| Brain chemistry | Donepezil hydrochloride (Aricept) |
| Tacrine | Rivastigmine (Exelon) |
| Metrifonate | Galanthamine |
Nerve cells in the brain communicate with one another by means of chemicals called neurotransmitters. There are some 80 different types of neurotransmitters which have a role to play. Post-mortem analyses show that many of these are deficient in people with Alzheimer's disease and related dementias.
Recent research has concentrated on the nerves containing a transmitter called acetylcholine. The timing of the transmission of acetylcholine, its amount and concentration are in turn controlled by a chemical called acetylcholinesterase. It has now become possible to control the production of acetylcholinesterase with a class of drugs known as the acetylcholinesterase inhibitors.
Drugs known as acetylcholinesterase inhibitors work on one part of the system of chemical messages. They prevent or inhibit acetylcholinesterase from working. This means that the acetylcholine which carries the chemical messages is able to remain long longer within nerve cells and there is more chance of the acetylcholine being passed on to the next nerve cell and transmitting the message.
There are a number of acetylcholinesterase inhibiting drugs that have been developed recently. These are described below. However, research suggests that it is unlikely that a defect in acetylcholine is the only or indeed the main cause of Alzheimer's disease. This is only one possible approach to treating the symptoms.
In development, donepezil hydrochloride was known as E2020. It will be marketed by drug companies as Aricept.
Donepezil is a relatively new drug which has been made specifically for the treatment of people with Alzheimer's disease. It works in a highly selective way by targeting the acetylcholine receptors in the brain ' not those outside the central nervous system in the muscles of the heart and intestine. For this reason, it is expected that there will be fewer side-effects than with some other drugs.
There have been three main trials of donepezil on people with Alzheimer's disease. These trials, carried out in the UK and Europe, are currently being analysed and the results are due by the autumn of 1997.
The standard way to measure improvements in someone on a trial drug is to use a mixture of objective tests of cognitive function (memory loss, language abilities) and activities in daily life plus a general (global) assessment of how someone has changed during the trial. To ensure as independent a rating as possible this is usually carried out by someone who is not involved in the testing of patients and who has access to the patient and their carer.
The results of the first trial of donepezil on 161 patients in the USA who took it in doses of 1, 3 or 5mg for 12 weeks were published in 1996. Tests of cognitive function showed that only 11 per cent of patients taking the 5mg dose declined over the trial compared to 20 per cent of patients on the placebo. There was a close association between the chemical activity of the drug (which can be measured in the blood) and how much memory improved.
The group taking the active drug suffered no more adverse effects than those on the placebo. Patients were asked to rate their quality of life on a scale; those on the actual treatment indicated an improvement.The second study involved a higher dose of the drug (5 and 10mg) and lasted for 15 weeks. Four hundred and sixty-eight patients with an average age of 73 entered the study. Eight-eight per cent completed it.
Improvements in cognitive function and the global rating of patients were observed, particularly in those taking the 10mg dose. Diarrhoea and insomnia were more common in all those taking the drug; nausea was more common in people taking 10mg. Blood tests showed that donepezil does not damage the liver.
The third trial took place over a longer period, 30 weeks in total, using 5mg or 10mg doses of donepezil compared to the placebo. Of the 473 patients in the trial, 93 per cent of those in the placebo group completed compared to 83 per cent of those on 10mg of the drug. Patients showed similar improvements to those in the earlier studies. Side-effects attributable to the medicine included diarrhoea, muscle cramps, fatigue, nausea and vomiting and were worse in patients on the higher dose.
Donepezil is certainly effective in some people with Alzheimer s disease. When groups of patients are examined there are significant improvements in objective tests of memory and a general impression that they have improved as a result of the drug. However donepezil is not a cure for Alzheimer's disease and it will not halt or slow down the disease process.
Donepezil has no serious side-effects and seems to be well tolerated by the majority of patients. An advantage is that because of how long the drug lasts in the body, it can be given once a day which has clear benefits in people with Alzheimer's disease. Licensing of donepezil
Donepezil was granted a UK licence in February 1997 and was launched in April 1997. It is being co-marketed as Aricept by Eisai in the UK and Pfizer for the rest of Europe.Aricept should be available on the NHS, after clinical assessment, to all individuals who might gain some benefit. A consultant should initiate prescription and ensure monitoring. Following this, further prescriptions could be made by GPs.
Tacrine was first used in the treatment of Alzheimer9s disease in 1982. The results were described as modest. Another more highly publicised study in the USA undertaken in 1986 confirmed these modest results although the research methodology was seen as controversial by some scientists.
In August 1987, a large multicentre trial of tacrine, jointly sponsored by the National Institute of Ageing, the Alzheimer Association of the USA and the Warner-Lambert/Parke Davis company which developed the drug, commenced in the USA and was later extended to the UK.
The results of the trial were published in April 1994 in the Journal of the American Medical Association. Of the 653 patients with mild to moderate Alzheimer's disease recruited, approximately 45 per cent remained in the study at the end of 30 weeks. Another group of patients were given a placebo.
The trial showed that tacrine produced statistically significant improvements according to doctors and carers but it required a high daily dose of 160mg to achieve this. The Clinician Interview Based Impression Score showed a 23 per cent improvement in the tacrine-treated patients compared to 17 per cent of those on the placebo.
Unwanted side-effects were the main reason for patients not completing the trial. Potential liver damage was a problem for 28 per cent of patients and usually occurred in the first 12 weeks of treatment. (Regular monitoring is required every two or three weeks to check the liver.) Sixteen per cent of patients withdrew because of nausea and vomiting.
The effects of tacrine appear to confirm that a minority of patients may show a meaningful improvement in their mental state on the highest dose. Even so the overall effects are modest.
Tacrine, marketed as Cognex, was given a licence in the USA in 1994 and was granted a licence by the UK medicines control agency in May 1997. However its manufacturers, Parke-Davis, have not yet decided to make it available, although they may do so in the future. People are strongly advised not to try to obtain the drug from the USA or elsewhere.
There are a number of other drugs that are currently being tested in clinical trials and may become available in 1998. You may read in particular about three drugs called Exelon, Metrifonate and Galanthamine (see below). There are however an estimated 300 drugs for Alzheimer's disease currently under development.
Click for more information on Exelon
This drug is a centrally active acetylcholinesterase inhibitor and is under development by Sandoz in USA and in Switzerland. It appears to have fewer side effects than tacrine with little if any liver toxicity and occasional side effects of nausea and vomiting are transient. There has been a large trial involving 2,800 patients in 11 centres in 10 countries including the UK. The results of the trials have not yet been published. Sandoz has set up International Safety Monitoring Board to give advice, monitor and review the clinical trials programme.
This a long acting acetylcholinesterase inhibitor which is under development by Bayer. Trials have taken place in the USA, UK, France and Germany. It can be taken once daily. It shows an improvement in memory loss and is well tolerated in most patients w with no liver toxicity and only mild symptoms of nausea and diarrhoea.
This drug has been defined as a tertiary alkaloid originally isolated from bulbs of snowdrop and narcissus and is also an acetylcholinesterase. It is under development by a company called Shire and trials are taking place in the USA and Europe. Initial re results have indicated that patients have achieved a highly significant improvement in cognitive performance. There has been good overall tolerability to the drug and low withdrawal rate.To date no abnormal liver function effects have been observed.
There is no evidence to suggest that any of these drugs will be a cure or the definitive treatment for Alzheimer s disease. If such a treatment is ever found it is likely that it will only be a result of a far greater knowledge about the cause of the disease and why it has such a devastating effect on the brain.
Nevertheless we should be cautiously optimistic that drugs like donepezil may give some measurable relief to some patients who are in the mild to moderate stages of Alzheimer's disease. This will also then ease the stress on carers. This in itself would represent a major advance in treatment.
We acknowledge with thanks the assistance of Professor Brian Leonard, Professor Alistair Burns, Professor Jim Edwardson, Dr Nori Graham and Dr Richard Harvey in the compilation of this information sheet.
November 1997 with thanks the assistance of Professor Brian Leonard, Professor Alistair Burns, Professor Jim Edwardson, Dr Nori Graham and Dr Richard Harvey in the compilation of this information sheet.
Page Text supplied by The Alzheimer's Disease Society of Great Britain