Anti Inflammation agents for CNS
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Transcript of Anti Inflammation agents for CNS
Anti-Inflammatory Agents for CNS Diseases
Brian J. Piper, Ph.D., [email protected]
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
---------------------------------------------
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
-----------------------------------------------------------------------------------------252
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
-----------------------------------------------------
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