Animal models in addition to the search as long as anti-rheumatic drugs Objectives To underst in addition to t
Machamer, Claire, Online Editor has reference to this Academic Journal, PHwiki organized this Journal Animal models in addition to the search as long as anti-rheumatic drugs Objectives To underst in addition to the problems with existing therapies as long as RA The reasoning behind screening cascades in addition to the position of in vivo pharmacology To appreciate the specific problems related to animal experimentation To underst in addition to how to manipulate in vivo models (immune/non immune etc) To give an example of a tertiary model of arthritis its similarities in addition to differences to RA Rheumatoid arthritis Diagnosis of rheumatoid arthritis Morning stiffness 1h Three or more joints involved Arthritis of h in addition to joints Symmetric arthritis Rheumatoid nodules Rheumatoid factor (positive < 5% normal subjects) Radiographic changes (must show erosion/decalcification) Present as long as 6wk Any 4 of the following must be present to allow diagnosis of RA:-
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Pathology of rheumatoid arthritis Exper imental therapy High dose corticosteroids Cyclophosphamide Methotrexate, azathiaprine Hydroxychloroquine Sulphasalazine Gold salts NSAIDs Low dose prednisone Patient education Physical therapy Occupational therapy High dose salicylates Surgery Intra-articular corticosteroids Traditional pyramid as long as treatment of RA Assumptions:- 1) RA relatively benign disease 2) NSAIDs less toxic than DMARDs
Sawtooth strategy as long as treatment of RA Current therapies: Treatment cascade & limitations NSAIDs Volterol, Vioxx, Celebrex (GI ulceration & Bleeding. Not DMARD) DMARDs Methotrexate, Leflunamide, Hydroxychloroquine Efficacy (refractory), Safety Myelosuppression, Hepatic toxicity BIOLOGICALS Enbrel, infliximab, Adalimumab, Anakinra (IL-1r) Expensive, inconvenient Admin, Partial/Non-responders, Safety TB, Op infection, CHF, Demyelinating Disease, Lymphoma NCEs in addition to NBEs NCEs generally work well across species tend to target well-conserved sites eg enzyme active site NBEs are often species specific Large molecular interactions are less likely to be well-conserved May need parallel reagent as long as animal models with final testing of human reagent in primates Use human transgenic animal Use human explant tissue
Screening cascade as long as NCE Isolated protein Functional cell assay Ex vivo assay In vitro toxicology CYP induction/inhibition Mini Ames Micronucleus test In vitro Metabolism Microsomal stability CaCO-2 studies In vivo PK In vivo efficacy Primary model Secondary model Tertiary model Counter screens as long as selectivity Screening cascade as long as NBEs: concept of parallel reagents In vitro studies isolated target in addition to murine cell systems Single dose PK Medium term secondary models Tertiary disease model Furry test tube Primary model Multidose PK In vitro studies isolated target in addition to human cell systems Human explant studies Furry test tube Hu-Mouse transgenic Primate studies Murine parallel reagent Human therapeutic Clinical trial Animal models: considerations as long as use in addition to interpretation of data Ethical concerns: When to use. Distress scoring. Legal: Licensing issues. Practical concerns: Is this a good experiment Statistical concerns: Group sizes. Most appropriate analysis. What to do with data from culled animals.
Effects of compound on plasma TNF 90 mins after challenge with LPS Paw oedema Sub plantar injection of irritant eg carrageenan Reaction usually maximal by 3 hours Readily quantified by plethysmometry Not an arthritis Not amenable to histological or biochemical assay End point is crude Very popular in industry! Disadvantages Measurement of paw oedema using plethysmometry Results expressed as paw volume (ml) or change in paw volume (ml)
Cavity models Peritonitis Pleurisy Air pouches Exudate volume Total in addition to differential cell counts Amenable to biochemistry Advantages Effects of experimental compound on exudate volume recovered from a 4 hour carrageenan pleurisy in the rat Means s.e.m., n=8/9 per treated group, n=4 in untreated group Statistical analysis: One way ANOVA followed by a Bonferroni’s multiple comparisons test p<0.01, p<0.001comparison with vehicle control Vehicle= 10% DMSO in addition to 90% Labrafil Drugs were administered 30 mins be as long as e carrageenan injection Effects of experimental compound on total cells recovered from a 4 hour carrageenan pleurisy in the rat Means s.e.m., n=8/9 as long as treated groups, n=4 in untreated group Statistical analysis: One way ANOVA followed by a Bonferroni's multiple comparisons test p<0.05, p<0.001comparison with vehicle control Vehicle= 10% DMSO in addition to 90% Labrafil Drugs were administered 30 mins be as long as e carrageenan injection Air pouches No interfering visceral organs Pouch lining cells have similarities to synovial cells Prolonged inflammation can be induced Disadvantages Pre as long as med cavities (6-day-old-pouches) give best results Accumulation of cells in a murine 6-day-old air pouch in response to LPS Manipulation of cavity models Non-immune models -complement dependent -complement independent Immune models -active (sensitisation in addition to challenge) -passive (adoptive transfer of serum or cells) Models of arthritis Polyarthritis Monoarticular arthritis -Adjuvant arthritis -Collagen II arthritis Matrix degradation -non-immune -Immune Collagen induced arthritis Susceptibility linked to MHC immunologically mediated Erosions of cartilage & bone Autoimmunity to collagen seen in some RA patients Arthritic rather than multisystem Disease is induced The model resolves New bone as long as mation more marked No synovial vasculitis No cycles of relapse & remission No RF No sex predilection Similarities to RA Differences to RA Collagen induced arthritis Animals (rats or mice) sensitised to collagen ll in adjuvant Booster injection (mice) Distress scoring Examine as long as clinical signs Measurement of hind paw volume (rats) Histology
Assessment of CIA Clinical assessment Disease score Body weight Analgesia Immunology CII Ab Ex vivo lymphocyte proliferation Hypersensitivity to CII Serum markers of disease progression Acute phase protein COMP Bone sialoprotein Joint pathology Histology Radiographs Drug specific Plasma levels Bioactivity markers Clinical presentation of murine CIA Score 1 2 3 Pictures Remi Okoye NORMAL WRIST SWOLLEN WRIST + PAD SWOLLEN WRIST + PAD + DIGITS SWOLLEN 0 Effects of an experimental compound on rat CIA Paw volumes Change in paw volumes AUC Days 14-24 Means s.e.m., n=10/group Statistical analysis ANOVA With Bonferroni post test p<0.01 vs Vehicle Effects of leflunomide on murine CIA Vehicle Leflunomide Animals dosed day -1 Leflunomide 3mg/kg PO once daily Vehicle = 1% Methyl Cellulose DBA/1 mice N = 15 P= <0.05 Day 31/32 P= <0.01 Day 30/33-36 Dosing strategies in CIA Clinical score Sensitisation Boost Prophylactic dosing Therapeutic dosing Dosing through sensitisation period Time CIA Histopathology Score 3 Score 0 0 normal 1 inflammatory cell influx, 2 cell influx & focal erosion cartilage & bone 3 loss of joint architecture X-ray changes in CIA CLINICAL SCORE = 0 CLINICAL SCORE = 3 Serological markers Anticollagen II antibodies in addition to their isotypes Acute phase proteins Cartilage oligomeric matrix protein (COMP) Bone sialoprotein Summary There remains an unmet need in the treatment of RA In vivo models of inflammation are an essential part of drug discovery The strategy as long as NCEs in addition to NBEs is different Efficacy in models helps define species as long as toxicology Models can help with calculation of therapeutic dose in man in addition to with identifying surrogate markers of drug activity as long as use in the clinic
Machamer, Claire Online Editor
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