Dementia & Alzheimer's Disease

Dementia- is a state of cognitive impairment resulting from the progressive lose of previously acquired mental abilities

• Cognitive impairment - which prevents the normal accomplishment of tasks of daily living such as cooking, cleaning etc.
  
• A deline in memory- makes independant living impossible
  
• A deline in thinking, planning and organising daily activities
  
• Gradual loss of orietation in space and time
  
• A deline in emotional control or motivation or a change in social behaviour
  

Condition causing Dementia

• Alzheimer's disease (AD)
  
• parkinson's disease (PD)
  

Alzheimer's Disease (AD)

Aetiology

• AD is characterised by both cell structure and biochemical changes

- it is associated with the presence of amyloid plaques and neurofilbrillary tangles in the brain. These cause neuronal death in cortical and subcortical regions.

- Amyloid plaques are formed by the accumulation of beta-amyloid of tau proteins. The reasons why these occur are not understood.

1st explaination
- Amyloid precursor protein (APP) abundantly expressed in the membranes of many nerve & gila cells and they are used as function for cell structure and cell-cell recognition.
- In normal life APP is produced and then secretase enzymes sever the chain and release A-beta peptide into the extrecellular space.
* In AD, too much A-beta is produced or it is not being removed properly - so formed the beta-amyloid plaques.
- as the plagues increase in size, they appear to stimulate an autoimmune inflammatory response.
- they inferfere with synaptic function and the regulation of transmitter reuptake.
- excess extracellular transmitter due to impaired reuptake may generate excitoxicity; so eventually cells adjacent to the plaques die.


2nd explaination

• it is also thought that declining memory and cognitive function results from a lack of acetylcholine and an excess of excitatory amine acids, especially glutamate
• Acetlycholine is normally broken down by 2 cholinesterase enzymes, actylcholinesterase and butyrylcholinesterase. In AD, the deline in activity of acetylcholine in accompanied by a decrease in the production of acetylcholinesterase, further contributing to the deline of acetylcholine levels.
  
• Glutamate is a major excitatory neurotransmitter. Its action on the NMDA ( N-methyl-D-aspartate) receptor can lead to overstimulation of neurones, causing permanant damage.

Hypothese on causes of AD

• Genetic factors : Faulty genes
  
• Environmental Factors : Health and degeneration
  

Risk Factors

• Female ( Because females tend to live longer than males)
  
• Head injury
  
• Parkinson's disease
  
• hypothyroidism
  
• chronic exposure to aluminium
  
• cardiovascular disease
  
• smoking
  
• chronic high alcohol intake
  

* Average survial time from diagnosis is 10 years, although patients and their familiesand carers often experience a significant decrease in quality of life for a large part of this time.

Sign and symptoms

AD is characterised by a gradual decline in cognitive and memory function. Therefore, it can present in many ways. Physical signs are:

1. unable to perform daily activities, such as dressing, washing, feeding
   
2. behaviour problems
   
3. reduced muscular function
   
4. sleeplessness
   
5. aggression
   
6. apathy - the feeling of not being interested in or enthusiastic about anything
   
7. delusion and hallucinations
   
8. loss of autonomic control

Symptoms

1. Amnesia - memory impairment ( impaired ability to learn new information or recall info)
   
2. Aphasia - Language disturbance
   
3. Apraxia - impaired ability to carry out motor activities despite intact motor function
   
4. Agnosia - failure to recognise or identify objects despite intact sensory function
   
5. Disturbance in executive function ( planning, organising, sequencing and abstracting)
   

Faulty Genes

• Chromosome 21: APP gene
  
• Chromosome 19: APO E4, a form of apolipoprotein
  
• Chromonsome 1 & 14: Protein called prosenilin-2 & presenillin-1
  

Role of Apolipoprotein E (APO E)

• it is a plasma lipoprotein that is one of the principal constituents of chylomicrons and a very low density lipoprotein (VLDL)
  
• it plays a vital role in cholesterol transport in the blood.
  
• 3 known isoforms of APO E, coded by APO E2, APO E3 and APO E4 genes.
  
• APO E4 genotype : implicated as a risk factor for AD
  
• Recent studies : APO E4 may influence the CNS 's response to injury

Investigations

• As the condition predominately affects cognitive and memory functions, the investigations focus on these areas rather than physical examinations.
  
• it is also possibke to make a presumed diagnosis of AD, as a definiti diagnosis in only possible through autopsy
  
• A number of assessment methods can be utilised that define both cognitive and memory function. This includes:
  

1. Mini Mental State Examination (MMSE) - 5 x cognitive Domain Tested
   
   • Orientation: ( what day of the week is it? / what building are we in? )
     
   • Memory (1) : Immediate word recall
     
   • Attention & calculation: Counting & spelling backwards
     
   • Memory (2) : Delayed recall
   • Language Writing & drawing: Shown 2 daily item & name them. Following simple instructions, sentence writing & intersecting shape drawing.
     
   Maximum score of 30: AD patients will score <26
2. Alzheimer's disease Assessment Scale
3. The blessed test of information
   

Neuroimaging- using techniques such as :

• MRI ( Magnetic Resonance Imagining) - AD's patients shown enlarged ventricles and sulci
  
• CT
• PET (Position emission Tomography) scans- show the differences in brain activity between a norma brain and a brain affected by AD.
  

Management - the aim of treatment is to relieve symptoms and prevent the progression of the disease.

• Four drugs are currently available in the UK

1. Cholinesterase inhibitors- donepezil
   
2. Galantamine
3. Rivastigmine
   
4. NMDA-receptor antagonist - Memantine

Cholinesterase inhibitors ( e.g. Donepezil) CI

- Approximately 30-50% of patients show a definable decrease in their rate of cognitive decline after 3 months of treatment.
- the same degree of modest improvement in approx. 30-40% of patients with mild to moderate AD.

- The major effect of CI lies in their potential to reduce severity of symptoms & slow the rate of symptom progression , but it does not cure it.
- they do not stop the essential pathological process.

Mode of action:

• they reversibly bind with and inactivate the enzyme cholinesterase which breaks down acetylcholine.
• they potentiate the duration of action of ACh in the cholinergic synapse.
  

Side effect/ Adverse effect:

• The main adverse effects are from their cholinergic activity, such as nausea, vomiting, diarrhoea, anorexia, urinary frequency and depression.
  
• This can be a problemas those with AD often losing weight through the disease

(To decrease the potential side effects, the drugs are introduced gradually with a steady dose tituation )

Dose

• One 5mg tablet daily ( can be increase up to 10mg over 4 weeks)
  

Galanthamine

Mode of action

• it is a reversible non competitive inhibitor of acetylcholinesterase + direct nicotinic agonist. They bind to inactivate the enzymes to breakdown acetylcholine and act as an agonist to acetylochine nicotinic receptors.

Side effect/ AE:

• N/V
• Dizziness
• agitation ( an state of excitment, disturbance or worry)
  

Dose

• one 4 mg tablet twice daily for 4 weeks. ( can be increased up to 8mg twice daily for 4 weeks then maintain 8-12 mg twice daily)
  

Rivastigmine

Mode of action:

• same as Donepezil
  

Side effect/ AE:

• N/V
• confustion
• angina
  
• agitation

Dose

• one 1.5mg table twice daily, increased by 1.5mg gradually.

Memantine

Mode of action

• Glutamate transmits its signal via the NMDA receptor.
  
• NMDA receptor activation and Ga2+ influx are important for learning processes
  
• Glutamate is recycled in glial cells
  
• Beta Amyloid inhibits glutamate recycling
  
• excessive glutamate masks the neuronal singal transmission.
  
• so... Memantine blocks effects of excess glutamate and restoration of physiological transmission occurs.
  
• in result to improvement of the symptoms of AD.
  

Side effect/ AE:

• Dizziness
• confusion
• anxiety
• cystitis
  

( so do not use in cases of renal impairment)

Dose

• One 5mg tablet daily ( can be increased up to 10mg twice daily gradually)
  

* Atypical antipsychotic drugs such as SSRI or Lithium and Haloperidol are sometimes used to manage the behavioural problems that can occur in AD.

Particle size Analysis

Primary Characteristics - relating to basic material properties, particulate size shape and SA

Secondary Characteristics - Bahavioural properties such as flow, bulk and tapped density, compactibility, lubricity

particle shape terminology

• Acicular: needle-shaped
• anglular: sharped edged ; having a roughly polyhedral shape
• fibrous: thread-like
• Flaky: plate-like
• Granular : irregular but approximately spherical overall form
• irregular: lacking of symmetry
• Modular : rounded, irregularl shape.

Thickness: the height of the particle ---> when it is resting in its position of max stability

Breath ( width) : minimum distance b/w the two tangential plane- perpendicular to defining the thickness and breadth.

length : the distance b/w 2 planes which are perpendricular to those defining the thickness and the breadth.

Shape factors

circularity

dissolution

range of particle size and units

individual particle characteristics

measures of particle size

- volume equivalent sphere

-volume equivalent diameter

ESD?

- Arithmetic mean

- Geometric mean

- surface mean diameter (SMD)

-VMD

- volume-number mean diameter (VSMD)

particle sizing of powder

Particle size distribution

Particle size Reduction

Particle size

Basic principle

1. The study of particle sizes are important in achieving optimum production of efficacious medicine.
   
2. Virtually all of the solid materials which are in common use--> in a powder/ granular form.
   

Examples

1. Pharmaceuticals ( drugs a+ excipients could be powder handling)
   
2. foods ( grain, flour, sugar)
   
3. Materials technology ( Ceramics , abrasive)
   
4. building materials (sane + cement)
   

* Uses of powders in pharmacy

Example 1

• The bioavailability of poorly soluble drugs exhibiting dissolution rate-limited absorption can be influenced by the state of subdivision of the drug ( like Griseofulvin)
• • Particle size reduction leads to increased surface are per unit weight and faster dissolution rate.
  • Specific surface area --> is when a solid is meassured the total surface area per unit of mass 1. Surface area divided by the volume or 2, Surface area divided by the mass.
    
  --> the reduction in particle size to improve rate of dissolution and bioavailability is not always benefical because, for example, the toxicity effect of nitrofurantoin

Exampe 2

• In inhalation aerosole, particle size is critical to achieve maximum penetration and deposition into the deeper airway of the drug.
  
• it has been estimated that 85% of particles >5 um are retained in the upper respiratory tract ; 90% of particle in the 1-5um range are retained in the alveolae . Particles <0.5um>

Example 3

• Drug particle size influences the content uniformity of low dose drugs in solid dosage forms --> tablets and capsules
  
• Partiicle size reduction increase the number of particles per gram. --> the greater the number of particles per dose, the lower the variability between dosage units
  

Example 4

• Both the physical stability and bioavailability of suspension can be related to the particle size achieved in the product.
  
• Sedimentation rate is proportional to the particle size ( Stoke's law) --> is a law describing that when a resisiting force on a particle movthing through a viscous fluid and shown a maximum is reached in such case.
  
• The large surface area (SA) of finely divided suspended insoluble or poorly soluble drug ensures a high availability for dissolution --> hence absorption
  

Example 5

• The mechanical irritation of topical ( cream or ointment) applied to diseased or traumatized tissues is a function of particle size.
  --> a common '' rule of thumb '' is that particles should pass through 325 mesh sieve ( 44um) to minimise mechanical irritation.
  

Example 6

• Good flowability is essential to ensuring uniform feeding of formulations to high speed tablet machines and capsule filling machines.--> determines uniformity of tablet and capsule weights ( and uniformity of doses, assuming uniformity mixing of drug and excipients had been achieved )
  --> smaller particles with high SA do not flow as well as larger particles. * the greater the SA, the more dominant are surface interactions * ( friction, cohesion/adhesion) that interact with flow.
  
• Irregular shapes do not flow as well as very smooth shapes ( soft particles)
  

Significant effect of particle shape.

1. effect on product quality
   
2. more angular materials had a greater weight variations
3. tablets made with more angular materials had highter strength --> increase in particle interlocking
   
4. better flow will occur with spherical particles
   

Particle Size
Micromeritics : The science and technology of small particles

• Colloidal dispersions particles : are too small to be seen in the ordinary microscope
• unit of particle size used most frequently in um = 10-6 m = 10-4 cm = 10-3 mm
  
• 
  

Comminution : Is an alternatve name for particle size reduction

• derived from the latin minuere meaning less, but size rediction is to be preferred as a more straightforward title
• Crushing, disintegration, dispersio, grinding and pulverization have been used synonymously with comminution depending on the product, the equipment and the process
  

Why is important?
Because it helps to improve the existing active ingredients to be delieved. Particle size influences the performance if the medicine and the pharmacological performance of the drug. For example, powder with different sizes have different flow and packing properties, which alter the volumes of powder during each encapsulation or tablet compression event. Therefore, to avoid this problem, the particle size of drug may be defined during formulation. Because, if there are any interferences with the uniformityof a fill volumes may alter the mass of drug that incorporated into the tablet or capsule and hence reduce the content uniformity of the medicine.

The following factors are infuencing size reduction

• Brittle ( How easy that a particle cracks) - Crack propagation and Toughness
  
• Plasticity - stickiness
  
• surface hardness - Slipperiness
  
• melting point
  
• Glass transition temperature
• environmental factor- moisture ( To be continued)
  

Crack propagation & toughness

• Comminution is carried out by a process of crack propagation, whereby localised stresses produce strains in the particles, which are larger enoug to cause bond rupture and propagate the crack - Cracks are generally propagated through regions of a materials that possess flaws or discontinuities and are related to the strain energy in specific regions according to Griffith's theropy of crack propagation
  
• Following crack initiation, crack tip propagate so rapidly- velocity ~ 40% of the speed of sound in the solid --> This crack propagation is so rapid that excess energy from strain relaxation is dissipated through the material and concentrates at other discontinuties, where new cracks are propagated.
  
• Thus, a cascade effect occur and almost instantaneous brittle fracture occurs
  

Are all materials exhibit brittle behaviour? - Not all materials exhibit this type of brittle behaviour and some can resist fracture at much larger stresses.

why some materials can resist fracture at much larger stress? - because these tougher materials can undergo plastic flow, which allow strain energy relaxation without crack propagation. When plastic flow occurs, atoms or molecules slip over one another and this process of deformation requires energy.

* Thus, the ease of comminution depends on the brittleness or placticity of the material because of their relationship with crack initiation and crack propagation.

Surface hardness

- Size reduction may be influenced by surface hardness. The hardness of a material can be described by its position in a scale devised by a German mineralogist called Mohs.
- Mohs's scale is a table of materials :

1. at the top of the table is diamond, which Mohs hardness > 7 , and this has a surface that is so hard that it can scratch anything below it.
   
2. At the bottom of the table is tale, with Mohs hardness <3,>
3. Materials such as Rubber which are soft under ambient condition.
   
4. Waxy substances such as stearic acid which soften when heated
5. Stick substances such as gums are capable of absorbing large amounts of energy through elactic and plastic deformation without crack initiation and propagation- This type of material, which resist comminution at ambient or elevated temperature can be more easily size reduced by lowering the temperature below the glass transition point of the material. When it is done, brittle behaviour and crack propagation is facilitated. Toughness - it is often more important than hardness
   

• problems in size reduction: it relates to moisture content in the material. ( compare green twig with dry one)
  
• toughness can be reduced by treating the material with liguid nitrogen
• Freezing the material below its glass transition temperature - be aware: the material may melt into waxy substance. ( the mill can be cooled with water jacket or by passing a stream of air through the mill.
  

Stickiness : because of heat - complete dryness and addition of inert substances like kaolin may help
Slipperiness : the reverse of stickiness property like the lubricant effect of materials, magnesium stearate.

Environmental factor

• Moisture content of the feed material , which are material is dry or wet but not damp.
  - Moisture content <>
• - Moisture content >5 % is suitable for wet milling.
  

Energy requirement of size reduction process

- only a very small amount of energy affects size reduction (~2%) . the remainder is lost in many ways.

• Elastic and plastic deformation without fracture
  
• Deformation to initiate cracks that cause fracture
  
• Deformation of metal machine parts
  
• inter particle friction and particle -machine wall friction
  
• Heat
  
• Sound
  
• vibration
  

Criteria for size reduction


An ideal crusher :

• a large capacity
  
• require a small power input per unit of product
  
• Yield a product of the single size distribution desired
  

* The cost of power is a major expense in comminution, so the factors that control this cost are important - To be continued

Milling Equipments

Cutting Methods

• Cutter mill ( C mill)
  

Compression Methods

• Morter and pestle
  (M & P )
  
• End-runner mill (End Mill)
• Edge-runner mill ( Edge Mill)

Impact methods

• Hammer Mill (H mill)
  
• Vibration Mill (V mill)
  

Attrition Methods

• Roller Mill (R Mill)
  

Combined impact and attrition methods

• Ball Mills (B mill)
  
• Fluid energy mill ( FE mill)
  

C mill consists of a series of knives

1. - Size reduction occurs by fracturing particles between stationary and rotating knives
   
2. - a screen is fitted to retain the material in the mill until a sufficient degree of size reduction is reached.

M & P - End/ Edge mill

• End-runner - the pestle is turned by the friction of material passing beneath it as the mortar rotates under power
  
• Edge-runner- the pestle mounted horizontally and rotate against the powder bed.
  

H mill - different shapes are available : Square-faced. tapered to a cutting edge, stepped form.
Priniciple :

• During milling - the hammer swing out radiallly from rotating shaft. The higher velocity of the hammers cause brittle fracture to the particles. Small particles are less prone to fracture than larger particles

• it produces powder with narrow size distributions. Particles are retained within a mill by a screen which allows only adequately comminuted particles to pass through.

V mill - Filled to appro. with 80% total porcelain or steel balls

• During milling: the whole body of the mill is vibrated and size reduction occurs by repeated impaction
  
• milled particles fall through a screen at the base of the mill. the efficiency of vibratory milling is greater than for conventional ball miling.
  

R mill- use of the principle of attrition to produce size reduction of solid in suspensions, pastes or ointment.

• 2 or 3 rolls ( porcelain or metal) are mounted horizontally with an adjustable gap (~20um)
  
• the roller rotates at different speeds , the materia is sheared as it passes through the gap, the material is transferred from the shower to the faster roll, from which is removed by means of a scraper.
  

B mill -Milling efficiency depends on:

1. Feed : too much material - producing a cushioning effect ; too little - causes loss of efficiency and abrasive wear of the mill part
   
2. Size of the balls : - large balls break down the coarse feed material , the smaller helps to form the fine product by reducing the void space between balls.
3. Speed of rotation : -
   

• Low angular velocities : little movement of the balls , so that the size reduction is minimal
  
• high angular velocities: the ball are thrown out of the mill wall by contrifugal force and no size reduction occurs
  
• at about 2/3 of critical angular velocities: centrifuging occurs, a cascading action is produed . Maximum size reduction occurs by impact of the particles with the balls and by attrition.
  

Jet / fiuld energy mill ( FE mill)



P mill

• Lower cylinder rotates at high speeds against the upper fixed cylinder
• particle size reduction occurs by impaction with the pins and by attrition between pins as the particles travel outwards under the influence of centrifugal force.