Lect 2 Side Effects and Their Role in Drug Development (1)

7/28/2019 Lect 2 Side Effects and Their Role in Drug Development (1)

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Side Effects and their role inDrug Development

New drugs with reducedside-effects- NSAIDs

Chris Benham

DDD Code: 6PHA0002

Lecture 2


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Analgesics

1899

1902(morphine)


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Analgesics

1899

1999 Cox-1Cox-2

identified


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Aspirin , NSAIDs, Cyclo-oxygenase

Aspirin, acetylsalicylic acid irreversibly inhibitscyclo-oxygenase, blocks inflammatoryprostaglandin (PG) synthesis- nociceptive pathways analgesia

- hypothalamus antipyretic Blocks production of cytoprotective PGs in gut wall

- about 1200 deaths pa in UK due to NSAIDs Blocks thromboxane production in platelets

- anti-coagulant- platelets have no nuclei, no new enzymesynthesis- Aspirin effective on platelets in low doses


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Pain pathways

Noxious

stimulus

C-fibre

activity

ExciteTransmission

neuron

CortexPain!

Sensory nerve spinal cord

Descendingpathways

tissue

Opioids+

Opioids

-

-

BrainStem

Peri-aqueductalGrey (PAG)

NSAIDs NSAIDs

--

Dorsal hornOf spinal cord


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NSAID improvements

1970s, gut sparing NSAIDse.g. etodolac, nimesulide,meloxicam

Used in vivo animal modelsto empirically improve therapeutic index- carrageenan induced oedema- adjuvant induced arthritis- fasted rat stomach inflammation for GI effects

Molecular basis of improved profile notunderstood


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Novel NSAIDS


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Discovery of Cox-1 and Cox-2

Cox-1 cloned 1988, Cox-2 cloned 1991

1990s in vitro screening against enzymeisoforms

1999, Vioxx (rofecoxib), Celebrex,(celecoxib) launched

2003 sales of Cox-2 inhibitors $5Bn

CYCLOOXYGENASES 1 AND 2 J. R. Vane, Y. S. Bakhle1, and R. M. BottingAnn Review of Pharmacol and Toxicol 38: 97-120 (1998)


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Coxib Pharmacology

Garret A. FitzGerald

Nature Reviews Drug Discovery2, 879-890(November 2003)

Rofecoxib (Vioxx) more Cox-2 selective than celecoxib

Celecoxib = Celebrex


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Arachidonic acid

COX-1constitutive

TXA2platelets

PGE2PGF2PGD2

PGI2endothelium

PLA2

Arachidonic acid metabolism pathways

COX-2Induced

by inflammation (TNFa)

Block stopsInflammation

pain

PGGut wall

Block causesgastric ulcers

Block stops platelet

aggregation

AspirinX XCox location andhence substrateavailability determinesproducts

Block causes

Platelet aggregationSmc proliferation

Non- selective compounds


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Arachidonic acid

COX-1constitutive

TXA2platelets

PGE2PGF2PGD2

PGI2endothelium

PLA2


COX-2Induced

by inflammation (TNFa)


pain

PGGut wall

XVioxx

Cox location andhence substrateavailability determinesproducts

Block causesPlatelet aggregation

Smc proliferation

Cox-2 selective compounds

thromboxaneProtective

PGs


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Cox inhibition-balancing act

Pro-thrombotic anti-coagulant

Pro-thrombotic

GI protective prostaglandins

GI damageNon-selective compounds

Cox-2 selective compounds

Some concernsin 1999 about thishypothetical

(at the time)risk


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KO mouse studies suggest balance betweenprostacyclin and thromboxane activity

Prostacyclin receptor (IP) knockoutresults in thickening of blood vessel wallAnd increase in wire induced damage(c.f. Cox2i , no Prostacyclin))

Thromboxane receptor (TP) knockoutresults in reduced thickeningand reduced damage

Double knockout is no different fromWildtype (c.f. AspirinNo prostacyclin, no thromboxane)

Garret A. FitzGerald

Nature Reviews Drug Disco very2, 879-89 ( 2003)

IPTP

IPTP


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Cox-2 inhibitor side-effects?

VIGOR 2000 (NEJM 2000 343:1520-1528 )Comparison of upper GI events in RA patients treatedwith naproxen or Vioxx2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib,

as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95

percent confidence interval, 0.3 to 0.6; P


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APPROVe trial

History of colorectal adenoma

25 mg rofecoxib vs placebo

Cancer prevention and CV outcomes CV Outcome composite of MI, unstable

angina, stroke, thrombosis

RR with rofecoxib 1.92 (1.19-3.11)

( Zarraga et al. J Am Coll Cardiol 2007, 49;1-14)


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Merck yanks arthritis drug Vioxx

Drugmaker says ongoing trial shows medicationboosts risk of heart attack; shares tumble 27%.October 6, 2004: 7:50 AM EDT

NEW YORK (CNN/Money) - Merck & Co. on Thursdayrecalled its arthritis drug Vioxx after an ongoing trial

confirmed the medication increases the risk of heartattack and strokes. The news sent stock down nearly27 percent and erased $25 billion from its marketvalue.

CNN News Oct 6th 2004


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2007 update

Vioxx settlement to total $4.85bn

The maker of Vioxx has agreed to pay $4.85bn tosettle legal claims that the controversial drug causedmany users to suffer strokes and heart failure.

Merck & Co said it was setting up a fund to compensatevictims, adding that claimants would only receivepayment if certain key conditions were met.

To qualify, individuals must prove they suffered seriousillness, at the most two weeks after they bought the drug.

The deal may end multiple lawsuits but Merck has notadmitted any liability.

BBC News Friday, 9 November 2007


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What about other Cox-2 inhibitors

Many retrospective analyses of patientstreated by Cox inhibitors

Cox-2 inhibitors should not be given topatients with history of myocardialinfarction (Circulation 2006 113(25):2906-13 )

Celebrex remains on market- sales about $2Bn in 2006


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Copyright restrictions may apply. McGettigan, P. et al. JAMA 2006;296:1633-1644.

Point Estimates and Summary Relative Risks forCardiovascular Events With Rofecoxib and

Celecoxib (Observational studies)

Overrall analysis of rofecoxib shows significant risk, but not for celecoxib


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Copyright restrictions may apply.McGettigan, P. et al. JAMA 2006;296:1633-1644.

Point Estimates and Summary Relative Risks forCardiovascular Events With Naproxen and Diclofenac

Are other older NSAIDs safe?


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Other uses of aspirin

Exploiting side-effects


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Arachidonic acid

COX-1constitutive

TXA2platelets

PGE2PGF2PGD2

PGI2endothelium

PLA2



pain

PGGut wall

Block causesgastric ulcers

Block stops platelet

aggregation

AspirinX X

Block causes

Platelet aggregationSmc proliferation

COX-2induced

Once daily low dose(200 mg)aspirin preferentiallyblocks platelet functionirreversiblyNew platelets neededto restore Cox-2


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Other uses of aspirin

Colorectal cancer prevention

- Low dose aspirin

- See Lancet (Oct 2011)


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NSAID Summary

Empirical side-effect titration, animalmodels, produced moderate improvementin GI bleed risk

Cloning Cox-1and 2 provided means toproduce highly selective compounds

Dramatic reduction in GI risk

Other side-effects brought to fore Highly selective drugs may bring their own

problems


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Summary this week

Cox2i, almost a triumph of rational design

Documents

Lect 2 Side Effects and Their Role in Drug Development (1)