Drug treatment of alzheimers disease


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Recent advances in treatment of Alzheimers disease

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  • THE neuropathologic features of Alzheimer’s disease include the accumulation of microglia around plaques, a local cytokine-mediated acute-phase response, and activation of the complement cascade.This inflammatory response may damage neurons and exacerbate the pathologic processes underlying the disease.Nonsteroidalantiinflammatory drugs (NSAIDs) may influence this inflammatory response by inhibiting cyclooxygenase- 1 and cyclooxygenase-2 and by activating the peroxisomeproliferatorg (PPAR g ) nuclear transcription factor.In addition, cyclooxygenase-mediated oxidation is important in the calcium-dependent glutamate signaling pathway that involves N -methyl- D -aspartate. In this way, NSAIDs may be able to protect neuronsdirectly by reducing cellular responses to glutamate.The results of observational studies have been inconsistent with regard to the association between NSAIDs and Alzheimer’s disease.Some have suggested a protective effect, whereas others have not. In almost all the studies, information on NSAIDs was obtained retrospectively from patients or relatives or from medical records. These methods are vulnerable to misclassification
  • In 1901, Alzheimer observed a patient at the Frankfurt Asylum named Auguste Deter. The 51-year-old patient had strange behavioral symptoms, including a loss of short-term memory. This patient would become his obsession over the coming years. In April 1906, Mrs. Deter died and Alzheimer had the patient records and the brain brought to Munich where he was working at Kraepelin's lab. Together with two Italian physicians, he would use the staining techniques to identify amyloid plaques andneurofibrillary tangles. A speech given on 3 November 1906 would be the first time the pathology and the clinical symptoms of presenile dementia would be presented together.
  • memory loss is the first feature of the diseaseLoss of cholinergic neurons in the hippocampus and frontal cortex is feature of the disease And is thought to underlie cognitive deficit and loss of short term memory They also appear in normal brains although in small numbers
  • Cleavage of APP at different sites gives rise to AB , predominant form being AB-40 which is weakly amyloidogenic , mutations in APP or presenilins increase proportion of APP which is degraded via amyloidogenic pathway and also increased proportion converted to much more amyloidogenic AB-42
  • Cholinergic deficiency contributes to cognitive decline in ADIt may contribute to behavioral symptoms of ADPsychosis-agitationApathy-indifferenceDisinhibitionAberrant motor behaviorAtrophy of the nucleus basalis of Meynert, the source of cholineacetyltransferase, causes deficit Cholinergic therapy may partially improve behavioral symptoms of AD Cholinergic therapy does not interrupt the disease process
  • First second generation reversible cHE- inhibitor Recently FDA has also approved 23 mg extended release tablet of Donepezil for treatment of moderate to severe alzheimers disease
  • Newer second-generation cholinesterase inhibitor
  • Increased uptake of choline and acetic acid for synthesis Increased resynthesis of acetyl choline
  • Switching is a relatively new concept in AD treatmentMany physicians stop ChE inhibitor treatment altogether if patient fails to show response or loses response to current agentHowever, evidence suggests that switching between ChE inhibitors represents a valuable therapeutic option to maximize treatment benefits over a longer periodThe availability of multiple ChE-Is presents the practitioner with the option of switching from one to another. Co-administration of two ChE-Is has not been studied and is not recommended. Two studies had addressed switching from donepezil to rivastigmine. In an open-label study of patients who were intolerant of donepezil or who declined cognitively or functionally despite donepezil therapy, 56% experienced improvement or stabilization on a global measure and 50% evidenced a 1-point improvement or stabilization on the MMSE with rivastigmine (73). Poor tolerability with donepezil did not predict poor tolerability to rivastigmine. Similarly, in a survey of practitioners in British memory clinics, Bullock and Connolly (74) found that 55% of patients switched from donepezil to rivastigmine were reported to have improved. A post-hoc analysis found that patients switched to galantamine from another ChE-I had the same average magnitude of response as patients without previous ChE-I treatment (75). No Class I evidence is available on switching effects and adverse events.The optimal procedure of switching from one ChE-I to another is controversial. Zero- to 7-day drug-free periods have been suggested when switching from donepezil (76), but several experts have recommended switching with no interruption of therapy (77—79). This recommendation, however, has been contested, since it represents co-administration of two ChE-Is. Given the long half-life of donepezil; additive toxicity is possible (80). A conservative strategy suggests that when switching from one agent to another, cessation of therapy for five half-lives using the terminated agent will minimize the opportunities for adverse drug interactions. Thus, patients should be off donepezil for 15 days and off rivastigmine or galantamine for 2 days before initiating therapy with the subsequent ChE-I.Indications for switching include allergic responses, unmanageable side effects, family preference, and unmitigated cognitive decline after at least a 6-month trial of treatment.
  • A phenomenon called excitotoxicity such excitotoxicity ultimately leads to calcium overload and apoptotic cell death
  • Ketamine which causes dissociative anaesthesia
  • Minimal CYP450 INTERACTION
  • Coughing , dyspnoea, UTI, INSOMNIA, diarrhoea, bronchitisMild and reversible adverse effects
  • Ketamine high affinity block
  • Another therapeutic option to increase cholinergic function is to administer nicotinic receptor agonist
  • Aged garlic extract Vitamin E study compared effect alone and together with selegeline against placebo Improvement in outcome like time to death
  • Physiological mode of action: Attributed to a combination of the flavonoid glycosides and the diterpene lactones (ginkgolides).
  • Treatment with ginkgo increases the production of NO (nitric oxide) through NOS (nitric oxide synthase).NO increases the activity of KCa channels and invokes the influx of Ca2+ into endothelial cells.This mode was double checked against a known Ca2+ channel blocker (TEA) and inhibited the effects of ginkgo.Ginkgo does not affect ATP K+ channels.
  • Novel strategy to already existing treatment paradigm Peroxisomeproliferator activated receptor are family of nucleur receptors play important role in lipid peroxidation, cellular proliferation, differentiation PPAR gamma is a ligand activated transcription factor which plays important role in lipid metabolism and inhibits inflammation
  • IDENTITY – XT Trial: includes patients who have completed one of two studies17 august 2010
  • Favourable effect on synaptic Plasticity Dimeboline also interacts with NMDA receptors , ACHE and voltage gated calcium channels Produces acute enhancement of short term social recognition memory How ever phase 3 connection study in mild to moderate AD fail to meet primary and secondary end points as compared to placebo
  • DESFERRIOXAMINE AFTER 2 YRS ALSO DECREASED THE AL LEVELSRECNTLY NANO PARTICLES: CONJUGATED TO CHELATORS HAVE A UNIQUE ABILITY TO CROSS BBB CHELATE METAL COMPLEX AND EXIT THROUGH BBB with the complex . This novel technique may be able to stave off the harmful effects of oxidative damage done by metal ions in Alzheimers disease Clioquinal is metal chelating agent also amoebicidal drug , itself has toxic effects in human which preclude routine clinical use Less toxic metal chelating agents are under development
  • The transgenic mouse, whichoverexpresses mutant human APP (in which the aminoacidat position 717 isphenylalanineinstead of the normal valine), progressivelydevelopsmany of the neuropathologicalhallmarks of Alzheimer’sdisease in an age- and brain-region-dependentmanner.
  • Cause of vasculits is not known same fate Elan pharmaceuticals
  • Antibodies bind to beta amyloid and clear it from the body
  • Solanizeumab
  • Drug treatment of alzheimers disease

    1. 1. Drug treatment of Alzheimer`s disease Dr Naser Tadvi Associate Professor, Pharmacology KIMS, Narketpally
    2. 2. Objectives• Introduction• Pathophysiology of Alzheimer`s• Drugs used in treatment of Alzheimer`s – Approved drugs • Cholinesterase Inhibitors • Memantine – Experimental drugs (Under evaluation) • Nicotinic receptor agonists • Gamma secretase inhibitors • Others: – 5 HT6 antagonists, Statins, NSAIDS, PPAR Agonists, Heavy metal chelators, estrogen , Antioxidants
    3. 3. Introduction• Alzheimers Disease (AD) is a devastating neurodegenerative disorder manifested by – detoriation in memory and cognition – Impairment in performing activities of daily living – Behavioural and neuropsychiatric disturbances• Most common form of dementia in old age• Risk of AD ↑es with age but AD is not a part of normal ageing
    4. 4. Introduction• Alzheimers disease was first described by German Physician Dr Alois Alzheimer in 1906
    5. 5. Symptoms of Alzheimer`s Disease• Language problem – Cannot find right word or name for familiar person, object, place• Loss of recent memory• Loss of sense of time and place• Decline in activities of daily living• Personality changes
    6. 6. Pathogenesis of Alzheimers• Two microscopic features are characteristic of Alzheimers`s disease – Extracellular amyloid plaques • Consisting of amorphous extra cellular deposits of A protein – Neurofibrillary tangles • Comprising of filaments of phosphorylated Tau protein
    7. 7. Pathogenesis of alzheimers Disease
    8. 8. Pathogenesis of Alzheimers
    9. 9. Targets of drug action for AD
    11. 11. Cholinergic Hypothesis• Role – Acetylcholine (ACh) is an important neurotransmitter in brain regions involved in memory• Impact – Loss of ACh in AD correlates with impairment of memory• Treatment approach – Enhancement of cholinergic function may stabilize or improve cognitive function and may affect behavior and daily functioning
    12. 12. Tacrine• Aminoacridine• Dose dependent effect: 40 mg-160 mg/day• Half life : 3-5 hrs• Metabolized by CYP450• Adverse effects: – Nausea, vomiting, diarrhoea – Hepatotoxicity• No longer actively marketed
    13. 13. Donepezil• Long plasma half life – 70 hrs• Dose- 5 -10 mg daily• Several controlled trials have shown modest benefits in cognition and behaviour• Not hepatotoxic• Adverse effects: Nausea, diarrhoea, vomiting, fatigue, muscle cramps, bradycardia• Generally safe & well tolerated
    14. 14. Rivastigmine• Higher affinity for brain AcHE than peripheral• Inhibits both acetylcholinesterase & butrylcholinesterase• Half-life of 2 hours• Dosing (bid) of 3 to 12 mg/day• Patch 9.5 mg/24 hr available• Metabolism is almost totally independent of the hepatic cytochrome P450 system• Gastrointestinal adverse events are common, including weight loss
    15. 15. Galantamine• Galantamine has a dual mechanism of action – Competitive inhibition of acetylcholinesterase1 – Allosteric modulation of presynaptic and postsynaptic nicotinic receptors• Galantamine improves major aspects of AD (eg, cognition, behavior, function)• Galantamine is generally safe and well tolerated
    16. 16. Chemistry: a tertiary alkaloid , natural or synthetic.extracted from bulbs of the Amaryllidaceae family(snowdrops, daffodils)
    17. 17. Dual Mechanism of Action Presynaptic nerve N = nicotinic terminal M = muscarinic ACh = acetylcholine M receptor N receptor Galantamine Galantamine • Choline ACh and other ACh • Acetic acid neurotransmitters Postsynaptic M receptor N receptornerve terminal
    18. 18. Galantamine: Potential Advantages of Nicotinic Receptor Modulation • May increase release of Ach in synaptic cleft • Increased resynthesis of Ach by increasing uptake of choline • May have a neuroprotective effect
    19. 19. Galantamine Safety (cont) Galantamine Galantamine Placebo 16 mg/day 24 mg/day (n = 286) (n = 279) (n = 273) Adverse events* (%) (%) (%) Nausea 4.5 13.3 16.5 Vomiting 1.4 6.1 9.9 Anorexia 3.1 6.5 8.8 Agitation 9.4 10.0 8.1 Diarrhea 5.9 12.2 5.5* 5% of patients receiving galantamine andmore often than in patients receiving placebo.
    20. 20. ChE Inhibitors: Pharmacokinetic Characteristics Dual AChE/ AChE Inhibitors BuChE InhibitorCharacteristic Donepezil Galantamine RivastigminePlasma half-life (hour) ~70 ~6 ~1Brain half-life 70 6 12Elimination 50% kidneypathway Liver 50% liver KidneyMetabolism by2D6/3A4 isoenzymes Yes Yes MinimalAdminister with food? No Yes Yes
    21. 21. Drug Type of inhibition Duration of action and Side effects dosageTacrine ∼6 h Cholinergic side Not CNS selective 2-3 times daily oral effects hepatotoxicity dosage Monitoring for hepatotoxicity neededDonepezil CNS, AChE ∼24 h Slight cholinergic side selective Once-daily oral dosage effectsRivastigmine CNS selective ∼8 h Cholinergic side Twice-daily oral dosage effects that tend to subside with continuing treatmentGalantamine Affects both AChE ∼8 h Slight cholinergic side and BuChE Twice-daily oral dosage effects Also enhances nicotinic ACh receptor activation by allosteric action
    22. 22. Guidelines for Switching ChEIs Donepezil or galantamine Donepezil or rivastigmine to rivastigmine to galantamine Unsatisfactory treatment Is the patient on donepezil 7-day washout is stabilized on current recommended or therapy (ie, no NO Patient experiencing until symptoms Safety or tolerability tolerability lack of response or resolve problem problems)? loss of efficacy YES Washout for 7 days or No washout period until symptoms resolve No washout period required required Initiate rivastigmine therapy at 3 mg daily (1.5 mg twice Initiate galantamine therapy at daily) 8 mg daily (4 mg twice daily) Minimum of 4 weeks 4 weeks Monitor patient for efficacy, safety, and tolerability, Monitor patient for efficacy, safety, and tolerability, as as with standard dosing guidelines with standard dosing guidelines Escalate dose to 16 mg daily (8 mg twice daily) andEscalate dose to 6 mg daily (3 mg twice daily) and recheck in 4 recheck in 4 weeks weeks*
    23. 23. NMDA receptor antagonists• Glutamate is principal excitatory neurotransmitter in brain• Which acts on post synaptic NMDA receptors• Glutaminergic overstimulation may result in neuronal damage (excitotoxicity)• Implicated in dementia and pathogenesis of Alzheimer`s disease• Memantine is NMDA receptor antagonist
    24. 24. Memantine (Mechanism of action)• NMDA receptor antagonist approved for treatment of moderate to severe AD – Uncompetitive – low affinity – voltage dependent – Interacts with Mg2+ binding site of channel to prevent excessive excitation while sparing normal functions
    25. 25. Memantine (Pharmacokinetics)• 100 % bioavailability• T ½ = 60-80 hrs• Rapidly crosses Blood brain barrier• Undergoes little metabolism 75% -90% excreted unchanged in urine• Minimal drug interactions and food interaction• Starting dose – 5 mg OD , recommended target dose is 20 mg/day
    26. 26. Memantine (Adverse effects)• Dizziness• Headache• Confusion• Constipation• Agitation
    27. 27. Other NMDA receptor antagonists• Remacemide – Low affinity blocker – Approved for treatment of epilepsy• Riluzole – Used in treatment of Amyotropic Lateral Sclerosis• Newer glutamate antagonists in development – L-701252 – LY-235959 – WIN-634802
    28. 28. Recent advances in Alzheimer`s treatment
    29. 29. Nicotinic receptor agonists• 4 2 & 7 nicotinic receptor types localized in areas of brain associated with dementia and memory loss• 7 nicotinic receptor agonist : – 4 OH-GTS21 • Protective action on cholinergic neurons • Antiamnestic effect in Alzheimers disease type amnesia – EVP-6124: Currently in phase2
    30. 30. Antioxidants• Recent research has found link between antioxidant intake and decreased incidence of Alzheimers – Garlic extract – Curcumin – Ginko biloba – Vitamin E – Green tea
    31. 31. Ginko Biloba• Ancient use in China and Japan as a tonic. – Poor Circulation – Inner ear disorders – Absent- mindedness, Dementia, Depressio n, and Hypertension in the elderly – Impotence in men• Chinese used leaves and nuts• Use dates back over 5000 years
    32. 32. Physiologic Mode of Action Cont’d• Acts by releasing nitric oxide & PGI2• ↑ blood flow throughout the circulatory system & hence ↑oxygen & nutrient delivery to the tissues including brain .• ↓ blood viscosity• ↑ in the release of neurotransmitters• Antioxidant activity• Prevention of free radical damage
    33. 33. Side effects• hemorrhage, hematoma (rupture of blood vessels), and hyphema (bleeding in eye).• In all trials <0.5% reported minor side effects including headaches, GI distress and allergic skin reactions.• Overall, ginkgo is relatively safe.
    34. 34. PPAR agonists• PPAR agonists inhibit inflammatory gene expression , alter Amyloid homeostasis & exhibit neuroprotective effects• 15-30 mg pioglitazone daily in patients of AD – Improved agitation & regional cerebral blood flow in parietal lobe – cognitive and functional improvement
    35. 35. Gamma Secretase Inhibitors• Disease modifying agents in AD• Semagacestat – ↓ plasma and CSF A- Concentration – Phase 3 started in March 2008 • Interrupting Alzheimers Dementia by Evaluating Treatment of Amyloid Pathology (IDENTITY -1 Trial) – IDENTITY -2 trial started in September 2008 • Did not slow disease progression & worsened cognition and the ability to perform activities of daily living • ↑risk of skin cancer • Eli Lily halted the development
    36. 36. 5-HT6 receptor antagonists• SB-271046 – Enhanced retention of learned position in AD experimental models – No effect on learning during training phase – ↑Neuronal Cell Adhesion Molecular (NCAM) Polysialation : contributes to learning & increased dendritic remodelling in CNS• Dimeboline: antihistaminic from Russia – In phase III for Alzheimer`s Disease
    37. 37. Statins• Higher Cholesterol risk factor for AD• Lovastatin prevented death of nerve cells in animal experiments• Results of various studies not promising• No difference between drug and control in terms of dementia, cognitive function and neuropsychological tests
    38. 38. Heavy metal chelators• Amyloid beta plaques bind copper and zinc & removal of these metal ions promotes dissolution of Plaques• Levels of iron & zinc abnormally ↑ in brain in AD• Desferrioxamine : ↓ dementia in a trial• Clioquinal: regression of Amyloid plaques in animal models of AD
    39. 39. Estrogens• AD more common in postmenopausal women• Estrogen – Modulate ApoE gene – ↑ APP metabolism – Protects against oxidative stress – ↑cerebral blood flow & prevent neuronal atrophy• Clinical trials are inconclusive
    40. 40. NSAIDS• Inhibit COX enzymes – ↓production of cytokines , & microglial activation – ↓ platelet aggregation – ↓ iNOS – ↓ beta secretase• Only Ibuprofen and Indomethacin have demonstrated clinical benefit in Alzheimer`s disease
    41. 41. Immunization for Alzheimers disease?• In one study, transgenic animals were immunized with A 42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid- déposition and several of the subsequent neuropathological changes were well established.
    42. 42. Immunization for Alzheimers disease?• immunization of the Young animals essentially prevented the development of -amyloid plaque formation, neuritic dystrophy and astrogliosis.• Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies.• Hence the possibilty possibility that immunization with amyloid-b may be effective in preventing and treatingAD
    43. 43. TYPES OF VACCINATION αβ peptide with adjuvant Anti- αβ antibodyA) Active immunization Anti- αβ AntibodyB) Passive immunization
    44. 44. Active immunization• Acute meningoencephalitis: drug withdrawn• ACC-001:
    45. 45. Conclusion for first immunotherapy tests Although immunisation with Aβ42 resulted in clearance of amyloid plaques in patients with Alzheimer’s disease, this clearance did not prevent progressive neurodegeneration. IMMUNOTHERAPY CAN BE ALWAYS A GOOD WAY FOR TREATMENT OF ALZHEIMER DISEASE? 47
    46. 46. Passive immunization Monoclonal antibodiesHow to avoid meningoencephalitis symptoms ? Anti- αβ Antibody 48
    47. 47. BAPINEUZUMAB WHAT IS A –ZUMAB ? of mouse humans 1994- 1975 1999 …momab …mumab chimerics humanized 1988- 1984 1991 …ximab …zumab HUMANIZATIONImmunogenic +++ less immunogenics 49
    48. 48. Mechanism of action
    49. 49. Safety Results 94 % Bapineuzumab 90 % mild to moderateMost patients reported Adverse Effects in severity 90 % PlaceboAEs occuring >2 times as often as placebo rate and seen in >5% of bapineuzumab patients Back pain 12,1% vs 5,5% Weight loss 6,5% vs 1,8% Anxiety 11,3% vs 3,6% Paranoia 6,5% vs 0,9% Vomiting 9,7% vs 3,6% Skin laceration 5,6 % vs 2,7% Vasogenic Edema 9,7% vs 0% Gait disturbance 5,6% vs 1,8% Hypertension 8,1% vs 3,6% Muscle spasms 5,6 % vs 0,9%
    50. 50. Conclusion• AD is one of the most debilitating diseases affecting the old age• Clear benefit for treatment of symptoms in mild to severe AD using AcHEIs & memantine is seen• Also there is cautious optimism for sucessful disease modification using number of agents currently under study