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Alzheimer

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Alzheimer summary. parthenogenesis and treatment

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Alzheimer

  1. 1. Presented by Kirmal Masih Medicinal Chemistry March 25th
  2. 2. Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia. This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.
  3. 3. Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception. Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (β- amyloid protein) in the brain that leads to nerve cell death.
  4. 4. • Generally, it is diagnosed in people over 65 years of age, although the less- prevalent early onset of Alzheimer’s can occur much earlier. • In 2006, there were 26.6 million sufferers worldwide. • Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.
  5. 5. 1) Early Stage This is considered as a mild/early stage and the duration period is 2-4 years. Frequent recent memory loss, particularly of recent conversations and events. Repeated questions, some problems expressing and understanding language. Writing and using objects become difficult and depression and apathy can occur. Drastic personality changes may accompany functional decline. Need reminders for daily activities and difficulties with sequencing impact driving early in this stage.
  6. 6. 2) Second stage This is considered as a middle/moderate stage and the duration is 2-10 years. Can no longer cover up problems. Pervasive and persistent memory loss impacts life across settings. Rambling speech, unusual reasoning, confusion about current events, time, and place. Potential to become lost in familiar settings, sleep disturbances, and mood or behavioral symptoms accelerate. Nearly 80% of patients exhibit emotional and behavioral problems which are aggravated by stress and change. Slowness, rigidity, tremors, and gait problems impact mobility and coordination. Need structure, reminders, and assistance with activities of daily living.
  7. 7. 3) Moderate stage Increased memory loss and confusion. Problems recognizing family and friends. Inability to learn new things. Difficulty carrying out tasks that involve multiple steps (such as getting dressed). Problems coping with new situations. Delusions and paranoia. Impulsive behavior. In moderate AD, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought
  8. 8. 4) Last stage This is considered as the severe stage and the duration is 1-3 years. Confused about past and present. Loss of recognition of familiar people and places Generally incapacitated with severe to total loss of verbal skills. Unable to care for self. Falls possible and immobility likely. Problems with swallowing, incontinence, and illness. Extreme problems with mood, behavioral problems, hallucinations, and delirium. Patients need total support and care, and often die from infections or pneumonia
  9. 9. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.
  10. 10. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computer tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.
  11. 11. . PET scan of the brain of a person with AD showing a loss of function in the temporal lobe.
  12. 12. Neuropsychological tests such as the mini-mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Psychological tests for depression are employed, since depression can either be concurrent with AD, an early sign of cognitive impairment, or even the cause.
  13. 13. • When available as a diagnostic tool, SPECT and PET neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination. In a person already having dementia, SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts employing mental testing and medical history analysis.
  14. 14.  Scientists don’t yet fully understand what causes AD, but it is clear that it develops because of a complex series of events that take place in the brain over a long period of time. It is likely that the causes include genetic, environmental, and lifestyle factors. 
  15. 15.  Some drug therapies propose that AD is caused by reduced synthesis of the neurotransmitter acetylcholine.  Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid leading to generalized neuroinflammation.
  16. 16. • Alzheimer's disease is characterized by a build-up of proteins in the brain. Though this cannot be measured in a living person, extensive autopsy studies have revealed this phenomenon. The build-up manifests in two ways:  Plaques– deposits of the protein β- amyloid that accumulate in the spaces between nerve cells  Tangles – deposits of the protein tau that accumulate inside of nerve cells
  17. 17. Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein.
  18. 18.  Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
  19. 19. Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid – β peptides and cellular material outside and around neurons.
  20. 20. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe.
  21. 21. Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-β and tau proteins in the brain. Plaques are made up of small peptides, 39– 43 amino acids in length, called 𝜷-amyloid (also written as A-β or Aβ). β-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane.
  22. 22. • APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. • One of these fragments gives rise to fibrils of β-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques
  23. 23. AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein.
  24. 24. • In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.
  25. 25.  Exactly how disturbances of production and aggregation of the β amyloid peptide gives rise to the pathology of AD is not known.  The amyloid hypothesis traditionally points to the accumulation of β- amyloid peptides as the central event triggering neuron degeneration.  Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis).  It is also known that A β selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilization of glucose by neurons.
  26. 26.  Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response  Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been described in AD
  27. 27. • Apolipoprotein E (APOE) found on chromosome 19 appears to be a predisposing genetic risk factor for the late onset of AD – the most typical AD. • APOE helps carry cholesterol in the bloodstream. • APOE comes in several different forms, or alleles. • Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.
  28. 28. Treatment for Alzheimer’s Disease
  29. 29. Treatment Goal • Currently there is no current therapy to treat Alzheimer’s disease. Current therapy is aimed at prolonging the patient’s cognitive function and secondary goals include symptomatically treating psychiatric and behavioral abnormalities • Current therapy has not been shown to prolong life, cure AD, halt or reverse the pathophysiological degradation of the disease
  30. 30. Natural Disease Progression • Alzheimer’s Disease Assessment Scale- Cognition (ADAS-cog) scores worsen by an average of 4 points over 6 months and 7 points over 1 year • 4 points represents a clinically significant change • In clinical practice a Mini Mental Status Examination (MMSE) is used due to time requirements of the ADAS-cog – An untreated patient has an average decline of 2-4 points per year
  31. 31. Brain Comparison
  32. 32. Ideal Treatment • Improving symptomatic decline by improving cognitive function, daily activities, and behavior – Current therapy • Arrests the neurodegenerative molecular process – Research needed
  33. 33. Treatment Algorithm • Cholinesterase Inhibitor • NMDA Antagonist • Cholinesterase Inhibitor + NMDA antagonist • Titrate doses to recommended maintenance therapy as tolerated • Symptomatic approach is used to treat behavioral symptoms
  34. 34. Cholinesterase Inhibitors
  35. 35. Cholinesterase Inhibitors • Donepezil (Aricept)- used in mild to severe disease • Galantamine (Razadyne)- used in mild to moderate disease • Rivastigmine (Exelon)- used in mild to moderate disease • Combination of more than one cholinesterase inhibitor is not recommended • Choice of therapy often selected based on ease of use for the patient, cost and safety issues • Switching can occur if patients are not tolerating the initial treatment or a treatment failure – If MMSE decline is greater than 2-4 points in one year changing therapy is warranted
  36. 36. Cholinesterase Inhibitors • Donepezil, Rivastigmine and Galantamine • All show similar efficacy and adverse event profiles with gastrointestinal complaints being the most common symptom • Dose titration over several months can help tolerability of urinary incontinence, dizziness, headache, syncope, bradycardia, muscle weakness, salivation and sweating • Abrupt discontinuation is discouraged due to worsening of cognition or behavioral problems in some medications • Avoid use with anti-cholinergic medications which is especially important when trying to treat behavioral abnormalities.
  37. 37. Cholinesterase Inhibitors Mechanism of Action • Donepezil- specifically and reversibly inhibits acetylcholinesterase • Rivastigmine- inhibits both butylcholinesterase and acetylcholinesterase • Galantamine- selective, competitive, reversible acetylcholinesterasse inhibitor and also enhances the action of acetylcholine on nicotinic receptors • Clinical relevance is unknown
  38. 38. NMDA Antagonist
  39. 39. N-methyl-D Aspartate (NMDA) Antagonist • Memantine- used in moderate to severe disease – Not recommended in early stages of the disease – Only NMDA-antagonist available – Blocks glutamatergic neurotransmission by antagonizing NMDA receptors • Glutamate an excitatory neurotransmitter in the brain – Most common side effects include constipation, confusion, dizziness, headache, hallucinations, coughing, and hypertension
  40. 40. Dosage Forms • Galantamine (Razadyne)- capsule, tablet, and solution • Donepezil (Aricept)- tablet (oral disintegrating tablet) • Rivastigmine (Exelon)- capsule, patch, and solution • Memantine (Namenda)- tablet and solution
  41. 41. Treatment for Non-cognitive Symptoms • Psychosis • Disruptive behavior • Depression • Environmental interventions then pharmacological therapy • Limited clinical data; therefore, treatment is empirical • General guidelines: reduced doses, close monitoring closely, slow dose titrations, and careful documentation • Cholinesterase inhibitors and memantine should be considered as first line therapy in patients with behavior abnormalities in the beginning stages of AD
  42. 42. Antipsychotics • Haloperidol • Olanzapine • Quetiapine • Risperidone • Ziprasidone • Treatment of psychosis: hallucinations, delusions, suspicions • Treatment of disruptive behaviors: Agitation and aggression • Not FDA approved
  43. 43. Concern with Antipsychotics • Worsening cognitive impairment, oversedation, falls, tardive dyskinesia, neuroleptic malignant syndrome, hyperlipidemia, weight gain, diabetes mellitus, cerebrovascular accidents • A dose reduction or discontinuation should be considered periodically in patients • Physical restraints should be limited to patients who pose imminent harm to themselves or others.
  44. 44. Antidepressants • Citalopram • Escitiolopram • Fluoxetine • Paroxetine • Sertraline • Venlafaxine • Trazadone • Treatment of depression: poor appetite, insomnia, hopelessness, anhedonia, withdrawal, suicidal thoughts, agitation, or anxiety • As many as 50% of AD patients suffer from depression
  45. 45. Anticonvulsants • Carbamazepine • Valproic Acid • Treatment of agitation or aggression
  46. 46. Standard of treatment • None exists • Duration of treatment ranges from clinician to clinician. May be months to years • No clear standard of care for dosing from clinical trials • No clear standard of when to discontinue therapy in very severe stages of AD – Many clinicians do discontinue therapy when the patient becomes bed ridden
  47. 47. Key Non-pharmacological Methods •Education •Preparation •Communication
  48. 48. • Educating patient and family at the time of diagnosis – Discussion of the course of illness – Expectations from treatment – Legal and financial planning including a durable power of attorney – Quality of life issues – Re-enforcing the importance of communication between the patient and family members – Decreasing environmental triggers and personal discomfort
  49. 49. Non-Pharmacological Interventions • Physical well-being • Increased overall well being • Stimulation oriented treatments: recreational activity, art therapy, music therapy, pet therapy and aromatherapy may be useful, but lack of sufficient evidence to validate effectiveness but used in clinical practice
  50. 50. Caregivers • Find time to rest, relax and tend to personal affairs because stress will impact the health and quality of life of both the patient and the caregiver • Help patients to discover a structured level of autonomy using reminders and explanations • Be aware of signs and symptoms of decline • Knowing when to institutionalize a patient
  51. 51. Interventions • Patients should be assessed every 3-6 months • Patients may need to stop driving even at mild levels of treatment • Sleep disturbances common in people with dementia, proper sleep hygiene should be implemented before beginning pharmacological therapy
  52. 52. Behavioral Management • Sleep disturbances • Wandering • Urinary Incontinence • Agitation • Aggression • May be useful to try this before beginning drug therapy
  53. 53. Epidemiological Correlations • Brain Vascular Health • Lipid lowering agents • Non inflammatory agents • Vitamin B 6, B12 and B12 deficiency • Hyerhomocysteinemia
  54. 54. Brain Vascular Health • New studies have evidence brain vascular disease plays an important role in the progression of dementia • Brain vascular disease may accelerate deposition of β amyloid plaques and increase amyloid toxicity to neurons and the neural synapses • Brain vascular health includes managing blood pressure, glucose, cholesterol and homocysteine. – Elevated homocysteine levels correlate with decreased performance on cognitive tests • Importance of stating physically, mentally, and socially active
  55. 55. Folate, Vitamin B1, Vitamin B6 • Defects in these vitamins are associated with neurological and psychological dysfunction • In elderly patients there is increased concern of satiety, atrophic gastritis, and decreased function of the olfactory functions • Increased homocysteine has a direct correlation with a deficiency and these vitamins
  56. 56. Estrogen Therapy • Epidemiological studies post menopausal women who took estrogen replacement therapy had a lower incidence of AD • Studies did not show an improvement in behavioral or functional outcomes when estrogen used to treat cognitive decline • Estrogen has a risk of stroke and other cardiovascular events
  57. 57. Anti-inflammatory Agents • Epidemiological studies suggest patients on anti- inflammatory agents have a lower incidedence of AD • Treatment less than 2 years proved beneficial in some patients • Clinical studies does not show evidence of cognitive benefit and tolerability was an issue
  58. 58. Lipid Lowering Agents • Epidemiological studies and AD show a correlation between higher midlife total cholesterol rates and AD • Correlation between people on lipid lowering therapy and lower incidences' of AD – Pravastatin and lovastatin but not simvastatin were associated with a lower incidence of AD – More trials are needed to address the impact of cognitive benefit, the duration of treatment, class effect, and optimal dosing for its role in AD • Role of therapy should remain for people with indications for their use
  59. 59. Therapies in the Pipeline • Vitamin E • Atomexetine • IGIV 10% • Thiazolidinediones (anti- inflammatory effects) • Over 900 studies occurring now phase 1-4 and • Ginkgo Biloba • Huperzine A • Semagacestat (LY450139) • Coenzyme Q10 • Acupuncture • Over 100 studies phase 3
  60. 60. Vitamin E • Antioxidant- may be useful because of the accumulation of free radicals associated with AD • Favorable side effect profile and low cost • Impaired hemostasis, fatigue, nausea, diarrhea, abdominal pain, and thinning of the blood • Increased mortality in older patients • Doses above 400 international units per day should be avoided in patients with AD • May be beneficial in combination with Selegeline: Phase III study-PREADVISE- examining anti-oxidant effects of Selegeline
  61. 61. Ginkgo Biloba • Increased blood flow, decreased viscosity of the blood, antagonizing platelet activating factor receptors, increased tolerance to anoxia, inhibiting monoamine oxidase, anti- infective properties, preventing damage of membranes caused by free radicals • If used for dementia should be used as soon as deterioration of cognitive functioning occurs • Side effects are typically mild and rare • Herbal products are typically poorly standardized
  62. 62. Huperzine A • An alkyloid isolated from the Chinese club moss, Huperzia serrata • Reversibly inhibits acetylcholinesterase and is administered orally in doses 50-200 mcg 2- 4 times daily • May be more promising for symptomatic treatment of Alzheimer’s disease • Promising product from clinical studies, but lack of product purity • Concurrent use with other available cholinesterase inhibitors should be avoided
  63. 63. Semagacestat (LY450139) • Inhibiting the enzyme gamma-secretase lowers the production of beta amyloid. Semagacestat (LY450139) a functional gamma-secretase inhibitor lowers the beta amyloid in the blood and spinal fluid in humans. • Effect of LY450139 a gamma-secretase inhibitor on the progression of Alzheimer’s disease as compared with Placebo- Currently Phase III • 60 mg orally titrated up to 140 mg
  64. 64. Immune Globulin Intravenous (Human), 10% (IGIV, 10%) • A Randomized, Double-Blind, Placebo- Controlled, Two Dose-Arm, Parallel Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% (IGIV, 10%) for the Treatment of Mild to Moderate Alzheimer's Disease – Phase III trial • The purpose of this study is to determine whether IGIV, 10% treatment, administered at two different doses results in a significantly slower rate of decline of dementia symptoms in subjects with mild to moderate (AD). • Approved in 2005 for primary immunodeficiency
  65. 65. Coenzyme Q10 • A natural antioxidant in the body • Role of therapy currently being explored, but limited clinical trials in humans for AD
  66. 66. Helpful links • www.aoa.gov • www.nia.nih/gov/alzheimers • www.alzforum.org • www.aarp.gov • www.thefamilycaregiver.org • www.ec-online.net
  67. 67. Economic Impact • US health care cost is greater than $100 billion • Annual cost for caring for an individual with advanced AD is approximately $50,000 • According to CDC, there is 231,900 patients in nursing homes with AD which accounts for 15.5% of the nursing home population • 4th leading cause of death in adults
  68. 68. Resources • http://www.gammagardliquid.com/about- gammagard-liquid/dosage- administration.html • http://www.nlm.nih.gov/medlineplus/drugin fo/natural/1003.html • cdc.gov • www.ncbi.nlm.nih.gov • www.novartis.com • www.alz.org • www.clinicaltrials.gov
  69. 69. Resources • National Guideline Clearinghouse (NGC). Guideline synthesis: Management of Alzheimer's disease and related dementias. In: National Guideline Clearinghouse (NGC). Rockville (MD): 2006 Nov (revised 2010 Sep). [cited 2011 June 13]. Available: http://www.guideline.gov. • Dipiro J,Talbert R, Yee G., Matzke G, Wells B, Posey L. Pharmacotherapy: A Pathophysiologic Approach. 7th. New York: McGraw-Hill, 2008. 1051-1066 • B Vitamins, Homocysteine, and Neurocognitive Function in the Elderly. American Journal of Clinical Nutrition. February 2000;71(2):614s- 620s. Accessed June 15, 2011.
  70. 70. treatment • Current therapy is aimed at prolonging the patient’s cognitive function and secondary goals include symptomatically treating psychiatric and behavioral abnormalities • Current therapy has not been shown to prolong life, cure AD, halt or reverse the pathophysiological degradation of the disease
  71. 71.  Aricept Used to delay or slow the symptoms of AD Donepezil • Loses its effect over time • Used for mild, moderate and severe AD • Does not prevent or cure AD  Celexa Citalopram Used to reduce depression and anxiety • May take 4 to 6 weeks to work • Sometimes used to help people get to sleep  Used to reducedepression and anxiety • May take 4 to 6 weeks to work • Sometimes used to help people get to sleep  Depakote® (DEP-uh-cote)
  72. 72.  Depakote Used to treat severe aggression Sodium Valproate • Also used to treat depression and anxiety  Exelon Used to delay or slow the symptoms of AD Rivastigmine • Loses its effect over time • Used for mild to moderate AD • Can get in pill form or as a skin patch • Does not prevent or cure AD
  73. 73.  Namenda Used to delay or slow the symptoms of AD Memantine • Loses its effect over time • Used for moderate to severe AD • Sometimes given with Aricept®, Exelon® • Does not prevent or cure AD  Razadyne Used to prevent or slow the symptoms of AD Galantamine • Loses its effect over time • Used for mild to moderate AD • Can get in pill form or as a skin patch • Does not prevent or cure AD  Zoloft Used to reduce depression and anxiety Sertraline • May take 4 to 6 weeks to work • Sometimes used to help people get to sleep  Trileptal Used to treat severe aggression Oxcarbazepine • Also used to treat depression and anxiety
  74. 74.  Tegretol Used to treat severe aggression Carbamazepine • Also used to treat depression and anxiety  Remeron Used to reduce depression and anxiety Mirtazepine • May take 4 to 6 weeks to work • Sometimes used to help people get to sleep
  75. 75.  Although there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management.  Mild/Moderate AD: Cholinesterase inhibitors increase the levels of acetylcholine in the brain, which plays a key role in memory and learning. This kind of drug postpones the worsening of symptoms for 6 to 11 months in about half of the people who take it. Cholinesterase inhibitors most commonly prescribed for mild to moderate Alzheimer's disease include Aricept (donezepil HCL), Exelon (rivastigmine), and Razadyne (galantamine).
  76. 76. • Moderate/Severe AD: Namenda (memantine) regulates glutamate in the brain, which plays a key role in processing information. This drug is used to treat moderate to severe Alzheimer's disease and may delay the worsening of symptoms in some people. It may allow patients to maintain certain daily functions a little longer than they would without the medication.
  77. 77. Razadyne • Razadyne (galantamine HBr) is FDA-approved for mild and moderate stages of the disease. • Razadyne is a cholinesterase inhibitor that prevents the breakdown of acetylcholine in the brain. Acetylcholine plays a key role in memory and learning; higher levels in the brain help nerve cells communicate more efficiently. Razadyne also stimulates nicotinic receptors to release more acetylcholine in the brain.
  78. 78.  Razadyne delays the worsening of Alzheimer's symptoms for 6 to 11 months in about half of the people who take it.  Razadyne is available in tablet and capsule form, and is commonly started at 4 mg twice a day. If it's well tolerated after 4 weeks, the dosage may be increased to 8 mg twice a day.  Razadyne also comes in an extended release, once-a-day tablet.  Razadyne is available in generic form (galantamine HBr).
  79. 79. Exelon (Rivastigmine) Exelon is FDA approved for mild and moderate stages of the disease; it is also approved for the treatment of mild to moderate dementia due to Parkinson's disease. Exelon is available as a capsule, liquid, and patch.
  80. 80. • Exelon is a cholinesterase inhibitor that prevents the breakdown of acetylcholine and butyrylcholine in the brain by blocking the activity of two different enzymes. Acetylcholine and butyrylcholine play a key role in memory and learning. • When given orally, bioavailability is about 40% in the 3 mg dose. The compound can cross the blood-brain barrier.
  81. 81. Aricept (Donepizel) • One of the most widely used drugs to treat the symptoms of Alzheimer's disease. Aricept is FDA-approved for mild, moderate, and severe stages of the disease.
  82. 82. • Aricept is available in tablet form or an orally disintegrating tablet form, and is commonly started at 5 mg a day. • Can cross the blood-brain barrier.
  83. 83. Namenda (Memantine) • Namenda is an N-methyl D-aspartate (NMDA) antagonist that regulates the activity of glutamate in the brain. Glutamate plays a key role in memory and learning, but excess glutamate can lead to the disruption of nerve cell communication or nerve cell death.
  84. 84. • Studies involving Namenda have shown that the drug can slow the rate of decline in thinking and the ability to perform daily activities in individuals who have moderate to severe Alzheimer's disease • A dysfunction of glutamatergic neurotransmission is thought to be involved in the etiology of AD. • Namenda is available in generic form (memantine HCL).
  85. 85.  A molecule designed by a Purdue University researcher to stop the debilitating symptoms of Alzheimer's disease has been shown in its first phase of clinical trials to be safe and to reduce biomarkers for the disease.  The molecule, called a β-secretase inhibitor, prevents the first step in a chain of events that leads to amyloid plaque formation in the brain. This plaque formation creates fibrous clumps of toxic proteins that are believed to cause the devastating symptoms of Alzheimer's.
  86. 86. • Researchers at Mount Sinai School of Medicine have found that a compound called NIC5-15, might be a safe and effective treatment to stabilize cognitive performance in patients with mild to moderate Alzheimer's disease. The two investigators, Giulio Maria Pasinetti, M.D., Ph.D. , and Hillel Grossman, M.D., presented Phase IIA preliminary clinical findings at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD) in Vienna on July 1
  87. 87. • NIC5-15's potential to preserve cognitive performance will be further evaluated in a Phase IIB clinical trial. Early evidence suggests that NIC5-15 is a safe and tolerable natural compound that may reduce the progression of Alzheimer's disease-related dementia by preventing the formation of β-amyloid plaque, a waxy substance that accumulates between brain cells and impacts cognitive function.
  88. 88.  http://www.sciencedaily.com/releases/2008/01/08012310 1629.htm  http://www.sciencedaily.com/releases/2009/07/09071214 5228.htm  http://www.nia.nih.gov/Alzheimers/Publications/CaringAD /other/medicines.htm  http://en.wikipedia.org/wiki/Rivastigmine  http://en.wikipedia.org/wiki/Galantamine  http://en.wikipedia.org/wiki/Donepezil  http://en.wikipedia.org/wiki/Mementine  Newsweek; 06/15/98, Vol. 131 Issue 24, p52, 2p,
  89. 89. • Harvard Mental Health Letter; Apr2010, Vol. 26 Issue 10, p7-7, 1/2p • Asian Journal of Animal & Veterinary Advances; 2010, Vol. 5 Issue 1, p13-23, 11p, 1 Chart, 2 Graphs • Medical Device Daily; 2/16/2010, Vol. 14 Issue 30, p1-6, 2p
  90. 90. • An Introduction to Medicinal Chemistry by Graham L. Patrick, pp. 589-590. • Abbott, Alison. Neuroscience: The plaque plan. Nature (London, United Kingdom) (2008), 456(7219), 161-164. • Bolognesi, Maria L.; Matera, Riccardo; Minarini, Anna; Rosini, Michela; Melchiorre, Carlo. Alzheimer's disease: new approaches to drug discovery. Current Opinion in Chemical Biology (2009), 13(3), 303-308.
  91. 91. • What are the three stages of Alzheimer’s Disease? • What are some of the diagnostic tools of diagnosing Alzheimer’s Disease? • What drugs are used to treat mild/moderate Alzheimer’s Disease? • Which drug is most commonly used to treat Alzheimer’s Disease? • Have current pharmaceutical agents been successful in slowing the progress of Alzheimer’s Disease? • Why is it important to develop ‘biomarkers’ for Alzheimer’s Disease?

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