Anti-Inflammatory Agents for CNS Diseases

Brian J. Piper, Ph.D., M.S.piperbj@husson.edu

February 13, 2013

Objectives

• Pharmacy students should be:– familiar with pharmacotherapies for Multiple

Sclerosis (see also DiPiro chapter 64)– able to evaluate the role of anti-inflammatory

agents in other neurodegenerative diseases (AD).

Cells in Brain ComparedNeurons Glia

size large small

action potential yes no

# few many

division in adulthood

no* yes

types pyramidal (cortex)Purkinje (cerebellum)

oligodendrocytes (CNS)Schwann cells (PNS)

SantiagoRamon yCajal

*except hippocampus & olfactory nerve

Blood Brain Barrier

Astrocyte ->

<- Microglia

<- Neuron

<- Endothelial cells

Bentivoglio et al. (2011). Brain Research Reviews, 66, 152-173.

Microglia

• Frequency: 10% of all glia• States– scanning: evaluate environment for sick cellular

elements– activated: • divide• move• phagocytose• Release pro-inflammatory cytokines (IL-1α, IL-1β, TNF- α)

Humorous Overview: http://www.scq.ubc.ca/creeping-into-your-head-a-brief-introduction-to-microglia/

Brodal, P. (2010). The central nervous system. Chapter 2.

Multiple Sclerosis• neurodegenerative disorder of CNS• autoimmune• Women = 1/200; Men = 1/400• myelin > neurons

1825 - 1893

Jean Martin Charcot“father of neurology”

Expanded Disability Status Scale

• Neurologist rates various functional systems (FS) (visual, cerebral, cerebellar, sensory, pyramidal)

• Total– 0: normal neurological exam– 1: minimal disability on 1 FS– 2.5: minimal disability on 2 FS– 4.5: able to walk without aid for 300 m– 6.5: constant bilateral support– 8.5: bedridden but some self-care maintained– 9.5: unable to communicate/eat/swallow– 10: death due to MS

Kurtzke, J. F. (1983). Neurology, 33(11), 1444-1452.

Multiple Sclerosis Subtypes

Relapsing Remitting85%

Primary Progressive15%

Example patient (20 sec – 3:55): http://www.youtube.com/watch?v=-BGBSsKBrbI

Interferon β• What:

– IFNβ-1a: Chinese hamster ovary, glycosylation +– IFN β-1b: E coli, glycosylation -

• Indication: to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations in RRMS

• MOA: ?– ↓ BBB permeability– Binds to IFN transmembrane receptors, reduces activation of myelin

reactive T cells– ↑ Nerve Growth Factor release from astrocytes

• AE: flu-like symptoms, depression

Mendes & Sa (2011). Arq Neuropsiquiatry, 69(3), 536-543.

Inverse Relationship Between Effect Size of Drug & Sample Size

Drug Dependent Measure Sample Size/groupL-DOPA motor function 5-10

heroin pain 5-10

sertraline delayed ejaculation 10

methylphenidate cognitive vigilance 15

sertraline antidepressant 100(s)

tacrine cognitive enhancement 100(s)

riluzole survival (ALS) 1,000

Effect Size = MeanDrug – MeanPlacebo

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Individual Differences

How to ↑Effect Size1) numerator2) denominator3) sensitive measures

Disease Modifying Treatment• Suggestive MS patients randomized to ITFβ1a

(N=154, 22 μg s.c./week) or placebo (N=155) for 2 years

CDMS: Clinically Definite Multiple Sclerosis = 2nd relapse

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569

Comi et al. (2001). Lancet, 357, 1576-1582.

ITFβ1a & Neurodegeneration• Suggestive MS patients randomized to ITFβ1a

(N=154, 22 μg s.c./week) or placebo (N=155) for 2 years

Comi et al. (2001). Lancet, 357, 1576-1582.

T2 = reversed (white matter-dark)

Glatiramer Acetate

• Structure: Glu-Lys-Ala-Tyr (also found in myelin basic protein)

• MOA: ?, decoy• Indications: ↓ relapse frequency in RRMS• AE: injection site reactions (50%)

Glatiramer & Neurodegeneration• black holes: – lesions initially appear hypointense on T1 scans– 40% of lesions progress to darkness intermediate

between gray matter & CSF • RRMS randomized to glatiramer (20 mg/day)

or placebo for 8 months

placebo (N = 120)

glatiramer (N = 119)

1 month 33.9% 31.3%

8 months 31.4% 15.6%*

Fillipi et al. (2001). Neurology, 57, 731-733.

*p < .05

MS Substrates• 1) reactive T lymphocytes cross BBB• 2) trigger inflammation• 3) axon demyelination• 4) nerve damage

Adhesion Extravasation

VCAM: Vascular Cell Adhesion Molecule; MadCAM: Muccosal adressin Cell Adhesion Molecule

MOA of Natalizumab (Tysabri)• Humanized mouse antibody (-zumab)• Binds to α4 integrins

Selewski et al. (2010). American Journal of Neuroradiology, 31, 1588-1590.

Adverse Effects of Natalizumab

• Anti-natalizumab antibodies (5%)• Hypersensitivity reaction (4%)• Progressive Multifocal Leukoencephalopathy (0.1%)– JC (John Cunningham) Virus– loss of oligodendrocytes– fatal

Horga & Tintore (2011). Neurologia, 26(6), 357-368.

Natalizumab Evaluation• RRMS with score < 5 on EDSS randomized to

natalizumab (300 mg, i.v. 1x/month; N=627) or placebo (N=315) for two years

17%

29%

Placebo Natalizumab

1 Year 6.1 1.2

2 Year 11.0 1.9*

# of new T2 Hyperintense Lesions

* P < .0001

Polman et al. (2006). New England Journal of Medicine, 354(9), 899-910.

Alzheimer’s Disease Projections

Source: http://strategicallyspeaking.com/register/AD2/monograph/index.html

Neuroinflammation & AD

• COX1: ↑ in activated microglia• COX2: high levels in pyramidal neurons

McGreer & McGreer (2007). Neurobiology of Aging, 28, 639-647.

Do COX Inhibitors Prevent AD?• Non-demented older

(55+) adults (N=6,989) were followed for 7 years

• Prescriptions of NSAIDs were examined

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Veld et al. (2001). New England Journal of Medicine, 346(21), 1515-1521.

Summary

• Interferon β1A/B & Glatiramer Acetate are 1st line treatments followed by Natalizumab for MS.

• Blocking inflammation has been useful to prevent, but not treat, Alzheimer’s Disease.

MRI

T1 & hypointensity T2 & hyperintensity