Isolation of Dementia Drugs from Nature
Introduction to Galantamine and its Uses
In the past, the Alzheimer's disease was considered a rarity. Nowadays its prevalence is on the increase, this has lead to a more focused approach in the research and development of treatment for the Alzheimer's disease.
Discovered by and named after the neuropathologist Dr Alois Alzheimer, the Alzheimer's disease (AD) is a neurodegenerative disorder characterised by a decline in cognitive function such as memory loss, disorientation, impairment of motor skills and emotional and behavioural problems. It is the most common form of dementia observed in the elderly population.
People with Alzheimer's have been shown to have a shortage of the chemical acetylcholine in their brains. Although there is no known cure for AD, there are treatments in place that help by maintaining existing supplies of acetylcholine systems at sites of neurotransmission in the brain. Some of the drugs used in the treatment of this disease include Tacrine (Cognex), Rivastigmine (Exelon), Galantamine (Reminyl) and Donepezil (Aricept). These treatments help slow disease progression of the disease in patients5. The main focus of my research will be examining one of the treatments, Galantamine. In this section I will be presenting a basic overview of Alzheimer's disease, including its history alongside the medical facts.
Historical Background - Disease Pathology
On the 25 November 1901, a woman named Frau Auguste D aged 51 suffering from dementia was admitted in the Municipal Metal Asylum in Frankfurt. Dr Alois Alzheimer a senior German physician, admitted her and recorded her severely disturbed and disoriented behaviour. In 1906 when Frau Auguste D died, her brain was sent to Dr Alzheimers in the Anatomical Laboratory of the Royal Clinic, Munich to be examined. Dr Alzheimer's focal attention was always given to brain structures. When Frau Auguste D died, it provided an opportunity for Dr Alzheimer's to examine her brain, so to understand her death from an unusual mental illness.
During a post-mortem study of Frau Auguste D's brain using the Bielschowsky silver technique (Silver staining technique) (Appendix 1), Dr Alzheimers observed abnormal clumps (amyloid plaques) of what he called ‘a peculiar substance' scattered all over the brain and tangled bundles of fibers (neurofibrillary tangles) within the brain, many of which had died. From his findings, he formed a hypothesis that the brain may have undergone neurological changes, these could have been chemical changes which may have occurred in the neurofibrills causing brain cell death and leaving the tangles as a marker of this cell death. He suggested that these changes may have been the cause of Frau Auguste D's condition and her death. In today's society, the amyloid plaques (Appendix 3) and tangled bindles of fibers (Appendix 4) along with neuronal loss are considered the main characteristics of a person suffering from Alzheimer's Disease.
Other researchers have reported cases similar to the behaviour reported by Dr Alzheimer: Fischer described sixteen cases of senile dementia (Appendix 2) in 1907, Bonfiglio 1908 and Perusini reported four cases in 1909. Despite the fact that it was Dr Alzheimer who was the first to report the known case of alzheimers in a patient of his Frau Auguste D, it was Emil Kraepelin who supported Dr Alzheimer's concept of the disease by publishing in greater detail with supporting evidence of what is known today as the Alzheimer's disease.
In 1910, Emil Kraepelin used Dr Alzheimer's study of Frau Auguste D to recreate the Alzheimer's disease18. Emil Kraepelin described the diagnosis of Alzheimer's as sub-type of ‘senile dementia'18. The recreation of Alzheimer's disease has lead to a enhanced understanding of AD, but most importantly has lead to diagnostics of people suffering from AD without them being perceived as people suffering from mental illness. Although the impact of Dr Alzheimers discovery was unknown at that time, his discovery has marked one of the most important disease of the twentieth century.
Causes and Symptoms of Alzheimer's Disease
The main causes of Alzheimer's Disease are not fully understood by scientist. What is clear is that Alzheimer's Disease develops as a results of neurological events that occur inside the brain over many years. The disease may be triggered by any number of changes during these events, probably as a result of different genetic and non-genetic factors in each individual.
Scientist classify the Alzheimer's disease in two types: a) ‘Familia' Alzheimer's disease, it follows a certain inheritance pattern where the genes that lead to the Alzhiemer's disease, are passed down from generation to generation and ‘Sporadic' Alzheimer's disease, they is no obvious inheritance pattern seen21. The most common AD observed in patients is that of Familia Alzheimer's disease and as many as 50percent of all Familia Alzheimer's disease cases are known to be caused by defects in three genes located on three different chromosomes (genetic factors) 21.
Alzheimer's can also be classified on the differences in age that us ‘Early-onset' Alzheimer's disease, occurring in people younger than 65 and ‘Late-onset' Alzheimer's disease, occurring in people who are 65 years or older21. One of the most notable differences between the ‘Early-onset' and the ‘Late-onset' Alzheimer's disease is that the Early-onset Alzheimer's disease often progresses faster in comparison to the Late-onset' Alzheimer's disease21.
Most published research material, note that getting older is a major risk factor associated with AD development1-21. During the normal aging process, our brain undergo a number of changes: some neurons and their processes shrink and function less well, importantly those associated with learning, memory, planning and other complex mental activities; tangles develop in neurons and plaques develop surrounding areas in brain regions; the mitochondria in cells become more prone to damage; oxidative stress (results in cell being damaged resulting in nerve cell damage and death) increases and inflammation increases21. These changes lead to people having poor memory, forgetfulness and speech problems21. In healthier older people these changes are minimal resulting in age related memory decline21. In people that develop AD, these changes are extreme and have overwhelming consequences21. Alzheimer's disease always begins slowly it leads to enhanced symptoms such as complete loss of memory, difficulties in speaking, understanding, reading or writing, delusions and most importantly incompetency in taking care of themselves leaving them needing someone else to care for them.
Finding a cure for Alzheimer's disease would be probably be ideal for those many sufferers in the world, but ideally scientifically we just began to understand what causes AD. Alzheimer's disease is classified as a degenerative disease (disease that worsens over time), however scientist have taken steps to develop effective drug treatments to help slow down the progression of the disease. Organisations such as the Alzheimer's Society along with many are committed to funding research into the cause, cure and care of the Alzheimer's disease with the aim to improving patient's lives.
Current effective treatment for Alzheimer's disease are aimed at boosting the amount of chemical acetylcholine in the brain, as people suffering from Alzheimer's disease have shown to have a shortage of this. The chemical acetylcholine is involved in helping pass messages between brain cells involved in memory. Alzheimer's disease involves mainly damaging the cells that produces and use acetylcholine, thereby decreasing the amount available to carry messages.
Development of cholinesterase inhibitors e.g. Donepezil, Rivastigmine and Galantamine have provided an opportunity to help slow down the breakdown of acetylcholine thereby increasing the amount of acetylcholine available to transmit messages in the brain. There are no major differences between these cholinesterase inhibitors, they are all designed to help the symptoms of Alzheimer's disease.
The cholinesterase inhibitors helps by slowing down the breakdown of acetylcholine by blocking the activity of the acetylcholinesterase enzyme in the synapse.
By maintaining the levels of acetylcholine, the drugs help by improving the brain's cognitive function. It is important to note that the cholinesterase inhibitors do not reverse the Alzheimer's disease. However they work by slowing down the symptomatic progression of the disease for some time (about six months to a year although some people have benefited over long periods of time). All benefit from these drugs is lost if medication is discontinued, therefore the importance of these drugs being easily available to patients has to be stressed.
With every pharmaceutical drug that becomes available in the market, issues arise and the cholinesterase inhibitors are no exception. In 2001 in the UK, the National Institute for Clinical Excellence (NICE) recommended the cholinesterase inhibitors; donepezil, rivastigmine and galantamine as the drugs which could make it easier for everybody suffering from alzheimer's to carry out everyday tasks. The National Institute for Clinical Excellence (NICE) role is to advise the National Health Service on the prevention, treatment of diseases and cost-effectiveness of different treatments. However in July 2005 they announced that their initial guidance notes for the Alzheimer's disease were changing. They stated that only people with mild-moderate (newly diagnosed patients) Alzheimer's disease would be prescribed donepezil, rivastigmine and galantamine26 and 27. The decision angered a lot of alzheimer's patients because they saw it as the National Institute for Clinical Excellence trying to deny patients access to treatment. The National Institute for Clinical Excellence (NICE) came to their decision after research into the cholinesterase inhibitors. Their findings concluded that the drugs do not make enough differences in patients lives for them to be recommended and to be used in all stages of the Alzheimer's disease and most importantly there were not good value for money. Although they has been a lot of protests against this decision and high court bids to reverse this decision, these guidelines continue to be intact in Wales and England whilst they are not applied in Scotland 26 and 27.
A lot can be argued about National Institute for Clinical Excellence decision, but what is notable is that the cost of managing patients with alzheimer's disease has increased considerably over age, covering patient care and medical care along with an increase in the people suffering from the disease. Therefore, studies into this disease have increased significantly leading to research in the development of alternative treatments and possibly in the future for the cure of the Alzheimer's disease itself. Alternative treatments for alzheimer's include: Memantine 23 and 26 which has been used in Germany for many years as treatment for dementia and works by effecting the glutamate released by dead nerve cells which can kill healthy nerve cells therefore damaging brain cells; Ginkgo Biloba23 and 26 naturally occurring substance from the leaves of a ginkgo tree works by enhancing memory and Vitamin E23 and 26 which works by slowing the progression of the alzhiemer's disease and is easily available in foods such as oils from soya bean, corn and whole grain foods. However, more research is needed to prove their full effectiveness.
Dosage and Formulation
Appendix 1: Bielschowsky silver technique
Appendix 2: Senile dementia
Appendix 3: amyloid plaques
Appendix 4: tangled bindles of fibers
(a) Alzheimer's disease Overview and Bibliography, ed. T. V. Bennington, ed. S. Boriotti and ed. D. Dennis, Nova Science Publishers , New York, 2002, 1. (b) K. Blennow, M. J. de Leon, H. Zetterberg, Lancet, 2006, 368, 387-403.
 B. Winblad, H. Brodaty, S. Gauthier, J. C. Morris, J. Orgogozo, K. Rockwood, L. Schneider, M. Takeda, P. Tariot and D. Wilkinson, Int. J. Geriatr Psychciatry, 2001, 16, 653-666.
R. W. Jones, H. Soininen, K. Hager, D. Aarsland, P. Passmore, A. Murthy, R. Zhang and R. Bahra, Int. J. Geriatr Psychiatry, 2004, 19, 58-67.
 (a) J. J. Sramek, V. Zarotsky and N. R. Cutler, Drug Dev. Res, 2002, 56, 347-353. (b) Alzheimer's Disease: Beyond the Medical Model, ed. M. V. Morrissey and ed. A. Coakely, Mark Allen Publishing, Wiltshire (UK), 1999, 7-8.
 Alzheimer's disease Overview and Bibliography, ed. T. V. Bennington, ed. S. Boriotti and ed. D. Dennis, Nova Science Publishers , New York, 2002, 3.
 (a) R. Cheston and M. Bender, in Understanding Dementia: The man with the Worried Eyes, Jessica Kingsley Publishers, London (UK), 1999, 22-45. (b)
 R. Cheston and M. Bender, in Understanding Dementia: The man with the Worried Eyes, Jessica Kingsley Publishers, London (UK), 1999, 22-23.
 R. Cheston and M. Bender, in Understanding Dementia: The man with the Worried Eyes, Jessica Kingsley Publishers, London (UK), 1999, 22-27.
 R. Cheston and M. Bender, in Understanding Dementia: The man with the Worried Eyes, Jessica Kingsley Publishers, London (UK), 1999, 22-45
 Alzheimer's disease: A Century of Scientific and Clinical Research, ed. G. Perry, ed. J. Avila, ed. J. Kinoshita, IOS Press, Amsterdam; Washington DC, 2006,
 R. Cheston and M. Bender, in Understanding Dementia: The man with the Worried Eyes, Jessica Kingsley Publishers, London (UK), 1999, 36-37.
 (a) R. Cheston and M. Bender, in Understanding Dementia: The man with the Worried Eyes, Jessica Kingsley Publishers, London (UK), 1999, 34-40. (b) Alzheimer's disease: A Century of Scientific and Clinical Research, ed. G. Perry, ed. J. Avila, ed. J. Kinoshita, IOS Press, Amsterdam; Washington DC, 2006,6-8.
 Alzheimer's disease: A Century of Scientific and Clinical Research, ed. G. Perry, ed. J. Avila, ed. J. Kinoshita, IOS Press, Amsterdam; Washington DC, 2006, 6-8.
 Alzheimer's disease Overview and Bibliography, ed. T. V. Bennington, ed. S. Boriotti and ed. D. Dennis, Nova Science Publishers , New York, 2002, 11-14.
Alzheimer's: Dementia care & Research, Great minds think differently: New frontiers in Alzheimer's Research, Alzheimer's Society, London (UK), 26-31
 Alzheimer's: Dementia care & Research, Great minds think differently: New frontiers in Alzheimer's Research, Alzheimer's Society, London (UK), 14-26
 R. Caims, J. Evans and M. Prince, Int. J. Geriatr Psychiatry, 2004, 19, 800-802
 Guidance on the use of Donepezil, Rivastigmine and Galantamine for Treatment of Alzheimer's Disease, National Institute for Clinical Excellence, London(UK), 2001