the arm Others were required to drink blessed water or recite from holy texts Ive had people giving me taweez all sorts Ive been I dont know people say different things You should do this you should do that Ive tried everything I was having it seizures and actually there was this lady who was giving me taweez and I went better for 1 year I didnt have a fit This taweez and she put dam on water blessed the water she used to give me that 31yearold Muslim female Five responders visited hakims herbal practitioners in the hope of finding a cure for their epilepsy A number of hakims practised in the district often advertising consultations or mail order treatments through newspapers for minority ethnic groups However the majority of people made use of hakims while on trips to visit relatives in IndiaPakistan primarily because of the difficulties of locating practitioners and the prohibitive costs involved in consulting locally in the UK A 23yearold Muslim man explained In this country people usually go to the doctor first because its free and the hakim charges money In Pakistan however the hakim is cheaper than the doctor Here we pay for the hakim in pounds over there in Pakistan we pay in rupees I think the hakims cure is better the cure is from Allah and both are ways of accessing the cure Younger people in particular expressed considerable scepticism about the effectiveness of such healers A 28yearold Muslim woman for example said I also went to see the hakims I tried everything people that give like prayers to read to get better I went to see them So what I did was I tried everything and sometimes Id feel better sometimes I wouldnt but I mean they say its kind of psychological as well Well you know you take it herbal medication for you take it and you dont have any fits for a week and then the next week youll have three and you think what was the point of taking that it hasnt made any difference Most of them were persuaded or coerced by their families into seeking this kind of treatment Some were reluctant to follow instructions prescribed by healers as they were a little sceptical as to how much they would benefit Weve been asking all those sorts of people but nobody can come up with any answer Theyve tried their best but if anybody does know but nothing Well they just said it comes from some say it comes from the ancestors old ancestors or somebody whos not a good psychic person or something One of them I overheard will say that when I was born Over in India one or two of them did say that it could be to do with black magic but I dont believe that stuff 42yearold Hindu male Someone once suggested I think it was in the family you know some pir sahib is really good he will do some dua recite prayers or something but I dont really believe in that stuff I mean Im sure there are many true people out there but theyre difficult to find arent they 28yearold Muslim female I went to this weve got this other one who goes to your house Pir Sahib they call him Thats what our lot believe in hes all right he gives taweez amulets and reads recites from the Koran still our faith Ive never worn them taweez dont believe in them 25yearold Muslim male Five responders however did report improvements to their condition It is possible that such improvements coincided with periods of stability that were seizurefree although some responders explained this in terms of the power of belief and the calming influence of recitation and prayer in reducing the stress that could provoke seizures There was very little overlap with more mainstream complementary therapies used by the white population 12 only two people reported using a nonSouth Asian alternative Reiki and a Chinese herbalist DISCUSSION Summary of main findings The study describes the influence of religion and religious and traditional treatments in a sample of patients drawn from South Asian communities in Bradford and Leeds This is an area where there has been little empirical research The study benefited from a robust sampling strategy and a considerable amount of fieldwork with 56 interviews and two focus groups Our sample included patients from a range of different religions socioeconomic backgrounds and ages in an attempt to capture the diversity of views and beliefs We also interviewed carers and professionals It should be noted however that our study sample was recruited from medical record data hence those who did not seek treatment from health professionals and perhaps used traditional therapies as a firstline treatment would not have been included A weakness of the study is the overrepresentation of Muslims in the sample reflecting the local population In addition the sample was limited to patients and carers from one geographical area in the UK However we have no reason to doubt that the findings are likely to be applicable to South Asian communities elsewhere in the UK The focus of the study was people with epilepsy and it may be that the findings about influence of religion are unique to this illness However we believe that our results are likely to be relevant to beliefs about the causes of and Beliefs about illness Among our responders we found that fatalistic beliefs about health were common Such fatalism has been described in many cultures 13 It has been found to be more widespread in South Asian communities with a potentially detrimental effect on health status 14 Belief in the will of God Qadr Allah is a particularly strong feature of the Muslim religion 15 However our data suggest that to assume this equates with fatalism and a passive attitude towards illness and health is oversimplistic Belief in the overarching power of a supreme being did not prevent people from searching for proximate causes for their illness or from taking active steps to alleviate their symptoms or seek a cure Spiritual and traditional treatments We found that there was a strong network of traditional South Asian healers being used both in Bradford and on the Indian subcontinent This network provides a parallel system of health care that is invisible to the mainstream NHS In the UK context peoples first recourse was to Western medicine which is free at the point of delivery Often the failure of Western medicine to offer a cure or adequate improvement to their condition prompted people to turn elsewhere for help In South Asia however where issues of accessibility to and affordability of Western medicine assume greater importance especially in Complementary medicine is known to be popular in the UK A recent survey highlighted that up to 33 of the population have used complementary therapies at some point 12 usually for the treatment of longterm chronic conditions for which conventional medicine has failed to provide an acceptable remedy However these complementary therapies predominantly involve the use of physical or homeopathic treatments as opposed to spiritual interventions 12 The family and wider social network was a major influence on the use of traditional South Asian therapies The existence of lay referral systems is well known 16 and previous research has described the significance of kinship networks in South Asian communities 17 Our study demonstrates the importance of family and kinship networks in the use of traditional South Asian therapies Although the pursuit of religious and other South Asian traditional treatments was common there was considerable scepticism about their effectiveness particularly among younger patients who were more likely to have been born and raised in the UK This may reflect a shifting balance of belief in the effectiveness of Western versus South Asian traditional treatments It also highlights the conflict between traditional cultural beliefs and the inevitable assimilation of normative values in immigrant populations 8 18 In addition it is unlikely that there would be any placebo effect of spiritual healing on the sudden episodic nature of epilepsy and so any initial faith in a cure might soon disappear A placebo effect may be more noticeable for other chronic diseases Traditional therapies however offered hope that Western medicine was unable to provide and part of their appeal may lie in their perception as shortterm solutions without the toxicity and side effects of conventional medicine Although probably not effective at reducing seizures these traditional therapies may be effective in other dimensions of health such as psychological coping Implications for practice Health professionals should be aware of the belief systems of people they see from South Asian communities and acknowledge and respect their convictions People of South Asian origin may commonly turn to religious and other healers Clinicians working with people of South Asian origin should have some understanding of the main South Asian therapies such as those practised by pirs gurus and hakims just as they have of more mainstream complementary therapies such as acupuncture and homeopathy Although traditional South Asian therapies could be regarded as potential competitors with Western health care in our study they were used as an adjunct to conventional medicine rather than a substitute Participants appeared to have a healthy scepticism about their effectiveness and clinicians should be reassured that their use does not appear to reduce adherence to medical therapy Supplementary information Additional information accompanies this article at httpwwwrcgporgukjournalindexasp Funding body Epilepsy Action British Epilepsy Association Ethics committee reference number Bradford Local Research Ethics Committee ARPB0109008 Competing interests None Supplementary Material Supplementary appendix Traditional South Asian therapies Click here to view 28K pdf Acknowledgments We would like to thank all the people who we interviewed for their time and contribution We are grateful to Ann Jacoby Mark Busby and members of the Epilepsy Service and to the members of the Research Steering Group for their enthusiastic support and commitment REFERENCES 1 Walsh F Strengthening family resilience New York The Guildford Press 1998 2 Ahmad WIU Ethnicity disability 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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Br J Clin Pharmacol v484 1999 Oct PMC2014378 Br J Clin Pharmacol 1999 Oct 484 471480 doi 101046j13652125199900026x PMCID PMC2014378 Acetylcholinesterase inhibitors in Alzheimers disease B M McGleenon K B Dynan and A P Passmore Author information Article notes Copyright and License information This article has been cited by other articles in PMC Introduction Alzheimers Disease AD is the most common single cause of dementia in our ageing society Traditionally thought of as an untreatable degenerative condition recent advances in drug therapy have challenged this view The disease is characterised by an insidious decline in cognitive and noncognitive function Classically short and longterm memory is impaired while language skills concentration and attention are often affected This results in impaired ability to learn and retain new skills as well as the loss of existing ones Noncognitive function is the global term used to describe problems such as depression agitation personality changes delusions and hallucinations These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers Diagnosis of AD is clinically based and using the Table 1 1 a diagnosis of probable or possible AD can be made Definitive diagnosis relies on pathological confirmation which in the majority of cases is rarely completed With the development of AD specific treatments definition of AD from other types of dementia is very important Table 1 NINCDSADRDA Criteria for clinical diagnosis of Alzheimers disease Go to Pathogenesis The pathogenesis of AD has not yet been elucidated It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD the most common form of the disease An understanding of the disease mechanism remains elusive and is the key to developing a disease modifying agent Currently it is proposed that beta amyloid protein abnormal tau protein or possibly both play key factors in the development of disease It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved As yet no product with The development of acetylcholinesterase AChe inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD 2 and the resultant cholinergic deficit contributes to the cognitive impairment of these patients 3 Although many believe this cholinergic hypothesis to be important others feel it represents a less significant component of the disease process 4 Many other neurotransmitters are affected in AD and the relative importance of each in relation to clinical findings has not been fully elucidated Initial work focused on the use of acetylcholine precursors using a similar rationale to dopamine therapy in Parkinsons disease A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function with only 10 out of 43 trials reporting any positive effect 5 There has been renewed interest in muscarinic agonists drugs which when first introduced had major problems with adverse cholinergic effects Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists Drugs such as xanomeline milameline and civimeline have reached clinical trials and the improvements seen in cognitive function are reviewed by Avery et al 6 There are also claims that these drugs have disease modifying properties with effects on APP processing and tau phosphorylation Muscarinic agonists remain in trial but have yet to fulfil their potential in AD treatment The only group of drugs currently licensed for AD treatment is the AChe inhibitors which act through inhibition of the enzyme acetylcholinesterase AChe responsible for the breakdown of ACh in the neural synapse A metaanalysis of the early AChe inhibitor treatments was encouraging 7 and these proceeded to larger placebo controlled doubleblind trials Go to AD assessments The advent of treatment for dementia has brought with it a confusing array of dementia assessments many designed specifically for the therapeutic trials The majority of these are unfamiliar to physicians as they have limited value in clinical settings However a cursory understanding of the many scores and abbreviations is essential for reviewing the published data Table 2 The primary outcome measures in these trials most commonly include the ADAS Cog Alzheimers Disease Assessment Scale Cognitive Subscale some form of global assessment such as the CIBIC Clinicians InterviewBased Impression of Change scale or the CGIC Clinical Global Impression of Change and a staging scale for dementia the CDR Clinical Dementia Rating scale Table 2 Scores and abbreviations used in assessing Alzheimers disease The ADAS Cog has been the mainstay of cognitive testing in recent dementia trials 8 It assesses the major cognitive functions of memory language attention orientation praxis and reasoning It is scored from 0 to 70 with a higher score indicating increasing severity The test is most sensitive in the middle phase of disease with moderately severe AD patients gaining approximately 711 points per year 9 10 The CIBIC Score usually performed by a separate rater is information from patient and carer CIBICPlus obtained during interview and focuses on general well being cognition behaviour and activities of daily living ADL It provides a global assessment of deterioration in the absence of any knowledge of the psychometric test performance It was derived from the CGIC a similar rating to the CIBIC score employed in earlier donepezil and tacrine trials 11 The CDR 12 is a consensual report from all assessors on six main functional domains memory orientation judgement community affairs home and hobbies and personal care The scale defines mild moderate and severe dementia Secondary outcome measures used in trials are more variable and attempt to assess areas such as daily function and quality of life Minimental state examination MMSE 13 and Activities of Daily Living ADL 14 are cited along with less well known assessments such as the Geriatric Evaluation by Relatives Rating Instrument GERRI 15 the Progressive Deterioration Scale PDS 16 and the Global Deterioration Scale GDS 17 which is used as a measure of severity rather than deterioration Non cognitive function is more difficult to quantify and assessments usually encompass some form of behavioural rating scale such as the ADAS noncognitive Score neuropsychiatric inventory NPI 18 or the Behavioural Pathology in Alzheimers Disease BEHAVEAD 19 A lack of consensus regarding appropriate noncognitive and functional assessments is reflected in the variety of scales used An obvious need for standardisation became apparent and in 1989 the American Food and Drug Administration FDA published guidelines outlining what they felt constituted a clinical response in dementia treatment 20 This has since been employed by the European Medicine Evaluation Agency EMEA 21 They designated a change of 4 points or more on an ADAS Cog score within a clinical trial setting to represent a significant clinical effect This was based on the calculation that the average AD patient will show a decline in their ADAS Cog score of 7 to 11 points per year in the middle stages of disease 9 10 Thus an improvement of 4 points in the ADAS Cog is felt to represent a gain of 6 months in terms of delaying decline Due to the heterogenous nature of AD a 6 month delay can represent a huge variation in clinical terms In practice this can mean improved insight better memory with less repeated questioning improved fluency in language improved recognition of people and revived interest in hobbies or everyday events A problem with using the ADAS Cog as a gold standard is that factors such as mood behaviour and functional ability are not considered Certain AChe inhibitor trials 22 and ADLs 23 In reference to this problem the FDA and EMEA have highlighted the importance of global assessments in conjunction with cognitive scores and these are included as measures of primary efficacy in clinical trials Go to AChe inhibitorspharmacology As a group these drugs show a dosedependent improvement in symptoms of AD with varying amounts of systemic cholinergic effects The early research into AChe inhibitors included tetrahydroaminoacridine tacrine physostigmine and velnacrine Of these only tacrine proceeded to largescale clinical trials and commercial launch in the USA and parts of Europe This has been followed by the more recent products donepezil rivastigmine and metrifonate Table 3 Table 3 Characteristics of some AChe inhibitors Tacrine an aminoacridine has several actions such as monoamine oxidase inhibition potassium channel blockade and interaction with subtypes of muscarinic and nicotinic receptors However the most prominent action is as a centrally active reversible cholinesterase inhibitor Tacrine is rapidly absorbed and cleared by the liver during a first pass metabolism 24 25 Due to hepatic hydroxylation tacrine itself has a very low bioavailability when taken orally at 2 to 3 that of an intravenous dose The short markedly variable elimination halflife of tacrine increases from 14 to 36 h with higher doses and multiple dosing The relationship between dosage and bioavailability is not proportional eg doubling the dose may triple or quadruple bioavailability Tacrine is rapidly taken up into the brain where its concentration is tenfold that in plasma 25 26 In summary the characteristics of tacrines pharmacokinetics are dose nonlinearity extensive distribution and rapid elimination through hepatic transformation mainly into the hydroxy metabolite velnacrine Donepezil is a specifically designed piperidine derivative with reversible acetylcholinesterase inhibitor activity It has a much higher specificity for acetylcholinesterase inhibition compared with tacrine 27 and its CNS selectivity is highlighted by the lack of activity in peripheral tissue such as cardiac tissue or gut smooth muscle 28 The pharmacokinetics are linear and dose proportional with peak plasma levels after approximately 4 h Plasma steady state appears to be reached between 14 and 21 days with a long halflife of over 70 h 29 Excretion is slow and occurs via renal and the cytochrome P450 system although it is not impaired in patients with hepatic or renal impairment 30 Rivastigmine is a brain selective carbamate AChe inhibitor It is known as a pseudoirreversible inhibitor because it mimics ACh by binding with the enzyme AChe forming a carbamylated complex This prevents further enzymecatalysed hydrolysis of ACh for several hours after the drug has been eliminated from the plasma Thus despite a halflife of only 1 h rivastigmine has a duration of action of about 10 h 31 32 Like donepezil rivastigmine has marked CNS selectivity 31 33 with animal studies showing specific effect in the cortex and hippocampus 33 Rivastigmine does not bind appreciably to plasma proteins and is inactivated by cleavage during the enzyme inhibition This avoids hepatic metabolism and the drug is rapidly excreted through the kidneys Metrifonate has a 30year history as a treatment for schistosomiasis Only in the late 1980s was it considered as a potential treatment for AD on the basis of its anticholinesterase properties It has a short halflife in plasma 2h but has long activity in the CNS due to its irreversible activity It is hydrolysed nonenzymatically to the active metabolite 22dimethyl dichlorovinyl phosphate DDVP It is this compound that binds stably to the catalytic site for the enzyme and provides sustained AChe inhibition in the CNS 34 It is rapidly absorbed and distributed to the brain although lacking in specificity for central inhibition In plasma it remains mostly unbound 15 to proteins and avoids the cytochrome P450 system Previous clinical experience of the drug indicated only mild cholinergic side effects with high levels of AChe inhibition 80 and short treatment periods 35 The safety of metrifonate in longterm treatment is currently under review with recent trials highlighting a possible link with muscle weakness Go to Efficacy Tacrine The early trials of tacrine roused interest by reporting improvements in cognitive function but the small number of patients limited their usefulness In the doubleblind placebocontrolled crossover study of tacrine plus lecithin reported by Eagger et al only 65 patients completed the treatment 36 However most of the findings were subsequently confirmed in the larger multicentre trials that followed In clinical trials involving around 2400 patients in the USA Canada and France tacrine showed a clinically observable response in 2030 of patients In one of the larger trials clinically significant improvements were seen in the ADAS Cog score P 0002 CIBIC P 004 and GDS P 001 at a dose of 160 mg 37 These changes were not statistically significant for the lower doses of tacrine in this study although they were seen to a lesser degree in another study 38 Forty percent of patients still taking the higher dose of tacrine 160 mg day 1 at completion showed the significant 4 points or more improvement in ADAS Cog However this figure drops to 27 in the intent to treat analysis ITT due to the huge withdrawal rate 70 at this dosage 37 Most patients withdrew because of elevations in serum alanine aminotransferase ALT The results of a 2year follow up study of AD patients in the open label phase of the above mentioned trial 37 showed that patients who tolerated tacrine at 80 mg day 1 dose had lower risk of nursing home placement NHP than those who either discontinued the drug or continued on lower doses 39 Highdose treated patients were 28 times less likely to be institutionalised than lowdose treated patients but these results need to be interpreted with caution due to methodological limitations of the study The major limitations are that the treatment assignment was not random nor was it blinded after 30 weeks so a causal relationship between higher dose tacrine treatment and more favourable outcomes can not be categorically stated Recently published data on the long term effects of tacrine in the same group of noninstitutionalised patients found only slightly different scores on the Physical Self Maintenance Scale PSMS a measure of basic ADLs in patients on high dose tacrine indicating less decline There were no significant group differences on the MMSE the GDS or the Instrumental Activities of Daily Living Scale The authors concluded that the conservative view was that tacrine had no appreciable benefits at 2 years after therapy initiation 40 A metaanalysis of 12 trials of tacrine encompassing 1984 patients with AD was recently published 41 This metaanalysis which only focused on the first 12 weeks of treatment provided evidence that tacrine has an overall beneficial but small effect on cognitive function and the CGIC They also found that effects observed on measures of behavioural disturbance were of questionable clinical significance and functional autonomy was not significantly affected The authors concluded that there remained three important issues that their study was not able to address and which have relevance to the other newer cholinesterase inhibitors First the relationship between treatment effect and dose was difficult to assess because in most studies the dose for each patient 39 40 that construction of well designed long term trials face major logistical difficulties because of issues relating to placebo control prolonged study duration and ethical considerations Donepezil Launched last year donepezil Aricept was the first AChe inhibitor available for prescription in the United Kingdom It was received with mixed reactions largely associated with questions of cost rather than efficacy In 1996 a 14 week doubleblind US trial enrolled 161 patients testing doses of 1 3 and 5 mg against placebo There was a significant difference in the ADAS Cog score with the 3mg P 0036 and 5mg P 0002 dose when compared with controls and evidence for an overall dose response trend This trend for improvement was also seen in the global assessment with 11 treatment failures in the 5mgs group compared with 20 in the placebo group P 0039 42 As a result of this study higher doses were needed in subsequent trials The most recently published donepezil trials have compared 5mg and 10 mg with placebo showing a dose dependent improvement in cognitive and global function 43 44 On completion of the 24 week trial ADAS Cog scores showed an average difference from placebo of 249 P 00001 and 288 P 00001 for 5 and 10 mg respectively 43 This trial also published data using the 4point ADAS Cog improvement with 533 of the observed cases OC on 10 mg achieving those targets compared with 268 of those on placebo When the ITT figures are used 26 of this high dose group achieved the 4point change The CIBIC score was marginally significant at 5 mg P 0047 and more convincingly improved at 10 mg P 00001 when compared to controls Quality of life scores did not show consistent statistical significance but the CDR score showed a significant mean drug placebo difference of 06 for both 5 mg and 10 mg at completion P 00008 Completion rates for the trial were good with 80 85 and 68 of the placebo 5 mg and 10 mg groups respectively reaching the 24 weeks reflecting an improved side effect profile There is now longer term data available with interim results at 98 weeks of an open label study using up to 10mgsday of donepezil 45 The improvements in ADAS Cog and CDRSB seen initially were maintained at 38 and 26 weeks respectively The lack of a placebo group means the subsequent clinical decline a rise of 66 pointsyear in the ADAS Cog in the study group is calculated to be less than that seen in a projected untreated group rise of 116 pointsyear when the baseline ADAS cog scores are taken into account This slower deterioration is also seen in the CDRSB which showed an average decline of 18 points per year compared with a predicted decline of 24 points per year in untreated patients 12 The safety profile at 98 weeks is similar to that seen in the shorter placebo controlled trials with no additional adverse events or clinically significant changes in monitored laboratory values Rivastigmine Rivastigmine Exelon a carbamate derivative is the latest in this group of drugs to be launched in the UK The ADENA programme is the name given to the Rivastigmine phase III clinical trials It is claimed to be the largest global study to date of a new treatment for AD In the four studies that it encompasses 3300 people with mild to moderately severe AD have been recruited The ADENA2 study 46 randomised patients with mild to moderately severe AD to treatment with placebo low dose rivastigmine 14 mg day 1 or higher doses 612 mg day 1 Of the 699 patients enrolled into the trial 78 completed treatment although in the high dose rivastigmine group 35 discontinued primarily due to adverse events The fact that a significant proportion of the subjects were in the older age range average age 745 years no upper age limit with a high rate of comorbidity seems to address the previous criticism of AD trials Patients receiving the high dose rivastigmine 612 mg day 1 maintained their baseline level of performance on the ADASCog in contrast to the placebo group who deteriorated with a treatment difference of 378 points P 0001 In the OC analysis one quarter of the patients on the high dose rivastigmine showed the 4 point rise in the ADASCog deemed by the FDA to be clinically meaningful The paper did not specify what proportion of subjects on the low dose rivastigmine or placebo achieved this rise nor did it state what proportion of the high dose group achieved this rise in the ITT analysis Less deterioration was seen in the CIBIC Plus rating in both high and low dose groups P 001 and P 005 respectively These changes were greater and of more rapid onset in the high dose group A quarter of the high dose group OC analysis showed a clinically meaningful improvement in the measurements of activities of daily living with a 10 improvement in the PDS score P 0006 This benefit was not seen in the low dose group A parallel study of almost identical design carried out predominantly in Europe has recently been published 23 A total of 725 patients were enrolled and randomly allocated to placebo low dose rivastigmine 14 mg day 1 or higher dose rivastigmine 612 mg day 1 At the end of the study the mean dose of rivastigmine was 104 mg day 1 in the higher dose group and 37 mg day 1 in the lower dose group these were slightly higher than the average doses in the earlier study of 97 mg day 1 and 35 mg day 1 respectively The results reported were similar to those of the previous study The 4 points or greater improvement in the ADAScog was seen in 24 of the higher dose group compared to 16 in the placebo group ITT analysis 29 vs 19 OC analysis Improvements in the CIBIC rating were also seen in both treatment groups at 26 weeks with 20 placebo group 30 lower dose group and 37 higher dose group showing marked moderate or minimal improvement in the ITT analysis The assessment of activities of daily living using the PDS showed significantly less deterioration between the higher dose group and placebo in the analysis of the last observation carried forward P 005 but this finding was not significant in the ITT analysis P 01 Significantly more patients in the higher dose group improved by at least 10 than in the placebo group 29 vs 19 ITT analysis No beneficial effects on the PDS were noted in the lower dose group Metrifonate Metrifonate is another AChe inhibitor which has reached phase 3 clinical trials In 1990 a small open label study highlighted the potential benefit of metrifonate in AD 47 This has been followed by two larger placebocontrolled trials assessing dosage regimens and efficacy in over 400 patients 22 48 Results have been comparable with the major donepezil trial Patients treated with a weight adjusted medium dose 03 mg kg 1 and high dose 065 mg kg 1 of metrifonate showed an average 13 P 0053 and 294 P 00001 point difference respectively in the ADAS Cog score compared with placebo CIBI plus score also reached a significant change from placebo in the medium and high dose groups with an average difference of 029 P 0005 and 035 P 00007 respectively 48 More interestingly in a trial of high dose metrifonate there was a significant change in the NPI with a 275 point difference between the treated and placebo group P 00161 In particular the incidence of hallucinations was significantly less in the treated group P 0002 22 The NPI is a noncognitive assessment and an area where AChe inhibitors have traditionally shown poor results The clinical trial programme with metrifonate has recently been suspended following a review of adverse events in the clinical data Go to Adverse events AEs Many of the side effects of the AChe inhibitors are attributable to peripheral cholinergic effects Nausea vomiting and diarrhoea were the most frequently reported Of the 2446 patients who received tacrine in clinical trials 49 had ALT levels greater than the upper limit of normal ULN on at least one occasion and 25 had ALT levels greater than three times the ULN Although in all cases discontinuing tacrine reversed the elevation the data suggested that careful monitoring of ALT levels was necessary for all patients on tacrine 49 Other frequent drugrelated AEs were nausea andor vomiting diarrhoea abdominal pain dyspepsia and skin rash Treatmentrelated AEs occurred in 34 of patients receiving placebo and 51 of those on tacrine The majority of adverse events 95 were mild to moderate in severity as rated by the study physician 38 No significant drug related effects on blood pressure heart rate or physical or neurological examinations were noted Cholinergic effects such as gastrointestinal upset were the predominant AE seen in all trials of donepezil and were predominantly described as mild to moderate and transient Trials using low doses of donepezil 1 mg 3 mg and 5 mg and placebo for a period of 12 weeks showed an incidence of AEs of 64 68 67 and 65 respectively 42 In trials using higher doses the number of AEs rose concomitantly Fatigue diarrhoea nausea vomiting and muscle cramps were more common P 005 in those patients on 10 mg compared with both placebo and 5 mg of donepezil during a 24 week trial 43 This higher rate of AE at 10 mg was attributed to rapid dose titration since in open label phase the 10 mg dose was titrated more slowly and no excess AEs were seen The overall incidence of AEs was 24 40 and 81 of patients randomized to placebo 5 mg and 10 mg of donepezil respectively In this trial none of the serious adverse events reported 6 were felt to be treatment related 43 The only laboratory abnormality reported was a low haemoglobin level in four patients receiving 10 mg donepezil n 157 two of which were attributed to preexisting disease An interim report of open label donepezil treatment showed the incidence of AEs after 92 weeks to be similar to the rates outlined above and were also found to be transient in nature 45 Of the 133 patients enrolled there were 3 deaths felt to be unrelated to treatment and 14 withdrawals of which 79 were considered unrelated to treatment No other abnormalities were seen in the laboratory analyses of both the placebocontrolled trials and the open label trial discussed above Treatment with rivastigmine was not associated with any increased risk for mortality significant AEs effects on laboratory parameters and ECGs or cardiovascular vital signs One death occurred in the study population during the trial but it was not considered related to drug treatment Most AEs were mild to moderate dose related and of limited duration In the high dose group 612 mg the incidence of nausea and vomiting was 48 and 27 respectively compared with 11 and 3 in the placebo group The nausea and vomiting occurred most commonly in the dose titration phase and resolved without treatment The commonest 46 In metrifonate studies nausea vomiting and diarrhoea constituted 55 of all AEs and were generally mild and transitory Diarrhoea leg cramps and rhinitis were the only symptoms seen with higher dose metrifonate compared with placebo with a difference greater than 5 22 No adverse events were recorded in laboratory serum analysis but a dose related reduction in heart rate was seen on ECG with three patients withdrawing due to asymptomatic bradycardia during the loading phase 48 No significant changes in blood pressure or weight were noted in either study Go to Clinical development With the continuing development of new AChe inhibitors certain characteristics have been improved to meet clinical needs Donepezil rivastigmine and metrifonate have certain pharmacological differences from the earlier drug tacrine Improved central selectivity for ACh enzyme inhibition is an important factor in the better side effect profile of donepezil and rivastigmine A lack of CNS specificity in metrifonate treatment may play a part in the problems of muscular weakness under investigation Tacrines greater peripheral cholinesterase inhibition is reflected in a higher incidence of reported adverse effects mostly gastrointestinal upset 37 Donepezil rivastigmine and metrifonate were developed with a longer duration of action Tacrine has the shortest halflife requiring dosage 4 times daily Donepezil has the longest halflife t 12 70 h and both donepezil and metrifonate can be given as a once daily preparation Rivastigmine requires administration twice daily although this has been promoted as giving greater flexibility in dose adjustment Generally it is accepted that less frequent regimens suit patients and carers alike It is also postulated that better tolerability of the newer drugs is in part due to the smoother AChe inhibition achieved with longer duration of action This avoids the fluctuations in enzyme inhibition and lessening cholinergic side effects The hepatotoxicity experienced in clinical trials with tacrine 49 has not been seen with the newer preparations which are predominately excreted through the kidneys Go to Pharmacoeconomics A full review of the pharmacoeconomics of these drugs is beyond the scope of this article Cost effectiveness is a contentious issue particularly for treatment in diseases not previously addressed In the case of AD and AChe inhibitors demands have been much more extensive than for other disease treatments The debate has been about cost not cost effectiveness and as a result there has been little focus on patients who may benefit from these agents Cost effectiveness is much easier to demonstrate where there are hard endpoints such as in cardiac failure or myocardial infarction rather than in areas of 50 UK estimates for 1996 indicate a total annual cost of 5365837 million of which 42 226245 million will fall to Health Social Services with the remaining 58 being borne by the client or Department of Social Security 51 Since AD affects cognition ADL and behaviour treatment with AChe inhibitors not only has direct benefits for the patient but can reduce caregiver burden and delay institutionalisation In the USA earlier data suggested that tacrine produced savings of approximately 4052 per person 52 In a small study prevention of a 2point decline in MMSE in moderate to severely demented elderly people living at home was seen to save US 3700 each year 53 It has been suggested that donepezil treated patients have a delay in deterioration in ADL for 1 year compared with placebo 54 Recently attempts at analysing cost effectiveness have taken into consideration cost of care at each stage of disease and the rate of disease progression in treated and nontreated patients When all these factors are evaluated donepezil at 5 mg and 10 mg has been shown to be cost neutral 55 This is explained by treated patients spending less time in the state of severe dementia with the associated higher care cost Cautious interpretation of this data is advised since it is based on a number of different clinical studies and also insufficient long term data led the authors to assume no differences in mortality rates for the donepezil and placebo group Along with economic projections of cost in the future the mortality rate is a key factor in projecting overall cost of care and we await more accurate data on the survival rates of treated patients A recent review also 51 These projections would also largely be dependent on mortality rates Go to Role of AChe inhibitors in Alzheimers disease Treatment with AChe inhibitors is simply one aspect of the package of care required for AD patients Most specialists have a holistic approach where pharmacological treatments are coupled with multidisciplinary team assessments of needs and institution of community supports where required On full assessment and diagnosis of AD initiation of an AChe inhibitor is recommended as early as possible since not all patients respond to treatment 3040 It is important that family and carers fully understand the limitations of treatment The Standing Medical Advisory Committee SMAC guidelines recommend withdrawal of the drug in the absence of any clinical response 56 When a patient is seen to respond initially the decision to withdraw treatment remains that of the clinician and sometimes is at odds with the familys wishes Full discussion when treatment is initiated can help to avoid any later misunderstanding The effect of treatment extends beyond the pharmacological involving psychological social and financial aspects for both patient and carers Despite the issues of cost and in the absence of any other immediate developments it is important that AChe inhibitor therapy is considered for patients with mild to moderate AD Go to References 1 Khann G Drachman D Folstein M Katzman R Price D Stadlan EM Clinical diagnosis of Alzheimers disease report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimers Disease Neurology 1984 34 939944 PubMed 2 Katzman R Saitoh T Advances in Alzheimers Disease FASEB J 1991 5 278286 PubMed 3 Becker RE In Cholinergic Basis of Alzheimer Therapy Becker RE Giacobini E editors Boston Berkhauser 1991 pp 122 Therapy of the cognitive deficit in Alzheimers disease the cholinergic system 4 Cutler NR Sramek JJ Veroff AE Alzheimers Disease Chichester John Wiley and Sons 1994 5 Becker RE Giacobini E Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type clinical pharmacological and therapeutic aspects Drug Dev Res 1988 12 163195 6 Avery EE Baker LD Asthana S Potential role of muscarinic agonists in Alzheimers Disease Drugs Aging 1997 11 450459 PubMed 7 Jorm AF Effects of cholinergic enhancement therapies on memory function in Alzheimers disease a metaanalysis of the literature Aust N Z J Psychiatry 1986 20 237240 PubMed 8 Rosen WG Mohs RC Davis KL A new rating scale for Alzheimers Disease Am J Psychiatry 1984 141 13561364 PubMed 9 Stern RG Mohs RC Davidson M Schmeidler J Silverman J KramerGinsberg E A longitudinal study of Alzheimers disease measurement rate and predictors of cognitive deterioration Am J Psychiatry 1994 151 390396 PubMed 10 KramerGinsberg E Mohs RC Aryan M et al Clinical predictors of course for Alzheimer patients in a longitudinal study a preliminary report Psychopharmacol Bull 1988 24 458462 PubMed 11 Guy W Rockville National Institute of Mental Health 1976 ECDEU Assessment Manual for Psychopharmacology pp 76388 Clinical Global Impressions 12 Berg L Miller JP Baty J Rubin EH Morris JC Fiegel G Mild senile dementia of the Alzheimer type Evaluation of intervention Ann Neurol 1992 31 242249 PubMed 13 Folstein MF Folstein SE McHugh PR Minimental state A practical method for grading the cognitive state of patients for the clinician J Psychiatr Res 1975 12 189198 PubMed 14 Lawton MP Brodie EM Assessment of older people self maintaining and instrumental activities of daily living Gerontologist 1969 11 545554 PubMed 15 Schwartz GE Development and evaluation of the Geriatric Evaluation by Relatives Rating Instrument GERRI Psychol Reports 1983 53 479488 PubMed 16 DeJong R Osterlund OW Roy GW Measurement of quality of life changes in patients with Alzheimers Disease Clin Ther 1989 11 545554 PubMed 17 Reisberg B Ferris SH de Leon MJ Crook T The Global Deterioration Scale for assessment of primary degenerative dementia Am J Psychiatry 1982 139 11361139 PubMed 18 Cummings JL Mega M Gray K RosenbergThompson S Carusi DA Gornbein J The neuropsychiatric inventory comprehensive assessment of 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Siedlik P Pharmacokinetics of tacrine in healthy subjects Pharm Res 1988 5 218 25 McNally W Roth M Young R Quantitative wholebody autoradiographic determination of tacrine tissue distribution in rats following intravenous or oral dose Pharm Res 1989 6 924930 PubMed 26 Neilsen JA Mena EE Williams IH Correlation of brain levels of 9amino1234tetrahydroaminoacridine THA with neurochemical and behavioral changes Eur J Pharmacol 1989 173 5364 PubMed 27 Sugimoto H Iimura Y Yamanishi Y Yamatsu K Synthesis and antiacetylcholinesterase activity of 1benzyl45 6dimethoxy1indanon2yl methylpiperidine hydrochloride E2020 and related compounds Bioorg Med Chem Lett 1992 2 871876 28 Rogers SL Yamanishi Y Yamatsu K In Cholinergic Basis for Alzheimer Therapy 3 Becker R Giacobini E editors Boston Birkhäuser 1991 pp 314320 E2020The pharmacology of a piperidine cholinesterase inhibitor 29 Bryson HM Benfield P Donepezil Drugs Aging 1997 10 234249 PubMed 30 Rogers SL Tiseo PJ Friedhoff LT Pharmacokinetics of donepezil HCL E2020 are unchanged in patients with impaired renal function Clin Pharmacol Ther 1997 61 217220 31 Anand R Gharabawi G Enz A Efficacy and safety results of the early phase studies with Exelon ENA 713 in Alzheimers disease an overview J Drug Dev Clin Pract 1996 8 109116 32 Anand R Gharabawi G Clinical development of Exelon ENA713 the ADENA program J Drug Dev Clin Pract 1996 8 117122 33 Enz A Amstutz R Boddeke H Brain selective inhibition of acetylcholinesterase a novel approach to therpy for Alzheimers disease Prog Brain Res 1993 98 431438 PubMed 34 Reiner RE Kraulhacker B Simeon V SkinjaricSpoiler M Mechanisms of inhibition in vitro of mammalian acetylcholinesterase and cholinesterase in solutions of 00dimethyl 222trichloro1hydroxyethyl phosphate trichorphon Biochem Pharmacol 1975 24 717722 PubMed 35 Nordgren I Bengtsson E Holmstedt B Pettersson BM Levels of metrifonate and dichlorvos in plasma and erythrocytes during treatment of schistosomiasis with Bilarcil Acta Pharmacol Toxicol 1981 49 Suppl 57986 PubMed 36 Eagger SA Levy R Sahakian BJ Tacrine in Alzheimers disease Lancet 1991 337 989992 PubMed 37 Knapp MJ Knopman DS Solomon PR Pendlebury WW Davis CS Gracon SI A 30week randomized controlled trial of highdose tacrine in patients with Alzheimers disease The Tacrine Study Group JAMA 1994 271 985991 PubMed 38 Farlow M Gracon SI Hershey LA et al for the The Tacrine Study Group A controlled trial of tacrine in Alzheimers disease JAMA 1992 268 25232529 PubMed 39 Knopman D Schneider L Davis K et al for the Tacrine Study Group Longterm tacrine Cognex treatment effects on nursing home placement and mortality Neurology 1996 47 166177 PubMed 40 Knopman D Schneider L Davis K Gracon S Smith F Longterm tacrine treatment effects Neurology 1998 50 5678 PubMed 41 Qizilbash N Whithead A Higgins J Wilcock G Schneider L Farlow M Cholinesterase inhibition for Alzheimer disease A metaanalysis of the tacrine trials JAMA 1998 280 17771782 PubMed 42 Rogers SL Friedhoff LT The Donepezil Study Group The efficacy and safety of donepezil in patients with Alzheimers disease results of a US multicentre randomised double blind placebocontrolled trial Dementia 1996 7 293303 PubMed 43 Rogers SL Farlow MR Doody RS Mohs R Friedhoff LT Donepezil Study Group A 24 week double blind placebo controlled trial of donepezil in patients with Alzheimers disease Neurology 1998 50 136145 PubMed 44 Rogers SL Doody RS Mohs RC Friedhoff LT Donepezil improves cognition and global function in Alzheimer disease a 15week doubleblind placebocontrolled study Donepezil Study Group Arch Intern Med 1998 158 10211031 PubMed 45 Rogers SL Friedhoff LT Longterm efficacy and safety of donepezil in the treatment of Alzheimers disease an interim analysis of the results of a US multicentre open label extension study Eur Neuropsychopharmacol 1998 8 6775 PubMed 46 CoreyBloom J Anand R Veach J The ENA 713 B352 Study Group A randomized trial evaluating the efficacy and safety of ENA 713 rivastigmine tartrate a new acetylcholinesterase inhibitor in patients with mild to moderately severe Alzheimers disease Int J Geriatr Psychopharmacol 1998 1 5565 47 Becker RE Colliver J Elble R et al Effects of metrifonate a long acting cholinesterase inhibitor in Alzheimers disease report of an open trial Drug Dev Res 1990 19 425434 48 Cummings JL Cyrus PA Bieber F Mas J Orazem J Gulanski B The Metrifonate Study Group Metrifonate treatment of the cognitive deficits of Alzheimers disease Neurology 1998 50 12141221 PubMed 49 Watkins PB Zimmerman HJ Knapp MJ Gracon SI Lewis KW Hepatotoxic effects of tacrine administration in patients with Alzheimers disease JAMA 1994 271 992998 PubMed 50 Ernst RL Hay JW The US economic and social costs of Alzheimers disease revisited Am J Public Health 1994 84 12611264 PMC free article PubMed 51 Bosanquet N May J Johnson N Alzheimers Disease in the United Kingdom Health Policy Review 1998 p 12 52 Lubeck DP Mazonson PD Bowe T Potential effect of tacrine on expenditures for Alzheimers Disease Med Interface 1994October130138 PubMed 53 Ernst RL Hay JW Fenn C Tinklenberg J Yesavage JA Cognitive function and the costs of Alzheimer disease An exploratory study Arch Neurol 1997 54 687693 PubMed 54 Friedhoff LT Rogers SL Donepezil lengthens time to loss of activities of daily living inpatients with mild to moderate Alzheimers Diseaseresults of a preliminary evaluation Neurology 1997 48 226 55 Stewart A Phillips R Dempsey G Pharmacotherapy for people with Alzheimers disease A Markovcycle evaluation of five years therapy using donepezil Int J Geriat Psychiatry 1998 13 445453 PubMed 56 Standing Medical Advisory Committee The use of Donepezil for Alzheimers Disease Department of Health May 1998 Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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