Most Common Type Of Dementia Biology Essay

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Alzheimers disease is the most common type of dementia. This Alzheimers disease named on scientist Dr.Alois Alzheimer in 1906 because first time Dr.alzheimer noticed the disease in one woman. Alzheimer's disease mental disorder due to the loss of nerve impulses like nerves in various part of brain. Alzheimer disease uniformly attack males and females. There is no difference on gender affect.

Mainly Alzheimer's disease an age-related neurodegenerative disorder. Means disease affect after the age 60 years, Alzheimer's disease mainly is an adult disease. Alzheimer's disease enhances with age, in total population 10-20% affecting over 80 years aged.

This is a disease which slowly progressive and slowly lost of neurons means neurodegenerative disorder. Alzheimer's disease one of the high economically costly disorder.

THE ALZHEIMER'S DISEASE DIVIDED INTO BELOW STAGES BY THOSE SYMPTOMS:

Alzheimer's disease mainly divides by three stages, because mechanism of formation of tangles and plaques in brain and causes brain damage. In this way different symptoms appeared.

A) MILD STAGE AD:

As increase of Alzheimer's disease, Memory loss continues and changes in other cognitive abilities occurred. Trouble handling money and paying bills, repeating questions, taking longs to finish normal daily tasks, poor decisions and small mood and personality changes.(ADEAR)

B) MODERATE STAGE AD:

In this division, damage happens in areas of the brain that dominated language, reasoning, sensory processing, conscious thoughts. Memory loss and confusion increase and people start to have problems in find family members and friends. Difficult to learn new things, they may have hallucination.(ADEAR)

C) SEVERE STAGE AD:

This is almost final stage means in this situation patient brain completely damaged due to the spread of plaques and tangles throughout the brain, causes person may be in bed most time as the body shut down.(ADEAR)

1.2) CAUSES OF DISEASE:

Mainly in Alzheimer's disease, three genes are involved to causes the disease,

Three genes are,

1,APP(Encoding amyloidal beta A4 precursor protein) located on chromosome 21.

2. Presenilin 1(PSEN1) which located on chromosome 14.

3. Presenilin 2 (PSEN2) which located on chromosome 1.

When mutation occurs in APP, PSEN1, PSEN2 genes, there are chances of disease occurrence in the subject; these get forwarded as an autosomal dominant trait with entire pen trance around age 60 years.

1) The APP717 VAL->lle mutation is commonly found in the gene APP.

2) Also mutation found in presenilin 1 and presenilin 2 genes which are located on chromosome 14 and chromosome 1

Alzheimer's disease initially thought to be due to the decreased synthesis of acetyl choline was found due to above genetic mutations on APP, PSEN 1, PSEN 2 (Alexis Brice,2002-2004).

1.3) MECHANISM OF ALZHIEMER'S DISEASE:

Alzheimer's disease is an irreversible damage of brain means it's destroy the brain irreversibly.

Main mechanism:

In Alzheimer's disease, damage of brain, due to two main features or two abnormal clumps formation.

1. Plaques

2. Tangles

These clumps, when found in brain parts, definitely it causes damage of brain.

a)Alzheimer's disease adult disorder. In damage of brain, first tangles begin to develop deep in the brain part called as entorhinal cortex and plaques form in other part of brain .As much as tangles and plaques develop in particular part of brain areas ,then healthy neurons start to work less efficiently, then the neurons lose their ability or capability to work and communicate with each other and finally causes neuron death, this damage affected brain parts start to weaken the brain ,in final stage of Alzheimer's disease brain tissue has shrunk significantly and causes subject almost death.

1.4) NEUROPATHOLOGY:

Alzheimer's disease is a neuronal disorder, so its characterized by loss of neuron sand synapses in brain cerebral cortex and sub cortical parts of brain tissue. This loss degenerate the vital parts of brain like temporal lobe, partial lobe, neurons and synapses get degenerated. In brain tissue increased synthesis of toxic protein amyloidal beta peptide then in brain forming amyloidal plaques leading to Alzheimer's symptoms.

1.5) BEHAVIOURAL SYMPTOMS IN ALZHEIMER'S DISEASE:

Alzheimer disease most commonly observed in elderly patients with loss of memory confusion,irritability,and aggression, mood swings, language breakdown,longterm memory loss. Mainly acetyl cholinesterase inhibitors are potentially need to be given to the non available for certain antipsychotics with behavioural symptoms associated by dementia.

1.6) ALZHEIMER'S DISEASE DIAGNOSIS:

Now a day's Alzheimer's disease diagnosis depends on dementia cases. At present, the only way to absolutely diagnosis Alzheimer's disease is through an autopsy of brain.

Alzheimer's disease diagnosis now consist several methods: observing recent history of mental and behavioural symptoms, physical examination, neuropsycological tests and laboratory tests.

Generally physician or doctor observe patients history, and obtain the behavioural symptoms from patient or family members. And mainly need to observe the patients history like symptoms and behavioural symptoms (memory problems and remembering and calculation and managing of money).

Physical test measurements like blood test and urine analysis are done. Generally thyroid function defines the Alzheimer's disease stage. Hypothyroidism and hyperthyroidism states cause the dementia.

B12 vitamin in blood levels also decides the Alzheimer's disease. Dementia also find by B12 levels means b12 deficiency.

A neuropathology test gives behavioural and mental symptoms which cumulated with brain abnormal conditions. A neuropathology test depends on symptoms and disease state of advancement. Generally physician conducts MMSE scale and screening tools which results to decide the Alzheimer's disease level.

1.7. ALZHEIMER' DISEASE DIGNOSIS TESTS:

a) MMSE-Mini Mental State Examination

b) ADAS-cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale)

c) Clock Drawing Test

d) Functional Assessment Staging (FAST).

An above all scales involved in Alzheimer's disease diagnosis.

1.8.PHARMACOLOGICAL EVENTS IN ALZHEIMER'S DISEASE:

Alzheimer's disease occurs due to the mutations in the genes such as PSEN1, PSEN2, APP, APOE kind genes.

Due to the mutations, below pathological events take place in Alzheimer's disease.

1) Abnormal hydrolysis in Amyloidal A4 Precursor Protein (APP)

2) Fibrillogenesis-formation of oligomers beta A type

3) Aggregation-formation of neurotic plaques.

4) Neurofibrillary degeneration-formation of oligomers beta A type.

5) Excess glutamate in synapses-causes excitotoxicity.

6) Imbalance of Copper, Iron, Zinc

7) Oxidative stress

8) Damage of the energy cellular system.

2.0) TREATMENT OF ALZHEIMER'S DISEASE:

A large number of mutations that dominate to the development of familial Alzheimer's disease, an essential aspect are the formation and development of beta amyloidal and its aggregation, followed by pharmacological actions all affect the brain different parts.

For these all symptoms stabilized by early initiation of acetyl cholinesterase enzyme inhibitors.Donepezil, revastigmine and galantamine three drugs are neuroprotective action, control the cognitive and functional status of Alzheimer's disease has monitored. These neuroprotective pharmacological drug therapies continue up to control of Alzheimer's symptoms.

Alzheimer's disease treatment drugs list:

DRUGS NAME

1.Donepezil

2.Revastigmine

3.Galantamine

4.Tacrine

GROUP

1.ACE inhibitor

2.ACE inhibitor

3.ACE inhibitor

4.ACE inhibitor

5.Memantine

5.Anti NMDA group

2.1. TREATMENT OF ALZHEIMER'S DISEASE STAGES:

Acetyl cholinesterase inhibitors are prescribed for different stages of Alzheimer's disease. All ACE inhibitors involved to control all stages symptoms by their action.

Medication of ACE inhibitors like Donepezil act on all stages of Alzheimers.and also medication of rivastigmine and galantamine act on mainly mild to moderate stage of disease.

Tacrine also used for Alzheimer's disease control purpose but this usage almost rare.

All acetyl cholinesterase inhibitors action not delays to control the symptoms of Alzheimer's disease.

2.2. ACE INHIBITORS ACTIONS ON ACETYL CHOLINESTERASE ENZYME:

Donepezil, rivastigmine and galantamie are acetyl cholinesterase enzymes inhibiotors.these act on acetyl cholinesterase enzyme on different actions.

Donpezil acts on deep part of acetyl cholinesterase enzyme and this drug also act on beta amyloidal actions and its aggregation. And this inhibitor double blind actions gives opposite protective actions against beta amyloidal toxicity. This inhibitor also effect on alpha nicotinic receptors and stimulate the sigma 1 receptors. This neuroprotective action helps in control of Alzheimer's disease.

Rivastigmine drug also inhibit the butyryl cholinesterase.Rivastigmine three double blind actions against Alzheimer's disease gives neuroprotective actions.

Galantamine action similar to donepezil, galantamine stimulate the alpha 7 nicotinic receptors then increase the protective action against the excess of glutamate actions.

Memantine also drug which act as anti NMDA drug. This drug protective action against the excitotoxicity action. In this, function memantine actions against microglia causes stimulate protein phosphate 2A.

2.3. ALZHEIMER'S DISEASE DRUGS THERAPY:

For the control of Alzheimer's disease acetyl cholinesterase and anti NMDA drug therapy used. In acetyl cholinesterase drug therapy only tacrine rarely used and remaining three drug used to control the mild and moderate and severe stage of AD.

Memantine drug therapy also used for control the Alzheimer's disease, but this in an anti NMDA drug. These all drugs also give different unwanted actions along with useful action.

2.4. CLINICAL TRIAL STUDIES:

Clinical trial studies require for new drug development. when a pharmaceutical industry invent a new drug, it's need to spend the compound or a new drug in a laboratory for testing on human or animal cells, after finish the laboratory trials then conduct trials directly on living animals or human beings.

When finish or success of these tests then pharmaceutical industries need to provides new drug development date to FDA for new drug approval, after finish the new drug approval then experimental drug allow to clinical trials under protocols.

2.5. CLINICAL TRIALS:

The clinical trial study is designed to mark what happens to the drug in a human body, mean its denote the how the new drug absorbed in human body and how its distributed and how its excreted and then how its work and how the human body react with the new drug actions, these all studies investigated by clinical trials.

Clinical trials only designed for find the drug and human body reactions in a such experiment conditions. Clinical trials require for a new experiment drug invention because without clinical trials we can not find the well new drug reactions in human beings or human organs.

These all clinical trials are based on a set of rules called as protocol.acccording to protocol, what kind of participants require to participate in clinical trial and what type of conditions require to done clinical trials.

Generally clinical trials conduct in in vitro or in vivo conditions.

2.6. CLINICAL TRIALS AND ITS DIFFERENT PHASES:

a. IN PHASES 1 CLINICAL TRIAL:

Phase 1 trials, this is a first stage of trial in new drug clinical trial.

In phase 1 mainly on safety condition. In phase 1 clinical trial, need to proven the new drug and its safety action on patients who are participate in clinical trial. In phase on clinical trial researcher trial the test in a small group of patients (approximately below 100) for determine the safety actions; evaluate a safe dose range and its adverse actions.

Phase 1 clinical trial takes several months time to finish and mostly 70 percent of drugs finish the first phase clinical trials successfully.

b. PHASE 2 CLINICAL TRIALS:

After finished of safety trials, then second phase trial starts, phase2 clinical trial randomized clinical trial.

Phase 2 clinical trials mostly on efficacy test on drugs. In this clinical trial, several hundreds of patient involved (approximately below 1000) these all patients receive drug randomly mean one part of patient receive experimental drug and remaining part of group receive placebo group.

Generally one third of drugs maximum finish its phase 2 clinical trials successfully. Phase 2 clinical trials are double blinded type clinical trials.

c. PHASE 3 CLINICAL TRIALS:

In this clinical trials thousands of patients involved to finish the clinical trial(approximately 1000 to 3000).In this phase 3 clinical trial studies mainly on effectiveness and benefits and range of possible side effects reaction of experimental drug.

These clinical trials are randomized masked trials. Phase 3 clinical trials takes sever years to finish the trials. About 70%-90% drugs finish this clinical trial successfully. When finish this phase clinical trials then pharmaceutical industries ask permission FDA for market of new experimental drug.

d. PHASE 4 CLINICAL TRIALS:

This is final study of clinical trials, these studies done after the drug has been marketed. In this studies,

a) Comparison of new drug with other old drugs which are already present in the successful market.

b)to evaluate the cost effectiveness of new drug with another marketed tradional drug and new therapies.

3. ALZHEIMER'S DISEASE CLINICAL STUDIES:

Alzheimer's disease clinical trials when finish approval with food and drug administration(FDA),then the process starts in the lab for investigation of cells then finally the drug treated on human being and animals by approval FDA permission and under protocol procedure.

Generally in clinical trial different groups involved,

3.0.a) PLACEBO GROUP:

In Alzheimer's clinical trials placebo has main role. Placebo mean in active form of drug which is not act by its action in human body. This is only a pill, syrup or powder with inactive particles. These placebo clinical trials mostly compare with experimental drug groups. This second standard or control inactive group.

3.0.b) EXPERIMENTAL GROUP: In Alzheimer's clinical trial, this an active form of drug, In a clinical trial a certain group of patients receive this control experimental active form drug for clinical trial of Alzheimer's drug.

3.0.c) MASKED OR BLINDED GROUP:

Patients who participate in clinical trial of Alzheimer's drugs, this group of patient do not which group of drug they receive.

3.0. d) DOUBLE BLINDED STUDIES:

Basically this is a masked study, means patient who participate here they do not know which group of drug they receive.

This study is one in which neither the patients nor the clinical trial members know which groups are receiving the active treatment and which ones are receiving either a placebo or a standard treatment.

These clinical trials are conducted, so neither the participants nor the physician's calculations about the experimental control drug can dominate the outcome.

3.0.e) MAIN ADVERSE EFFECTS:

Main adverse effects Alzheimer disease drugs,

Nausea,headache,vomiting,irritations,loss of hair, cardiac failure,diahorrea,gastric irritation like side effects possible by using of drugs.

3.0.f) USES OF CLINICAL TRIALS:

-Obtain active role in healthe care

-Success to provide ways for new treatments.

-Help to control unwanted actions

-Gather exact medical care at leading health care facilities in the clinical trial time. This trials help to medical researchers who are controlling the clinical trials.

3.0.g) PROBLEMS HAVE IN CLINICAL TRIALS:

-Main problem is the risk of healthe during the clinical trial studies.

-Due to drugs adverse actions also one problems in clinical trial.

-Some times clinical trial tests causes death also.

-Treatment of Alzheimer's disease may not be effective in always to patients.

4.0) ACETYLCHOLINESTERASE INHIBITORS ON ALZHEIMER'S DISEASE:

Acetyl cholinesterase inhibitors inhibit the synthesis of acetyl cholinesterase enzyme which involve on angiotension converting process. ACE treatment controls the Alzheimer's disease.

-NICE committee recommends the acetyl cholinesterase inhibitors suitable for control the Alzheimer's disease.

-Donepezil and rivastigmine and galantamine drugs mainly used in control if Alzheimer's disease.

-ACE inhibitors are inhibiting the mild, moderate and severe stage of Alzheimer's disease.

4.0.a) ACETYLCHOLINESTERASE INHIBITORS AND ITS TECHNOLOGIES:

Acetyl cholinesterase inhibitors inhibit the acetyl cholinesterase enzyme at site of neurotransmission.

ACE inhibitors on Alzheimer's disease:

ACE INHIBITORS

1)Donepezil

2)Galantamine

3)Rivastigmine

TECHNICAL NAME

ARICEPT

REMINYL

EXELON

GENERAL DOSAGE

-5 to 10 mg/day

-16 to 24 mg/daily

-3 to 6 mg twice daily

TECHNIQUIES

-Specific reversible acetyl cholinesterase inhibitors. this drug suitable for all stage of disease symptoms control by using donepezil drug.

Reversible and selective, competitive ACE inhibitors. controls moderate and severe stage of symptoms.

This is very special than remaining drugs because this also inhibit the butyrylcholinesterase

Enzyme. controls mainly on moderate and severe stage of AD

4.0.b) AETYL CHOLINESTERASE INHIBITORS TREAT MENT ON AD:

650,000 patients have dementia disease in all over the UK, in this 400000 struggled with Alzheimer's disease in UK, for spending of control Alzheimer's disease estimated money around £6.1 billion (US $11 billion, at 1998/1999 years)

Due to degeneration of cholinergic brain neurons, stimulate the cortex then its gives cognitive disorder which are seobserve in Alzheimer's disease. Acetyl cholinesterase enzyme inhibitors main role blocking of acetyl cholinesterase enzyme.

Donepezil, rivastigmine and galantamine drugs are used to block the acetylcholine abnormalities on brain neuron sites.

A higher percentage of patients were had maximum doses of donepezil (81%) and galantamine (67%).dose range also affect in different stages of Alzheimer's disease.

4.0.c) DIFFERENT TESTS IN CLINICAL TRIAL OF ALZHEIMER'S DISEASE :

These all tests are very useful to find the drug actions on Alzheimer's disease or inhibit the choline abnormities.

-ADAS COG: Alzheimer's disease assessment sub scale cognitive score.

-BADLS: Bristol activities of daily living scale.

-DSM IV: Diagnostic and statistical manual of mental disorders,4th publications.

-GHQ-30: General health questionnaire.

-MMSE: Mini mental state examination scale.

-NPI: Neuropsychiatric inventory.

-NINCDS ADRDA: National institute of neurological and communicative disorder and stroke and the Alzheimer's disease and related disorders association.

An above all scales indicate the Alzheimer's disease states.

5.0. DRUGS FOR ALZHEIMER'S DISEASE:

ACE inhibitors well knew drugs for control Alzheimer's disease.

5.0.a) DONEPEZIL:

Donepezil is an ACE inhibitors drug which is inhibits the synthesis of acetyl cholinesterase enzyme then treat the Alzheimer's disease.

Donepezil is a first licensed drug in UK,in march 1997 year. Then followed by remaining drugs rivastigmine and galantamine drugs.

Randomized clinical trial of three ACE inhibitors have shown improvements on cognitive tests and global calculation change in suitable selected patients who suffered with mild to moderate Alzheimer's disease over 3-12 months.

Donepezil randomized clinical trials in 10mg dose have shown better cognitive improvements than 5mg dose of donepezil drug.

CHEMICAL STRUCTURE OF DONEPEZIL:

DONEPEZIL DOSAGE AND ITS STORAGE CONDITIONS:

Donepezil dosage-5 mg to 10 mg /daily.

-Donepezil store in tightly closed suitable container require to store.

-Condition avoids from heat and maintains room temperature.

-Care full to keep away from children's.

ADVERSE ACTIONS:

Donepezil also gives adverse reactions on patients.

-Gastrointestinal damage,vomiting,diarrhea,nausea,headache,anorexia,dyspepsia,urinary tract infections,dizziness,confusion,insomnia and abnormal cramps most common.

SERIOUS ADVERSE ACTIONS:

Main serious adverse effect of donepezil is death. Chest pain, bloody vomiting.

SYMPTOMS OF OVER DOSAGE:

Confusion, dizziness, nausea most common symptoms over dosage of donepezil drug.

BRAND NAME OF DONEPEZIL:

Brand name of donpezil in market is ARICEPT. This is a drug used to block the acetyl choline enzyme and enhance the nerves system functions.

MAIN ROLES FOR DONEPEZIL DRUG CLINICAL TRIALS:

-Donepezil MMSE score between 5 to 7.

-Age range must be above 50 years (>50 years).

-Donepezil drug must able to swallow tablet medication.

-Avoid blood pressure raises.

-Subjects with thyroid disorder.

Above criteria inclusion criteria.(Love man E, Green C, Kirby J)

ELIMINATION CRITERIA OR EXCLUSION CRITERIA:

- Avoid age range below 50 years.(<50 years).

- Avoid exclusion of MMSE scores .Score range less than 4 or 25.

-Elimination the alcoholic drug abuse actions.

-Subject with well known hypersensitivity to piper dine derivatives.

-Subject with clinically important obstructive asthma disease.

5.0.b)DONEPEZIL DRUG CLINICAL TRIALS:

P Bentham Gray and Rafter, R Hills, and E Sellwood, S Edwards, C lend on

Long term donepezil in 565 patients with Alzheimer's disease (AD 2000).

The main cause that to determine donepezil produce suitable improvements in disability, behavioural, dependency and psychological symptoms.

In this clinical trilas, here donepezil treatment 565 patients involved to success these clinical trials of donepezil. These all patients have mild to moderate Alzheimer's disease stages. These clinical trials conducted in 48 week treatment.

In this studyfinds, cognitions averaged 0.8 MMSE scale points good (95%CL., 0.5 TO 1.2; P<0.0001).

-Bristol activities of daily living scale BADLS score 1.0 excellence points (0.5 to1.6;p<0.0001) with donepezil over the staring 2 years.

There is no significant advantages with donepezil compared with placebo in institutionalisation (42% Vs 44;at 3 year's; P=0.4).

-The relative problems of involving institutional care in the donepezil group balance with inactive placebo group was 0.96 (95% CL, 0.74-1.24;P=0.7)

In donepezil (DNZ) clinical trials 565 group of patients involved. These groups of patients first entered in to 12 weeks run-in period clinical trials and then entered into 48 weeks clinical trials.

DONEPEZIL CLINICAL TRIAL PROFILE:

565 patients with mild and moderate AD

282 for 12 weeks DNZ

283 for placebo

Finish of 12 weeks run in trial, 486 patients continues second randomisation.

244 patients - placebo

242 patients - DNZ (5-10mg)

293 patients complete phase 1.this is 48 weeks treatment.

111 patients finish phase 2.

20 patients finish phase 3 trial

3 of 3 suitable patients continue for phase 4

1 of 4 suitable patients enter into phase 4

5.0. c. DONEPEZIL TRIALS:

[Christina Wolfsan PhD, Mark Oremus Msc,Vijay Shukla PhD, Franco Momoli Msc,Louise Demers PhD, Anne Perrault Msc and Yola moride PhD].

In this clinical trials best example to determine donepezil efficacy a cost effectiveness.

In this clinical trials, patients Alzheimer's disease stages defined by MMSE scale points.

MMSE scale records and Alzheimer's disease stages:

DISEASE STAGES

MMSE SCALE

Mild Alzheimer's disease

Moderate Alzheimer's disease

Severe Alzheimer's disease

15 to 27 points.

8 to 14 points.

0 to 7 points.

In the randomized clinical trials of donepezil, that mean decrease in scores points on the Alzheimer's disease assessment sub scale cognitive score(ADAS-cog) points was higher with experimental active drug than placebo.

-Efficacy of donepezil, in this clinical trials ADAS-cog scale points act as a measurement for disease.

-Lower ADAS-cog scores indicate low cognitive deterioration.

-In this clinical trials, 214 patients receive donepezil and 217 people receive placebo form. Around 39% of donepezil and 33% of placebo recipients observed from total patients.

-32% donepezil and 20% placebo recipients completed 54 weeks clinical trials period.

-28% donepezil and 26% placebo recipients (from total participants) withdrawn because different reasons like adverse effects.

-Adverse effects like nausea, anoxia, diahorrea and urinary tract infections.

Donepezil and its ADAS-cog scale:

DONEPEZIL dosages

DURATIONS

SCORES

DONEPEZIL Vs

PLACEBO

STUDIES

1)1 mg/daily

3mg/daily

5mg/day

PLA

12 weeks

-0.9

-1.4

-2.5

0.7

-1.6

-2.1

-3.2

Rogers et al studies

2) 5mg/d

10 mg/d

placebo

24 weeks

-0.67

-1.06

1.82

-2.49

-2.88

Rogers et al studies

3) 5mg/d

10mg/d

PLA

24 weeks

0.08

-1.4

1.63

-1.5

-2.9

BURNS et al studies

An above all ADAS cog score value decrease by increase of dose of drug.

-Donepezil drug 1 mg/daily ADAS score -0.9 higher than 5mg/daily.

In this clinical trial, started with 431 patients treated with randomized clinical trials. Here 83%of the donepezil group and 80% placebo group of patients withdrawn due to adverse effects.

Adverse events like respiratory infections and nervous infections.

Donepezil results in open label extension studies:

STUDIES & DOSAGE

DURATION&

PATIENTS

QUANTITATIVE SCALES

RESULTS

ADVERSE EFFECTS

Rogers et al

DNZ 3mg/d

Initially, with maximum increase to 5,7 or 10 mg/d

240 weeks.

N=133.

Common ADAS-

Cog scale.CDR-SB points.

ADAS cog:

In 1yr-2.46,

In 2yr-5.41,

In 3yr-5.85.

Nervous and digestive disorder.

Matthews et al

DNZ 5mg/d for 4wk,upto 10mg/d

72 weeks.

N=80

NPI-D,MMSE,NPI,

ADAS-cog

At 3mo,ADAS-cog(39%),NPI(37%)

Had _>4-points improvements.

Nausea and abdominal cramps.

Doody et al

DNZ 5mg/d initially with increase to 10 mg/d after 6 wks.

90% receive 10 mg/d,10%receive 5 mg/d

144 weeks.

N=763

ADAS-cog,

CDR-SB POINTS

ADAS-cog scores at 1-3 yrs(24 week study/12 week study)

In 1 year:2.55/2.11

In year2:7.42/9.14.

In year3:10.17/10.49

[5 mg/d]

Nervous system

And digestive system damage.

These all studies help in find the functions of donepezil on Alzheimer's disease. By using ADAS cog scale, MMSE scale donepezil exact functions measured.

CONCLUSION:

Main conclusion of donepezil drug in Alzheimer's disease ,only this drug used now all stages of Alzheimer's disease, because its block the acetyl cholinesterase enzyme action, so donepezil ACE inhibitor has been approve to mild, moderate and severe stage of disease.

6.0. a.RIVASTIGMINE:

Cholinergic disorders observed in Alzheimer's disease, in Alzheimer's disease also find different abnormalities like signal transduction.P75 neurotrophin receptor concentration and also beta pep tidal dysfunction, these all dysfunctions inhibited by using rivastigmine.

Chemical structure of rivastigmine:

Chemical formula for rivastigmine-C14H22N2O2.

ADVERSE EFFECTS:

Rivastigmine gives also unrequited actions like nausea, diarrohea, dizziness, confusion,

Weakness, constipation, headache, vomiting.

SERIOUS ADVERSE ACTIONS:

Cardiac failure, infections like urinary tract.

OVER DOSE SYMPTOMS:

Headache, vomiting, due to infections painful urination symptoms occurred in rivastigmine additional dose using.

PRODUCT BRAND NAME:

Rivastigmine brand name in market is Exelon.

DOSAGE AND STORAGE CONDITIONS:

Dose of rivastigmine generally 3-12 mg/day. Rivastigmine need to store in tight container and maintain good conditions and avoid conditions like allow high sunlight, cool temperature. Maintain room temperature and keep in safe place, avoid from children's.

CLINICAL TRIAL CRITERIA OF RIVASTIGMINE:

INCLUSION CRITERIA: (Love man E, Green C, Kirby J)

-Rivastigmine advantages cognitive function in patients with mild cognitive impairment.

-Clinical trials treatment in Alzheimer's disease mostly according NINCDS-ADRADA.

-Alzheimer's disease diagnosis depends on MMSE and DSM IV criteria.

-Progression models of Alzheimer's disease were depending on cognition states alone.

-Rivastigmine transition probabilities derived from open label studies.

EXCLUSION CRITERIA:

-Past clinical data excluded.

-Points on MHIS (modified hachiniski ischemic scale more than 5.

-HAM scale for depression. Depression is a major role. To exclude depression as an active conformer of MCI, patients were required to have entry score less than 13 points.

6.0. b.CLINICAL TRIALS OF RIVASTIGMINE FOR ALZHEIMER'S DISEASE:

[Howard h Feldman, Steven ferris, Bengt Winblad, Nikolaos S fikas, Linda Mancions

Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from MCI]

In this study, around 1018 patients involved to success the trial. In this clinical trial operation, patients randomly assigned by drugs, 508 patients received rivastigmine, 510 patients receive placebo. Around 17.3% patients progressed on rivastigmine to Alzheimer's disease. And 21.4% progressed on placebo to Alzheimer's disease. [95%, CL 0.64-1.12; P=O.225].

There was no important difference between rivastigmine and placebo under the z score for the cognitive test battery determined as mean difference from baseline to last point(-0.10{95%,CL -0.63 to 0.44},P=0.725).

Generally rivastigmine dose (3-12mg/day).the study about rivastigmine clinical trial double blind, parallel group, placebo randomized controlled clinical trial.

In this rivastigmine starts with 0.5mg twice daily then after 2 weeks later doses were increased into 1.5 mg twice daily, then increase up to 3 mg by adding remaing dose then dose titration phase continue up to investigate maximum dose 12 mg/day.

In this clinical trial below scales included.

-ADAS-cog (11 items, 70 points)

-Global deterioration scale (GDS, 7 points)

-CDR scale (5 points)

These are all secondary study outcomes.

In this study, InDDEx study denotes, 1526 patients screened for this study,374(24%)were screening failure,134 patients inactive screening for further clinical trial randomization clinical trial.

The main observation of sample, 500 patients (49.1%) involved in the APOE genotyping sub study clinical trial. In this sample placebo contain more APOE E4 group than rivastigmine group (46.4% Vs 36.5%; p=0.025), in BCHE genotyping sub study 490 patients tested, win a higher proportion of k-variant peoples in the placebo group (35.9% Vs 29.7%;p=0.051).scanning of MRI scans possible for 513 patients(56.4%),here 254 (49.5%) were placebo contained group and 259(59.5) were rivastigmine group. The post baseline assessment for hippocampal volume available for about 513 patients.(MRI scans 513 patients).the one post baseline for brain available around 441 patients.

97.4% patients were containing medical conditions at baseline without any consequence difference between placebo and placebo.

-Hypercholesterolaemia, hypertensions type side effects occurred in this clinical trial.

-The average dose of rivastigmine is 6mg.

-In this clinical trial, around 3-4 years duration, 17.3% rivastigmine, 21.4% placebo progressed to Alzheimer's disease.(hazard ratio 0.85 [95% CL,0.69-1.12;p=0.225].

-In this performance, there was no consequence difference find between rivastigmine and placebo.

-I n this study, small important numerical use in favour of rivastigmine on delaying time to diagnosis of Alzheimer's disease.

6.0. c.ANOTHER CLINICAL TRIAL FOR RIVASTIGMINE:

In this study, 26 weeks, open label extension study of rivastigmine. In this total patients 235, here 187 receive placebo and remaining receive rivastigmine.

Coorey bloom and Rosler studies explained about rivastigmine available into two dosages

1. Low dose-1 to 4 mg/d

2. High dose-6 to 12mg/d.

* RIVASTIGMINE DOSES AND ADAS-cog SCALE CHANGES:

DIFFERENT ANALYSIS

DOSAGES

ADAS-cog points

DIFFERENCE Vs PLACEBO

Corey-bloom et:

Intent-to-teat analysis:

Observed case analysis:

Riva, low dose

(1 to 4mg)

Riva, high dose

(6-12mg)

PLA

Low dose

High dose

PLA

2.36

0.31

4.09

2.27

-0.79

4.15

1.73

3.78

1.88

4.94

Rosler et:

Intent-to-treat analysis:

Observed case analysis

RIVA, low dose

High dose

PLA

RIVA,

Low dose

High dose

PLA

1.37

-0.26

1.34

1.24

-1.17

1.41

-0.03

1.60

0.17

2.58

Open label extension study results, 151 patients received 1 to 4mg of rivastigmine, 125 patients received 6 to 12mgrivastigmine.according to open label extension studies, in first week all patients receive 1mg dose of rivastigmine, then it increase in high dose level, patients who receive 1 to 4 mg dose, the original trial of low dosage level explained by decrease or no changes in ADAS-cog scales. This is mostly between 1 to 12 week of clinical trial.

Then extension of 12 week study, rivastigmine dose increase in 6 to 12mg then ADAS-cog scale increased.

In total 26 week study, around 32% (48 patients from 151 patients)receive 1 to 4mg dose here no change occurs in ADAS-cog scale.

38% patients receive 6 to 12mg dose, here improvement in ADAS-cog scale, In this study common adverse event is gastrointestinal disorders.

These studies also explained economic results of rivastigmine.

RESULTS OF RIVASTIGMINE ECONOMIC STUDIES IN UNITED KINGDOM:

DRUG

TARGET

DURATION

ESTIMATION OF COST

YEAR

RESULTS OF PERIOD

Rivastigmine

And placebo

Mild to moderate

3years for progression of disease

2years for

Cost estimation.

Only include non medical and medical costs only not include rivastigmine cost.

1997 period

Rivastigmine:

£4619(mild)

£777(moderate)

£6763(moderate)

Placebo:

£5846(mild)

£7540(moderate)

CONCLUSION:

Rivastigmine is good tolerated and effectively active drug. It develops cognitions. And above studies denote that rivastigmine action now against mild to moderate stage Alzheimer's disease, but the trials for its action need to continue for further better improvements purpose because its gives also gastric infection and cardiac failure and cost like unwanted action.

7.0. a. GALANTAMINE:

Galantamine is acetyl cholinesterase reversible inhibitor.galantamine is an allosteric potentiating ligand on acetyl choline nicotinic receptors. Galantamine also progressive to Alzheimer's disease. Galantamine had lower mortality rate during clinical trial, may be due to this reason galantamine higher active than placebo studies of galantamine.Galantamine significantly progresses cognitive functions.

GALANTAMINE ADVANCE RELEASE:

Galantamine stimulate the increase the neurotransmitter concentration in the black triangle synaptic cleft along with blocking action of acetyl choline.

Daily dose of galantamine 24mg this is for extended release of drug ,for immediately release of galantamine dose is 12mg twice daily. Due to area under the plasma concentration curve values (AUC) ,extended release galantamine more effect than immediate release galantamine.

CHEMICAL STRUCTURE OF GALANTAMINE:

ADVERSE EFFECTS OF GALANTAMINE:

Urinary tract infection, vomiting, diarrhoea, nausea, fall, agitation, arthralgia, constipation,

aggregesion,depression,cystitis,pyrexia,anorexia,peripheral oedema,bronchchitis headache,cough,hypertension,dizziness.

SERIOUS ADVERSE EFFECTS:

Due to infection some times causes death also this is major problem with drugs.

SYMPTOMS WITH OVERDOSE:

Due to over dose of galantamine causes vomiting, nausea, phneumonia, falls, diarrhoea.

DOSAGE AND STORAGE CONDITIONS:

Galantamine effective dose is 24 mg/day, storage condition of galantamine keep the medication in tight containers and keep away from excess heat and cool. Keep away the drug from children's.

BRAND NAME OF GALANTAMINE IN THE MARKET:

Razadyne or Reminyl.

CLINICAL CRITERIA OF GALANTAMINE:

INCLUSION ROLE: (Love man E, Green C, Kirby J)

-Need to have MMSE scores between 10-12,but NICE committee suggests the treatment with ACE inhibitors should be stop the treatment when MMSE scores reached 10.

-Long time horizons.

-Lower mortality.

-ADAS-cog points at least 18 (according to Japanese studies).

EXCLUSION ROLE:

-Diagnosis of Parkinson's disease

-History about diseases like epilepsy, convulsion, peptic ulcer disease

-Require to avoid another addition agents like nootropic, estrogen drugs.

7.0. b. CLINICAL TRIALS OF GALANTAMINE:

Alistair Burns, Roberto Bernabei, roger bullock, Alfonso Cruz Jentoft, Lutz Frolich

This clinical trial explained about galantamine safety and efficacy studies.

In these studies 2003-2007 84 years aged patients with severe Alzheimer's disease (MMSE points 5-12) randomly assigned to galantamine treatment.

In this clinical trial, MMSE scale,MDS-ADL subscale, SIB score points involved, here 168(81%) of 207 patients received galantamine,161(81%) of 200 patients received placebo drug.SIB scores of galantamine drug increased by a1.9 (95% CL,-0.1to 3.9) SIB scores decreased by the 3.0 (-5.6 to -0.5)points with placebo group,MDS-ADL self performance points worsened by 1.6(0.8 to 2.3) points of placebo and 1.2 (0.6 to 1.8)points of galantamine.

In these clinical trial 8 patients who received galantamine and 21 patients who received placebo died because of adverse effects like abnormalities.

In these trials 505 patients screened, from that 407 randomly selected and proceed into further studies (age group 81 years and 81%women present) but remaining patients screened out from trials. In this 207 received galantamine active form and 200 received placebo drug. This is a 6 months treatment here 22 mg/day galantamine and 22.5mg/day placebo doses last mean doses in this trials.

During the clinical trials,81%of galantamine about 207 patients and 81%from 200 patients have at least one side effects example cardiac vascular disorders,figrillation,bradycardia.

Different scale readings for clinical trials:

SCALES

GALANTAMINE

(n=207)

PLACEBO GROUP

(n=200)

MDS-ADL scale

11.9 (7.6)

12.6 (7.5)

MMSE scale

8.8 (2.4)

9.1 (2.4)

SIB scale

66.8 (20.9)

67.8 (21.5)

Galantamine used safety and adult patients with severe stage of Alzheimer's disease.

SIB scale and MDS-ADL scale and MMSE scale measures the efficacy of the galantamine drug on choline enzyme blocking.

Galan amine clinical trial profile:

505 Patients allowed to screening the treatment

407 patients finished the screening

207 patients-receive galantamine drug

200 patients-receive placebo drug.

81% finished from 161 patients.

81% finished trial from 168 patients.

7.0. c. ANOTHER CLINICAL TRIAL FOR GALANTAMINE:

[Douglas W.Scharre, Thomas Shivotz, Young Zhu, Joan Amatniek].

In this clinical trial galantamine extended release titrated by using open label 12 weeks 1-week titration method. Here efficacy of galantamine also determined. In this clinical trial results of this titration compared with 4-week titration GALANTAMINE -ER and also with GALANTAMINE-IR.The primary analysis baseline compared measures of adverse effects. In this clinical trial 82 patients performed, more patients had at least one gastro intestinal side effect with 1-week titration. And in this trial 4 patients suffered with serious side effects and no death records occurred.MMSE scores of in this trials enhanced by 1.8 and 1.9 points in 4weeks and 12 weeks respectively.

In this clinical trials,82 patients involved starting, then 66 patients completed the 12 weeks titration. Remaining patients discontinued due to adverse effects. In this clinical trials significant comparison between 1-weeek titration with 4-week titration method, in 1-week titration method MMSE scores increase. In this study,51:,1-week titration patients and 27%,4-week titration method have gastric intestinal disorders at baseline. Compare to 4-week titration method patients (1.3%) ,1-week titration method patients(11%) suffered in higher percentage.

Cognitive efficacy of GALANTAMINE-ER as measured by MMSE scale.80 patient in 1-week titration method, for this population baseline MMSE scores 19.0(+_3.5).the baseline increased b 1.9 points at study end points about p value is<0.0001.after 4 weeks the treatment beginning like (in week 4, 1.8 point scores,<0.0001;week 12,1.9 point scores<0.0001).

In this clinical trial comparison of 1-week titration with historical GAL-ER and GAL-IR, the galantamine maintenance dose 16mg/day, there was no difference between 1-week open labels method and 4-week titration method the only difference between these two studies is adverse events. The GI disorder through in week 8 in the 1-week titration method and frequently measured diarrhoea adverse effect also in 1-weeek titration. But in overall there was no consequence difference between two methods.

CONCLUSION:

In 1-week titration trial for galantamine extended release safe and well tolerated. But only GI side effects appeared in this trial than 4-week trials.

But overall clinical trials explained galantamine suitable for mild, moderate and moderate severe Alzheimer's disease stages. Due to adverse action and other reasons need to do more trials for find better results purpose,

Galantamine also suitable for severe stage Alzheimer's disease also.

8.0. MEMANTINE:

Memantine is not an acetyl cholinesterase enzyme inhibitor. Memantine is NMDA antagonist.

Memantine major role on NMDA receptors regulating of glutamate, causes processing of information, good memory. Memantine first licensed by United States

MEMANTINE ACTIONS:

Generally memantine is suitable for severe Alzheimer's disease. For controlling of severe stage of Alzheimer's disease act as NMDA antagonist. In this, glutamate role important, glutamate allows the calcium into nerve cell. Excess glutamate over stimulate the NMDA receptor then it causes over allow of calcium into nerve cell, then its causes cell death,so.Namenda(memantine) act on NMDA receptor as an antagonist, by this action memory loss, delay functioning like Alzheimer' symptoms controlled.

LIMITS OF MEMANTINE DRUG:

-Memantine NMDA receptor antagonist, only used for moderate severe to severe Alzheimer's disease.

-FDA approved memantine is not suitable for mild stage of Alzheimer's disease.

9.0. COMPARISION OF DRUGS:

RIVASTIGMINE AND DONEPEZIL:

The efficacy data of both drugs explained the both drugs delay the cognitive impairment and detoriation for at least 6 months duration global health in patients with mild to moderate stage disease. For both drugs cost-effectiveness still not concluded.

(Christina Wolfson,Mark Oremus,Vijay Sukla).

MEMANTINE AND DONEPEZIL COMBINATION:

Memantine is an anti NMDA drug but donepezil is an ACE inhibitor, the combination with these drugs, Patients who suffered with moderate to severe Alzheimer' disease,then those patients received stable dose of donepezil and memantine,then better outcomes occurred in behavioural symptoms of Alzheimer's disease. The new approach is, memantine is better treatment for severe stage Alzheimer's disease.

[Pierre N.Tariot, MD; Martin R.Farlow, MD; George T.Grossberg, MD.]

COST AND CLINICAL COMPARISSION OF DONEPEZIL, RIVASTIGMINE, GALANTAMINE, MEMANTINE:

-For mild and moderate severe stage Alzheimer's disease treatment, global better outcomes measures positive for rivastigmine and donepezil bur negative in galantamine.Beahavioural and mood symptoms measures mixed for donepezil and galantamine and positive for rivastigmine. The global and functional outcome for memantine is better.

Cost effectiveness for donepezil, rivastigmine and galantamine, donepezil as not cost-effective drug but remaining two drugs cost-effective drugs. In memantitine issue there is no conclusion for cost effectiveness.

10. NICE COMMITTEE (TA111):

The review of NICE committee appraisal guidance 19' on ACE inhibitors drug rivastigmine, galantamine, donepezil drugs for the control of Alzheimer's mild to moderately severe Alzheimer's disease.

NICE committee guidance,MMSE scale divide the Alzheimer's disease into mild, moderate, moderate severe, severe stage Alzheimer' disease.

Donepezil, rivastigmine, galantamine treatment suitable for mild to moderate severe stage diseases.

Memantine for moderately severe to severe stage Alzheimer's disease.

The acetylcholine inhibitors donepezil, galantamine, rivastigmine are subjected as options in the management of patients group with Alzheimer's disease of moderately severity only. Because these MMSE scores 10-20 points).

Only experience and well specialists handle the care of patients with dementia, should start the treatment carer's thought on the patients baseline situation should be needed.

Patients, who want to continue the same drug, should be reviewed every 6 months by observing the MMSE and global behavioural assessment. These assessment handled by appropriate specialist.

Worthwhile effects of drug should be maintain or remain MMSE score above 10 points.MMSE score is not possible to apply in a language.MMSE use by itself would be an inappropriate tool for assessing the dementia severity in that individual patients case.

In some cases health and care specialists measured whether the patients has Alzheimer's disease of moderate severity by using the useful method of assessment. For the clarity doubts, clearly NICE committee recommended ACE inhibitors are as option to use Alzheimer's disease of moderate severity having patients.

When decision recommended the treatment therapy should be started with a drug with lowest effort cost. Memantine is not recommended for the control of moderately severe Alzheimer's disease to severe stage AD expect in case of well designed trials.

Patients who receive ACE inhibitors and memantine now receiving to control moderate severe to severe Alzheimer's disease, should be continued up to their carers permission to stop routine drug therapy.

Alzheimer's disease common dementia disease. Which is degenerate the cerebral disorders with significant neuropath logical and neurochemical actions.

Alzheimer's disease is a smooth, slowly injected disease; it will take several years to develop in the brain. Development of Alzheimer's disease means down fall of cognition (thinking, conceiving, reasoning actions) Alzheimer's disease affect in the 75 years time.

Who suffered with Alzheimer's disease they have forgotten do their daily activities like dressing, travelling, money counting. In Alzheimer's disease non cognitive actions like hallucination also one symptom.

NICE COMMITTEE RECOMENDED SEVERAL METHODS USED TO EVALUATE THE SEVERITY ALZHEIMER'S DISEASE:

1. MMSE: Mini Mental State Examination scale.

a) Mild stage Alzheimer's: MMSE scores 21-26

b) Moderate stage Alzheimer's disease: MMSE scores 10 to 20

c) Moderate severe Alzheimer's disease: MMSE scores 10 to 14

d) Severe stage Alzheimer's disease: MMSE scores <10

2. The Progression deterioration scale (PDS)

3. Clinical based impression of change (CIBIC)

4. Alzheimer's disease assessment cognitive sub scale-ADAS-cog (<_70 points)

HANDLING OF ALZHEIMERS DISEASE:

Alzheimer's disease management several below steps involved;

1. Diagnosis of Alzheimer's disease

2. Before start the treatment need to educate the patient or his family about drug therapy.

3. Then start the treatment with ACE inhibitors drugs like donepezil and rivastigmine and galantamine.

4. During the treatment need to observe the adverse effects.

5. Then patient revaluate with another drug. Due to adverse effects.

6. Based on MMSE and ADAS-cog scale then the treatment change into another drug therapy for every 6 months interval continues up to MMSE scores less than 10 points.

COST ANALYSIS OF NICE COMMITTEE:

The cost and benefits of the treatment calculated by using estimation of individual drug. Generally economic analysis carried out by manufacturer or by assessment groups. Then the economic analysis conducted by NICE committee secretariat. In the analysis several factors involved like cost of treatment models and cost of nursing population.

NICE COMMITTEE IMPLEMENTATIONS:

Nice committee recommended to NHS for providing proper funding and resources for medicines and treatment of alzheimer'disease.

-NICE has improved tools to help organisation implement the TA111 guidance.

a) Costing templates and costing report to determine the savings and cost associated with implementation.

b) Audit encourage for monitoring local practice.

NICE COMMITTEE RECOMENDATION FOR FURTHER STUDIES:

Research important to provoke robust and relevant data on both short and long term outcomes, cognitive progression and cost estimations of treatment of Alzheimer's moderate severe and severe stage disease with memantine.

-Research required estimating memantine actions on Alzheimer's disease.

-Required to research to judge the relation between disease progression of people with Alzheimer's disease and quality of life.

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