MP428 Lectures - Part II

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what is thought to trigger RA?

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what is thought to trigger RA?

immuno-genetically suceptible host exposed to an arthritogenic microbial antigen

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what is TNF-alpha's role in RA

induction of further cytokine production ; activator or expression of adhesion molecules ; growth stimulation

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what does TNF-alpha mediate

acute inflammation ; anti-tumour responses ; infection

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what are the two forms of TNF-alpha

membrane bound ; soluble

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what is TACE

TNF-alpha concerting enyme - converts membrane bound TNF-alpha to soluble via cleavage

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what are the two TNF-alpha receptors

TNFR-1 and TNFR-2

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what does TNFR-1 do

inducing cell death through a 'death domain' in the intracellular portion of the receptor. TNF binds and then is internalised where it recruits TRADD which leads to DNA degradation and cell death

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what does TNFR-2 do

incapable of apoptosis as no death domain - acitvation leads to the recruitment of TRAF2 which then activates NFkappaB pathway leading to cytokine production and inhibition of apoptosis

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what are the pro-inflammatory products of TNF-alpha transcription

TNF-alpha ; IL-1beta ; upregulation of adhesion molecules ; cytokines that further enhave immune response ; activators of inflammatory pathways

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what biologics can be used in RA

infliximab ; etanercept ; adalimumab ; golimumab

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when are biologics used in RA

in pt wh ohave failed tx with DMARDs

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what type of antibody is infliximab

recombinant chimeric antibody

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what are the MoAs of infliximab in RA

binding and neutralising solible an dmembrane bound TNF-alpha ; antibody dependant cell mediated cytotoxicity or complement dependent cell mediated cytotoxicity

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how is infliximab administered

by IV infusion withing 4 hours of reconstitution. supervised for 2 hours during infusion and 2 hours after in hospital

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what are the most common s/e of infliximab

infusion reactions ; headache ; abdominal pains

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what are examples of infusion reactions

itching ; flushing ; nausea

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what are short term s/e of infliximab

runny nose ; headahces; dizziness ; flushing ; rash ; stomach pain ; indigestion

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what are the potential anti-TNF-alpha targets

TNF-alpha molecule ; TNF-alpha receptors ; TACE ; molecules in TNF-alpha signalling pathway ; NFkappaB, MAP kinase, SAP kinase pathways

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what class of arthritis is RA

inflammatory seropositive

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what are the biggest issues in RA

fatigue, impaired ability, and pain

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what can be tested for in RA diagnosis

rheumatoid factor ; anti-cyclic citrullinated peptide antibodies ; serology

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why is rheumatoid factor no the best diagnostic tool

can be positive in people with other inflammatory conditions or in those who are healthy

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what is the benefit of anti-cyclic citrullinated peptide antibodies as a diagnostic tool in RA

just as sensitive but more specific than rheumatoid factor

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what does a positive serology mean

predictor of worse dx, mores erosions, and resistant disease

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what history is important to consider when diagnosing RA

number of joints involved ; type o fjoints involved ; involvement of other tissues/organs (skin, nailes, eyes, mouth, genitalia)

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what is synovitis charaterised by

pain (worse at rest) ; stiffness (worse inmoring for >1 hour) swelling (joint feels boggy on palpitation) symptoms are helped with movement and improve with NSAID use

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what are the stages of sinovitis examination

LOOK - swelling erthema FEEL - tenderness, warmth, swelling (hard/soft) MOVE - restricted movement, assess function

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what is the DAS28-CRP disease activite score

severity of RA activity using 28 tender jpint count and swollen joint count - pt self-reported healthscore, and recent CRP

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what is the one main draw back of the DAS28 score

does not include feet

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what are the score ranges for DAS28

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what is RA remision classed as a DAS28 score

<2.6

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what DAS28 score is eligible for biologic therapy

over 5.1

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what is the patient resource for RA?

Versus Arthritis

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what are the two ways to conjugate a drug to a linear polymer

pendent chain conjugation ; terminal conjugation

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what is the polymer analogues reaction

a leaving group is conjugated to the polymer (reactive polymer precursor) and is subsequently replaced with the drug molecule

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what is polymerisation in polymer drug conjugation

drugs attached to monomers before monomers under go polymerisation with non-drug-conjugated monomers. drug has to be stable during polymerisation process

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what are the four classes of water soluble polymers

synthertic polymers (non-degradable) synthetic polymres (degradable) natural polymers dendrimirs

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what are the two types of linkers

enzymatically labile (peptide) ; pH sensitive (hydrazone)

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what are the required characteristic of an enzymatically labile linker

stable in blood but cleaved by lysosomal enzymes to release drug (3rd order targeting)

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what are the required characteristics for pH labile linkers

stable in a neutral pH (blood) and degraded in high or low pH (usually acidic)

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what are polydispersed systems

chains can be different lengths - most polymer systems are polydisperssed

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what are monodispersed systems

all chains will be the same length - aim for polymer systems but very hard to achieve

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how can polymers be used to target inflammation

inflammation causes leaky vasculature allowing exploitation of the enhanced permeation and retention (EPR) effect

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what are the new developments for polymer drug therapies

combination therapies (multiple drugs conjugated to same polymer) ; drug inserted into polymer chain rather than pendents ; dendrimers

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what are polymer-protein conjugates are composed of

several polymers (usually PEG) attached to on protein

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what are challenges of protein drugs face (IV/SC administration)

rapid renal excretion ; proteolyti degradation ; immunogenecity ; antigenicity ; aggregation ; solubility ; difficulty formualting

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what is the purpose of the polymer chains in the protein-polymer conjugates

protect protein from proteolytic degradation and immunogenicity ; increase hydrodynamic radius reducing renal clearance ; prevent aggregation

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what is a negative effect of polymers in polymer-protein conjugates

can reduce interaction with receptor depending upon location of polymer conjugation

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what are the best amino acids for conjugation with polymer

tyrosine ; serine ; cysteine ; lysine ; histidine

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what type of polymer is the best for protein-polymers

monofunctional as polyfunctional can cause crosslinking with other protein-polymer conjugates

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what else can monofunctional polymers be called

semi-telechelic polymer

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what happens to non-biodegradable linkers like PEG

exocytose and accumulate in kidneys which can cause toxicity, but only in extremely high concentrations which is not found when used in conjugation

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what are the alternatives to PEG

XTEN which is a polypeptide and made at the same time as the protein leading to homogenous product

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what is zero order

when a constant amount of drug is eliminated per unit time but the rate is independent of the concentration - no matter how much is given it will always be released at the same rate

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how to implants release drugs

erosion or diffusion (usually both but one will dominate)

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what are gliadel wafers

biodegradable wafers containing carmustine, placed in gap where glioma is removed in brain

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how is carmustine activated and deactived

by hydrolysis

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what kind of effect do gliadel wafers have

local

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what is the properties of the polymer in gliadel wafers

hydrophobic and so keeps water out to prevent premature activation

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what are the advantages of polymer implants

local adminstration (reduced toxicity) ; put in a time of surgery ; tumour debulking prior to other treatment if injected into tumour ; good pt compliance

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what are disadvantages of polymer implants

limited drug loading, need a potent drug ; need a non-immunogneic polymer ; difficult to remove if ADR occur

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what are auto-antibodies

mainly IgM, attack self-antigens, in healthy individuals they target dead cells and wast products, in pathology they target specific self-antigens in the body, developing autoimmune diseases

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what are the risk factors of autoimmune disease

women 2x as likely (specifically childbearing) ; ethnicity ; genetic predisposition ; diet (western) ; bacterial/viral infection ; adverse drug reactions ; chemical toxins/environmental pollutants ; prior hx of AuID

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what are common sings and symptoms of NS autoimmune diseases

fatigues ; fever ; swelling/pain ; numbness/tingling in extremites ; rash ; muscle pain/weakness

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what diagnositc tools are used in MS and MG etc

MRI ; lumbar puncture ; antinuclear antibody test ; physical examination/symptoms (walking, eye examination, muscle tests, chest and lungs)

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what tx are used in MG and MS etc.

immunosuppressants (steroids, mAbs, disease modifying therapies) ; plasma exchange ; immunoglobulines ; analgesics ; lifestyle (diet, exercise, supplements)

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what are the different types of myasthenia

myasthenia gravis ; occular myasthenia ; lambert-eaton myasthenic syndrome

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what is myasthenia caused by

acetylecholine receptors are targeted by antibodies leading to interruptions in neurotransmission

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what can the interruption of Ach neurotransmission cause

weakness and fatigue in some/all muscles which is worse on exertion and towards the end of the day. it affects voluntary muscle movements.

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what are the symptoms of myasthenia

double vision ; weakness in limbs ; fatigue ; face can also been affected

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in which groups of people are most effected by myasthenia

early adult hood ; females

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what does myasthenia tx include

oral pyridostigmine ; steroids (prednisolone) ; immunosuppresants (azathioprine, MTX, mycophenolate, ciclosporin) ; plasmapheresis ; IVIG ; thymectomy

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what drugs should be avoided in myasthenia

antibiotics ; anti-psychotics ; beta-blockers

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what is gullian-barre syndrome

often occurs after (1-3 weeks) an infection. caused by T-cell mediated reaction against peripheral nerve myelin - weakness/numbness and pain in hands, feet, and limbs, as well as breathing and swallowing issues in severe cases.

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how is gullian-barre syndrome diagnosed

nerve tests such as nerve conduction studies, electromyography. lumbar puncture - CSF protein is elevated (usually takes 1-2weeks). exclusion of other diseases

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how is gullian-barre syndrome treated

IVIG ; plasmapheresis to speed up recovery

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what monitoring is required for gullian-barre syndrome

FVC to check for resp failure

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how is MS diagnosed

usually during mid life - neurological sx history ; MRI of CNS ; LP - Ab in brain ; rule out other possible conditions

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what is the tx of relapsing and remiting MS (RRMS)

DMTs (alemtuzumab, ocrelizumab, beta-interferons) ; steriods for acute relapses (methylprednisolone)

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what can primary progressive MS (PPMS) treated with

ocrelizumab

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what happens in harmful drug-drug interactions?

toxicity or reduced efficacy

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what happens in beneficial drug-drug interactions

synergism, increased convenience, reduced toxicity, cost reduction

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what is a pharmacokinetic drug-drug interactions

where one drug alters the level of another

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what is a pharmacodynamic drug-drug interaction

where there is no change in the drug level but the activity of the drug is altered by another drug

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