Evaluation of anti inflammatory drugs
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Evaluation of Anti-inflammatory drugs
SEMINAR ON
PRESENTER : Dr. Jill Mathew Dated :04/09/2013
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Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult
Pfizer took about 18 years to develop the anti-inflammatory drug piroxicam, which was launched in 1980 during the “golden age of rational drug discovery”
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CARDINAL SIGNS OF
INFLAMMATION
12
34
5
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Acute: vasodilatation & increased capillary permeability
Delayed: infiltration of leukocytes and phagocyte cells
Chronic proliferative: tissue degeneration and
fibrosis
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(1) Recognition of the injurious agent(2) Recruitment of leukocytes(3) Removal of the agent(4 ) Regulation of the response(5) Resolution
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ICAM-1 and VCAM-1
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MEDIATOR VASODILATATION
VASCULAR PERMEABILTY
CHEMOTAXIS PAIN
Histamine ++ _ +
Serotonin +/- _ +
Bradykinin +++ _ +++
Prostaglandins
+++ +++ +
Leukotrienes - +++ _
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Animals used: Albino Guinea pigs Test drug is administered -30 min before exposure Duration of exposure to UV –B rays : 20 sec Area of exposure : Depilated skin Degree of erythema estimated after 2 hours
visually on a scale 0-4
ADVANTAGE : Pure measure of the vasodilatory phase
Drawback: Accurate measurement of reaction not obtained, variability of response
DRUGS EFFECTIVE : NSAIDS like Phenyl butazone, Aminopyrene, Aspirin and Sodium salicylate
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Area 2: treated with topical H 1 antagonist (1.5% chlorphenoxamine hydrochloride in the same cream base, Allergex, Epico) twice daily.
Area 1: used as a control area and was exposed to -UVB and treated with cream base only twice daily.
Area 3: treated with topical H 2 antagonist (2% famotidine in the same cream base) twice daily
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Rat-paw edema (Acute and Subacute phases) Drugs: Carrageenan (1%, 0.1 ml SC.),
indomethacin 2 mg/kg IP Site : Subplantar region of left hind paw
Experimental injury cascade of events
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Biphasic 1 – release of histamine,5 HT and kinins 2- release of prostaglandins
Parameter : Paw volume up to the ankle joint is measured in treated and untreated groups before and after carrageenan
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Advantage: Simple ,easy, short lasting and
reproducible
Disadvantage : Non –specific and difficult to quantify
and examine cells & their modification by anti-inflammatory drugs
Avoid in both the hind paws because of unalleviated pain and deformity
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% of edema produced by carrageenan alone = A – B X 100 = X % B % of edema produced by carrageenan after
treatment with drug = C – D X 100 = Y % D % reduction of edema by drug = X –Y= %
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1. Carrageenan – COX 2. Mustard3. Dextran4. Egg-white
Phlogistic agents5. Compound 48/806. Yeast, Zymosan-LOX7. Serotonin, histamine8. Kaolin9. Substance –p, nystatin, glass powder,
cobra venom
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an instrument for measuring changes in volume within an organ whole body or limb
The mercury displacement due to dipping of the paw can be directly read from the scale attached to the mercury column
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TUBE A
TUBE B
RAT PAW IS IMMERSED INTOTHE TUBE ‘A’ & THE READING IS CHECKED THROUGH THE TUBE ‘B ’ SOME SET UPS HAVE A DIGITAL DISPLAY ATTACHED TO IT
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Inducer of arthritis: Silver nitrate in the tibiotarsal joint of rats Intra articular talc injections in pigeons
Locomotor activity with inflammed paws
is impaired Drugs effective: NSAIDS,
steroids ,DMARDS Anti-histamines
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Induction of Pleurisy: Carrageenan , turpentine, Evan’s blue, Arabic
gum, glycogen, dextran , antigens , microbes, mast cell degranulators
Advantage: Quantitation of anti-inflammatory activity and M.O.A of new test drug
Drugs effective: Steroid, NSAIDS & Gold Index of activity of drug: The volume of exudate is decreased
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1. Croton oil induced ear edema ( Croton tiglium)
2. TPA-induced ear edema - Protein kinase C , NF-кB ,
phospholipase A2 PG
3. Arachidonic acid induced ear edema
4. Xylol induced ear edema
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Predictable model for topical anti-inflammatory drugs
Inflammatory response measured by increase in ear plug weight & thickness at single time interval( at 6 hours)
Drugs tested : Steroids and NSAIDS
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Right -Control
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Std duration (27 sec) and Std intensity (55◦C)
thermostatically
controlled water
to the shaved abdomen of rat
Resultant edema can be measured by excising skin
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Egg albumin or horse serum Passively sensitized by
antibodies
Intra-dermal injection of Ag or Ab is made
Inflammatory reaction ASSESSMENT : by dye leakage or edema Drugs effective :Cortisone , Salicylates
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To study repair phase characterized by fibroblast proliferation and blood vessel formation
Suppression of granulation tissue parallels with anti-inflammatory activity
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For measurement of activity of anti-inflammatory drugs on proliferative component of ‘subacute & chronic inflammatory processes’
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Sterile Cotton pellets (wt :5mg -50mg ) sc sites of axilla , back ,groin Duration : 1-14 days Pellet along with granuloma removed
and weighed
Weight of granulomatous tissue = Dry weight of granuloma cotton -initial
weight of cotton pellet Drugs effective: corticosteroids
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Immunologically mediated model of chronic inflammation
It a delayed HS response to mycobacterial Ag
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Induction of Arthritis : Subplantar injection of Freund’s complete adjuvant or mycobacteria suspended in oil
Day 1 Day 4-5 Day 7 Local reaction Peak Systemic disease
Parameters : Foot thickness, wt, grip strength , deformity
measured Evaluation of chronically administered drug against
inflammation Drugs effective: Steroids ,Immunosuppressants, gold
,d-penicillamine
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Chronic exposure to foreign bodies like contact lenses leads to GPC
Levels of IL3,IL 4,IL5 ,Ig G, Ig E and Ig M is increased in Tears
Procedure : A sterile needle is inserted directly into conjunctiva of unsensitized animal
Pricking results in high number of neutrophil infiltration
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VCAM-1,ICAM-1 and E-selectin are derived from HUVEC ,HDMEC cell lines
Cell based ELISA –assay
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HUVEC,HMEC
TNF-ἀ as reagent
Test drug
20 min
BCECF labeled WBC
20 min
No drug
Adherent cells are lysed and fluorescence measured at 485 nmin ELISA reader
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Thrombin activated human platelets
Incubated with drug at 20 0 C for 10 min & mixed with Neutrophils at a ratio 10:1
Index of activity : Neutrophils with 2 or more and one or no adherent platelets are counted
Test drug : Blocks Adhesion
Drugs effective : NSAID ,chloroquine
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Dianzani etal the PMNs are challenged by FMLP to
generate 02- for screening anti-inflammatory compounds
Superoxide production was measured spectrophotometrically by measuring the superoxide dismutase inhibitable reduction
Drugs effective: Anti-oxidant drugs
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Stimulates A and C fibers producing pain Lowers BP by vasodilatation Test : detects compounds that inhibit binding of 3 H- Bradykinin in membrane preparation of
guinea pig ileum Evaluation: specific binding= total binding-
nonspecific binding % inhibition:100- specific binding
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Leptin is a proinflammatory cytokine Circulating leptin levels are increased upon
infectious and inflammatory stimuli such as LPS, turpentine, and cytokines
Leptin increased statin inhibitible free radical and cholestrol production invitro
CRP increased in obesity and reduced by statin JUPITER TRIAL, Leptin and Insulin resistance Fructose fed rat is a model of metabolic
syndrome.
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The compounds were found to be useful in OA,RA and Psoriasis
A HAPPY TEACHERS DAY TO ALL TEACHERS ON BEHALF OF US