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Elephants never get demented I wonder what drugs they’re on?

Elephants never get demented I wonder what drugs they’re on?. David Greenhouse, MD, CMD Director of Geriatric Education USC SoM. Stanley. 75 yo male seen in the FPC for f/u As part of geriatric curriculum resident performs Mini-Cog 3 object recall: moon, dog, watch Clock draw test

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Elephants never get demented I wonder what drugs they’re on?

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  1. Elephants never get dementedI wonder what drugs they’re on? David Greenhouse, MD, CMD Director of Geriatric Education USC SoM

  2. Stanley • 75 yo male seen in the FPC for f/u • As part of geriatric curriculum resident performs Mini-Cog • 3 object recall: moon, dog, watch • Clock draw test • Long term memory question • Why did Kennedy leave office?

  3. Results • 1/3 recall after clock draw distraction • “He was having an affair. He was voted out.” • MMSE 20/30

  4. Diagnosis • After some further testing and talking to family, you make the clinical diagnosis of Alzheimer’s type dementia

  5. Projected Prevalence of AD 3rd most expensive disease, $100 billion

  6. Heart disease Down 3 % Cancer Down 1 % CVA Down 2.8 % Alzhemier’s disease Up 5.8 % Kidney disease Up 1.4 Septicemia Up 2.6 % Diabetes Up 0.4 % Disease Specific Death Rates Knowable, unintended consequences We all have to die from something. As long as we make gains in treatment of Cardiovascular disease, other diseases will become more prevalent.

  7. Fantastic Voyage

  8. A Look Inside

  9. At the synapse Loss of acetylcholine neurons starting in hippocampus

  10. Plaques at the Cell Membrane Level Cholesterol modulates APP processing Cyp46 = 24S-cholesterol hydroxylase

  11. The Tangled Web • Plaques  injury  kinase activation • Kinases phosphorylates microtuble tau protein forming tangles

  12. Something New Under the Sun Excitotoxicity • Glutamate • Major excitatory neurotransmitter for cognition & learning • Glutamate neuronal loss correlates with degree of dementia

  13. N-Methyl-D-Aspartate forms ion channel for Ca entry • Ca intracellular messenger • Inactive receptor blocked by Mg • Uncontrolled activation causes cell death

  14. Glutamate in ATD • Glutamate transporter down regulated • Increased synaptic glutamate activity • Glutamate promotes APP synthesis • β-amyloid inhibits re-uptake of glutamate and enhances glutamate release • Increased NMDA receptor activity increases phosphorlyation of tau protein

  15. The Stroke Connection • Cognitive performance decreased in those with stroke risk factors • Abstract reasoning, visualspatial memory, visual organization, concentration most affected • Snowdon Nun Study

  16. Glutamate & Stroke

  17. Pathophysiologic model Glutamate β-Amyloid Excitotoxicity Neurofibrillary Tangle Cell death Inflammation Dementia

  18. Do we have anything to offer?

  19. Non-pharmacologic Strategies • Mental exercises • Higher education • Physical activity • Social activity • Diet (fish, low cholesterol) Think Medical School

  20. Pharmacologic Treatments • Anti-inflammatory agents: NSAIDs • Estrogen replacement • Antioxidants: vitamin E, selegiline • Ginkgo biloba • Statins • Control vascular risk factors • Acetylcholinesterase inhibitors • NMDA-receptor antagonists

  21. Anti-Inflammatory Drugs • Observational/epidemiological studies • NSIADs associated with reduced risk • Clinical trials • Failed to show benefit of prednisone, NSAID, COX-2 Aisen PS, JAMA 6/4/03; 289; 2819-26

  22. Women’s Health Initiative • Women’s Health Initiative Memory Trial • Hazard ratio of 2.05 for probable dementia • 1.89 % on E+P vs 0.9% on placebo • 12.5 % E+P vs 4.8 % on placebo VCI • 50.0 % E+P vs 57.1 on placebo  ATD • Yes, more women who developed dementia on placebo developed ATD • No protection for Minimum Cognitive Impairment Shumaker JAMA 2003; 289: 2651

  23. Vitamin E • Selegiline 5 mg bid or Vitamin E 2000 IU qd • Primary outcome: time to death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia • Vit E (670 d) >selegiline (655) >both (585) >placebo (440) • Did not reach statistical significance • Cochrane review: insufficient evidence Sano M, NEJM 1997; 336:1216

  24. This Just In • 4740 respondents regarding use of multivitamins, Vit E, Vit C and B-complex • Only people taking combination of Vit E & C had statistically significant protection (HR 0.36) • Vit E 1,000 IU and Vit C 500-1,000 mg • Other studies have found reduction in vascular dementia with combination Zandi, P. Arch Neurol 61 (1): 82-88

  25. Ginkgo biloba • Ginkgo 40 mg PO tid for 6-12 months in mild-moderate dementia • Ginkgo stabilized cognition • Serious side effects: coma, bleeding, seizure LeBars PL JAMA 1997; 278: 1327

  26. Statins • HERS reduced TC and LDL resulted in 50 % decrease in dementia • Epidemiologic studies: Statins decrease risk of AD • Jick, Lancet, 30 % reduction in dementia • Wolozin, Arch Neuro, 60 % reduction • Hajjar statin users had unchanged or improved MMSE (OR 2.81) • Statins decrease β-amyloid deposition

  27. AChEI therapy • Difference in titration, mechanisms of action and metabolism • All have benefits on cognition, behaviors and activities of daily living • Most studied class of medications for ATD • Neurostabilizers/neuroprotectors

  28. Donepezil (Aricept) • Introduced 1997; • Reversible inhibitor AChE; piperidine • No heptatoxicity • Highly protein bound = long half life • Once daily dosing • Simple titration • Cytochrome P450 system • Long term may up-regulate levels of AChE in CSF leading to decline in efficacy • Least GI side effects

  29. Rivastigmine (Exelon) • Slowly reversible inhibitor of AChE and BuChE; • G1 AChE selective (found in hippocampus and cerebral cortex) • Metabolized by target enzymes; not P450 • Low protein binding, bid dosing • More complicated titration • No up-regulation reported • Greatest GI side effects

  30. Galantamine (Reminyl) • Phenanthrere from Daffodil stamen • Low protein binding, BID dosing • More complicated titration • Inhibits AChE & modulates nicotinic receptors • P450 metabolism • Metabolite, sanguinine, 3x power of parent compound • Intermediate GI side effects

  31. AChEI long term benefits

  32. Head to Head Trials The Evidence is Lacking MMSE mixed differed End points different

  33. Rivastigmine v Donepezil • 12 week trial, 111 patients, mild to moderate disease • Donepezil better tolerated • Similar cognitive and functional outcomes • Too short to really titrate rivastigmine to most effective dosing Wilkinson DG. Int J Clinic Pract Jul 02; 56(6): 441

  34. Galantamine vs. Donepezil • 12 week trial • Donepezil better on cognitive and functional measures • Short term and galantamine requires slower titration to maximize dosing

  35. Galantamine vs Donepezil • Rater blinded, randomized, 12 month, open label, parallel group comparison • Galantamine 8 – 24 mg/d • Donepezil 5 – 10 mg/d • MMSE remained above baseline for 11 months for galantamine v 6 months for donepezil • No difference in functional measures McKeith, I Neurology 2003; 60 Suppl 5 A 141

  36. Several years later • Stanley has remained remarkably stable since starting an ACHeI. • On this f/u visit, his daughter relates more forgetfulness and decreased abilities • MMSE 12/30 • Daughter “Should we continue the medication? Do we have any other options?”

  37. New Kid on the Block

  38. NMDA receptor antagonist Studies focus on function Oral, 100 % bioavailable Minimal metabolism with 57-82 % eliminated unchanged in urine Does not inhibit P-450 Namenda (memantine)

  39. Stabilized at baseline for 12 weeks. Always above placebo Namenda

  40. Namenda dosing

  41. Add on to Donepezil • 404 patient MMSE 5-14 on Donepezil • Randomized to Memantine or placebo in addition to Donepezil • Additional improvements or stabilization in cognition, ADLs, behaviors compared to Donepezil alone Tariot, P. JAMA Jan 04: 291; 317-324

  42. Time Marches On • MMSE 10/30 • Decreased ADLs, incontinent • Moved into a Skilled Nursing Home

  43. FAQ • AChEI in late stages • Already in Nursing Home • One AChEI loses efficacy • Other dementias • Namenda in early ATD

  44. Donepezil in Advanced Disease • One double blind study and one case report demonstrate efficacy for Donepezil in advanced disease (MMSE 11) • Improvements seen in behaviors & ADLs • More long term studies on going • My take: use these meds for patients with MMSE > 10 or in those still independent in some ADLs • Ambulation, continence, feeding, initiation of activities Feldman, H. Neurology; 57: 613 Tariot, P. JAMDA; July 2003: 216

  45. Other studies in Mod-Severe ATD • Rivastigmine • 58 % improvement in irritability, aberrant behavior, apathy, hallucinations, disruptive night time behavior, agitation, delusions • Galantamine • MMSE 12; 6 month trial • Cognitive and functional improvements compared to placebo Cummings JL. Neurolgy 2000; 54: A469 Wilkinson DG Int J Clini Prac 2002; 56(7); 509-14

  46. Donepezil in the Nursing home • 208 pt, Mean MMSE 14, frequent behavior problems • 24 wk, placebo, blinded study • Results • Only improvement seen in agitation/ aggression • 61 % concomitant psychotropic • Stabilized MMSE compared to placebo • Overall improvement in function in facility Tariot P. JAGS 2001: 49; 1590-9

  47. Donepezil to maintain ADLs • 290 patients in Community or Assisted living, 24 weeks • Mean MMSE 12 • Psychotropics allowed but stable dosing • Improvement or stabilization of function compared & cognition to placebo • Care givers benefited ~ 1 hr/day Feldman H. Neurology 2001; 57: 613

  48. Rivastigmine after Donepezil • 382 outpatients (MMSE 16) on donepezil changed to rivastigmine in open labeled trial • 78 % changed due to lack of efficacy, 3 point decline in MMSE • Improvements seen in cognition, ADLs, behaviors over baseline

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