New treatment trends in alzheimer disease

NEW TREATMENT TRENDS IN ALZHEIMER DISEASEGUIDE: DR.APOORVA PAURANIKCANDIDATE: 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 RIVASTIGMINE

GALANTAMINE

MEMANTINE

Chemical class

piperidine carbamate phenanthrenealkaloid

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

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