New treatment trends in alzheimer disease
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New treatment trends in alzheimer disease

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Alzheimer disease new treatment trends

Alzheimer disease new treatment trends

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New treatment trends in alzheimer disease New treatment trends in alzheimer disease Presentation Transcript

  • NEW TREATMENT TRENDS IN ALZHEIMER DISEASE GUIDE: DR.APOORVA PAURANIK CANDIDATE: DR.SARATH MENON.R Dept. of Neurology, MGM MEDICAL COLLEGE,INDORE
  • OUTLINE  Treatment of AD  Treatment of secondary symptoms  Experimental therapy  Dietary measures  Social support  Prevention
  • ALZHEIMER DISEASE  Most common cause for dementia  24 milions has the disease at present  Incidence doubles every 5 yr after age of 60.
  • RISK FACTORS FOR ALZHEIMER’S DISEASE  Age  Family history  Lifestyle Physical exercise Mental exercise Diet Tobacco Head injury  Hypertension  Elevated serum cholesterol  Elevated serum homocysteine
  • PATHOPHYSIOLOGY  Beta amyloid plaques  Neurofibrillary tangles (NFT)  Amyloid formed from APP (amyloid precursor protein) by secretase  NFT - silver stained fibrils of abnormally phosporylated Tau protein
  • BIOCHEMICAL CHANGES  Decrease in cortical level of Acetyl choline,choline acetyl transferances,nicotinic receptors  Degeneration of cholinergic neurons in nucleus basalis of Meynert.  Degenertion of loculus ceruleus & dorsal raphe - noradrenergic & serotonergic depletion
  • CASCADE OF MECHANISM Amyloid inflammation abnormal tau phosphorylation free radical toxicity synaptic loss
  • CASCADE OF MECHANISM cholinergic dysfunction neuronal loss norepinephrine dysfunction serotonergic dysfunction
  • CURRENT TREATMENT
  •  Symptomatic - Cognitive - Behavioral
  • TREATMENT OF MILD-MODERATE AD  Choline esterase inhibitors - Donepezil - Rivastigmine - Galantamine  Improves cognition & daily activities
  • TREATMENT OF SEVERE AD  NMDA antagonists - Memantine  Slows intracellular Ca accumulation and delay nerve damage  Used in combination with Donepazil
  • DOSAGE  Donepezil – 5mg/day x 4-6 wks,then 10mg/d to max.tolerated dose. min dose-5mg/d  Rivastigmine – 1.5mg bd,then step up monthly to 6mg bd(max). min.dose-6mg/  Galantamine- 8mg/d,monthly increase to 16mg/d 24 mg/d (max). min dose- 16mg/d  Memantine – 5mg daily,in a week then 5mg Bd 15mg/d- (5 & 10), max dose-10mg bd
  • CURRENT AVAILABLE THERAPY characteristic DONEPAZIL RIVASTIGMIN E GALANTAMIN E MEMANTINE Chemical class piperidine carbamate phenanthrenea lkaloid Similar to amantadine Primary mechanism AchE inh AchE inh AchE inh NMDA antagonist Other mechanism None None Nicotine modulator HT3 receptor antagonist Half life 70 h 90 min 7 h 70 h Metabolism Hepatic Renal Hepatic Hepatic
  • Combined clinical trial data for the three licensed acetylcholinesterase inhibitors: rivastigmine (♦), donepezil (▴) and galantamine (•) versus placebo (▪). BULLOCK R BJP 2002;180:135-139 ©2002 by The Royal College of Psychiatrists
  • CURRENT STATUS OF ACHE INHIBITORS  Effective in 6 month & 12 month trials  Early initiation of therapy  Delay institutionalization  Decrease troublesome behaviours
  • TREATMENT OF SECONDARY SYMPTOMS  Behavioural intervention  Neuroleptic agents - FDA in 2005 black box warning for atypical neuroleptics - 2008 , haloperidol,chlorpromazine, thioridazine included -CATIE-AD study showed cognitive decline with atypical neuroleptics -recommended in low doses in frail, elderly
  •  Antidepressants & mood stabilizers -citalopram ( Nyth et al study) - 20 mg /day in elderly ,max-40mg - sertaline & fluvoxetine – no benefits (Wintraub & Petrecca et al study) - mirtazipine has no benefial effect ( Banerjee et al)  Anticonvulsants - gabapentin,valproate can be used
  •  Anti inflammatory agents - NSAIDs delay onset of AD - Breitner et al showed NSAIDs don’t protect against AD in very old  A double blind,placebo controlled trial ( Grundman et al 2003) showed rofecoxib & naproxen don’t delay AD progression
  • EXPERIMENTAL THERAPY
  •  Anti amyloid therapy - vaccination with amyloid species - monoclonal anti amyloid antibodies - IVIG containing amyloid binding antiboies - selective amyloid lowering agents - chelators of amyloid polymerization - beta secretase inhibitors  Till date no phase 3 trials for anti amyloid therapy shown acceptable efficacy
  • VACCINATION  Anti Abeta immunotherapy reduces amyloid deposition and improved spatial cognition in mice  Clinical trial in 298 patients with AD:18 developed inflammatory meningoencephalitis: study halted  Autopsy in one: “less amyloid than expected” Orgogozo J-M et al Neurology 2003;61:46 Mathews P & Nixon R Neurology 2003;61:7
  • VACCINATION  In subgroup of 30 patients, those who generated Abeta antibodies had reduced disease progression  Attempts being made to reformulate vaccine  Passive immunization considered Hock C et al.Neuron 2003;38:547 Wolfe MS. Nat RevDrug Discov 2002;1:859
  • ANTIBIOTICS FOR AD  Higher than normal titres of Chlamydia in people with AD  Multicentre Canadian double blind placebo controlled RCT  101 patients with mild to moderate AD (MMSE 11- 25)  Daily doxycycline 200mg plus rifampin 300mg or placebo for 3 months
  • ANTIBIOTICS FOR AD  Standardized ADAS Cog @ 6 months difference of 2.75/70 between treated and placebo group (significant @ 6 but not 12 months)  Standardized MMSE score 2.2/30 higher @12 (but not 3 or 6) months  Intriguing results!  Larger study in planning stages Loeb M, Molloy DW et al JAGS 2004;52:381
  • SECRETASE INHIBITORS  Inhibit production of Amyloid  Tarenflurbil and Semagacestat.  Two placebo controlled trials showed no efficacy
  •  Reversal of excess Tau phosphoryation  Free radical scavengers - vitamin E – reduce oxidative stress - high dose Vit E (2000U/day) for 2 yr slowed progression of AD ( large double blind placebo trial ,Sano etal 1997) - Alzheimer Disease Cooperative Study ( 769 pts) showed no benefit vs placebo (Peterson etal 2005) - cause cardiovascular side effects - not recommended currently
  •  Estrogen replacement therapy - postmenopausal woman - RCT with 351 pts for 2 weeks showed no beneficial effects  Cholesterol lowering agents -no beneficial effects - RCT,double blinded study with 748 pts for 6 months failed to prove efficacy
  • LIPID LOWERING AND AD  Previous observations suggested lower risk of AD in those taking “statins”  Recently presented at 8th International Symposium on Advances in AD therapy  Atorvostatin treatment associated with less decline in memory, function, mood & behaviour in people with AD  Premature to decide until full details available in peer reviewed publication
  • ONGOING TRIALS  Tramiprosate (Alzhemed) - homotaurine - binds to soluble & insoluble Abeta and in reduction - protect against amyloid neurotoxicity - reduce tau abnormal phosphorylation  RCT, double blind,placebo conrolled trial (2009)
  •  Cerebrolysin - peptidergic drug from purified pig brain - neurotrophic & neuroprotective  RCT,double blind, placebo controlled trial (2010)  Latreperidine(Dimebom) - anti histamine - inhibit burylcholine esterase, AchE, NMDA signalling pathway RCT, phase 3 trial ongoing ( jan 2011)
  • CLINCAL TRIALS - COMPLETED  Selegelline RCT trial conducted in 2010 failed to give promising results  Nimodipine - prevent Ca accumulation in neurons - cause vasodilation - RCT in March 2010 in 500 pts showed positive results - given 90mg/d & 180mg/d for 12,24,52 weeks - improves cognition & global impression
  •  Metal protein attenuating compound(MPAC) (clinoquinol) - solubilize & clearance of Abeta - RCT,double blind study with 36 pts has no change in ADAS Cog @ 36 wks.  Mertrifonate - irreversible AchE inhibitor - RCT, double blinded phase 3 study - 60-80mg/d for 26 weeks showed improvement MMSE-1.86/30 & ADASCog- 3.24/70
  •  Lecithin - major source of choline - RCT,double blind placebo controlled study failed to show efficacy
  •  Huperzine A from chinese club moss Huperzia serrata reversible AchE inhibitor RCT, double blinded Chinese study with 482 pts showed improvement in MMSE-2.8/30 & ADASCog -1.91/70 @ 6 wks
  •  Transcutaneous electrical nerve stimulation (TENS) - change neurotransmitters,help in neuro regeneration - 3 RCT in Netherland & Japan - duration,waveform,current amplitude, - data limilted ,shows little improvement
  • STEM CELL THERAPY  South Florida university with Cryo- cell International  Mouse model study in 2009  Several infusions of stem cells from umblical cord  Myeloid protein reduced by 62%  Cerebral amyloid angiopathy by 82%  Hope to begin human trials by 2014.
  •  Neural growth factor (NGF) -Injecting into spinal cord - trials going to formulate oral preperation - still on pipe line.
  • DIETARY MEASURES  No special diet for AD  Axona (caprylidine) improves cognition
  • PREVENTION OF AD  Omega 3 fatty acids - French study(2005) showed decrease in risk of AD in elderly > 60 yr - 2 RCT double blinded studies are ongoing  Mediterranean diet  Light to moderate alcohol -Finnish study showed no beneficial effects
  • Who are the AD Caregivers? • Spouses – the largest group. Most are older with their own health problems. • Daughters – the second largest group. Called the “sandwich generation,” many are married and raising children of their own. Children may need extra support if a parent’s attention is focused on caregiving. • Grandchildren – may become major helpers. • Daughters-in-law – the third largest group. • Sons – often focus on the financial, legal, and business aspects of caregiving. • Brothers and Sisters – many are older with their own health problems. • Others-friends,relatives Support for Caregivers Slide 37
  • Technology and Caregiving The NIA is studying how computers can provide information and support to family caregivers through: These features have become very popular among users because they reach many people at once, are private and convenient, and are available around the clock. • computer-based bulletin boards • chat rooms • Q & A modules • medical advice forums Support for Caregivers
  • CONCLUSION  Most common dementing disease worldwide  Pschyco-social,economic burden  Current therapy is symptomatic and limited  New clinical trials & treatment approaches on pipeline  Social support for caregivers & alzheimer support societies .
  • REFERENCES  Harrisons internal medicine – 18 th edition  www.clinicaltrials.gov  www.thecochranelibrary.com  www.alzheimers.org  www.alz.org  www.nia.nih.gov
  • THANK U….