Anti Inflammation agents for CNS
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This PPT is part of a lecture given to second year pharmacy students in a pharmacology & toxicology class.
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Anti Inflammation agents for CNS
- 1. Anti-Inflammatory Agents for CNS Diseases Brian J. Piper, Ph.D., M.S. piperbj@husson.edu February 13, 2013
- 2. 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).
- 3. Cells in Brain Compared Neurons Glia size large small action potential yes no # few many Santiago division in Ramon y adulthood no* yes Cajal types pyramidal (cortex) oligodendrocytes (CNS) Purkinje (cerebellum) Schwann cells (PNS) *except hippocampus & olfactory nerve
- 4. Blood Brain Barrier <- Endothelial cells Astrocyte -> <- Microglia <- Neuron Bentivoglio et al. (2011). Brain Research Reviews, 66, 152-173.
- 5. 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) Brodal, P. (2010). The central nervous system. Chapter 2. Humorous Overview: http://www.scq.ubc.ca/creeping-into-your-head-a-brief-introduction-to-microglia/
- 6. Multiple Sclerosis • neurodegenerative disorder of CNS • autoimmune • Women = 1/200; Men = 1/400 • myelin > neurons Jean Martin Charcot “father of neurology” 1825 - 1893
- 7. 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.
- 8. Multiple Sclerosis Subtypes Relapsing Remitting 85% Primary Progressive 15% Example patient (20 sec – 3:55): http://www.youtube.com/watch?v=-BGBSsKBrbI
- 9. 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.
- 10. Inverse Relationship Between Effect Size of Drug & Sample Size Drug Dependent Measure Sample Size/group L-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 How to ↑Effect Size 1) numerator --------------------------------------------- Individual Differences 2) denominator 3) sensitive measures
- 11. Disease Modifying Treatment • Suggestive MS patients randomized to ITFβ1a (N=154, 22 μg s.c./week) or placebo (N=155) for 2 years 569 ----------------------------------------------------------------------------------------- 252 CDMS: Clinically Definite Multiple Sclerosis = 2nd relapse Comi et al. (2001). Lancet, 357, 1576-1582.
- 12. ITFβ1a & Neurodegeneration • Suggestive MS patients randomized to ITFβ1a (N=154, 22 μg s.c./week) or placebo (N=155) for 2 years T2 = reversed (white matter-dark) Comi et al. (2001). Lancet, 357, 1576-1582.
- 13. 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%)
- 14. 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 glatiramer (N = 120) (N = 119) 1 month 33.9% 31.3% 8 months 31.4% 15.6%* *p < .05 Fillipi et al. (2001). Neurology, 57, 731-733.
- 15. 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
- 16. MOA of Natalizumab (Tysabri) • Humanized mouse antibody (-zumab) • Binds to α4 integrins Selewski et al. (2010). American Journal of Neuroradiology, 31, 1588-1590.
- 17. 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.
- 18. 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 29% # of new T2 Hyperintense Lesions Placebo Natalizumab 17% 1 Year 6.1 1.2 2 Year 11.0 1.9* * P < .0001 Polman et al. (2006). New England Journal of Medicine, 354(9), 899-910.
- 19. Alzheimer’s Disease Projections Source: http://strategicallyspeaking.com/register/AD2/monograph/index.html
- 20. Neuroinflammation & AD • COX1: ↑ in activated microglia • COX2: high levels in pyramidal neurons McGreer & McGreer (2007). Neurobiology of Aging, 28, 639-647.
- 21. 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.
- 22. 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.
- 23. MRI T1 & hypointensity T2 & hyperintensity
Editor's Notes
- The chapter on MS 64 would be helpful here.
- Antibodies, which the immune system uses to attack foreign substances in the periphery, don’t cross the BBB.
- Classical signs of inflammation (redness, swelling, heat, and pain) don’t work in the brain. The immune response is much slower in brain than periphery.
- Original Disability Status Scale was published in 1955, the expansion was later. Pyramidal refers to whether person is paralyzed; cerebellar = ataxia; brain stem = eye movements & ability to swallow; sensory = response to pain; visual = extent of visual impairment; cerebral = mood/cognition;
- The clinical definition of multiple sclerosis requires two or more episodes of symptoms and signs. There are no FDA approved agents for PP MS.
- Interferons (IFNs) are naturally occurring cytokines possessing a wide range of anti-inflammatory properties.Glycosylation refers to the joining of a glycan to a protein. 1a is glycosylated but the glycosylation is different from humans. 1b is not glycosylated as bacteria don’t glycosylate proteins. Glycosylation decreases immunogenicity but also decreases potency.Interferon B decreases leakiness of BBB by increasing the function of endothial cells.Elevations in NGF have been reported from astrocytes and endothelial cells.Good general description of 1st line therapies for MS: http://www.youtube.com/watch?v=OwanqcI4mHY
- Denominator of Cohen’s d is pooled Standard Deviation.
- All patients had had one relapse of symptoms but the 2nd was the key criteria to be clinically definite.
- For MRI, T1 is the longitudinal relaxation time. It indicates the time required for a substance to become magnetized after first being placed in a magnetic field or, alternatively, the time required to regain longitudinal magnetization following an RF pulse.T2 is the "transverse" relaxation time. It is a measure of how long transverse magnetization would last in a perfectly uniform external magnetic field.
- http://www.howjsay.com/index.php?word=glatiramer&submit=SubmitGlitiramer is a polymer of four amino acids that are found in myelin basic protein: glutamic acid, lysine, alanine, & tyrosine. Copaxone is FDA approved to reduce the frequency of relapses but not for reducing progression of disability.Injection site reactions are described by the National MS organization as “fairly common”
- Black holes represent lesions where severe tissue disruption has occurred.Gadolinium is a dye used with MRI to identify areas of active inflammation.T2 scan is shown.
- The currently predominant hypothesis of MS states that auto-reactive T lymphocytes cross the BBB and trigger inflammatory events which results in axonal demylination & neuronal damage.
- Pronounced:natiliz uh mab. Humanized antibodies are antibodies from non-human species whose protein sequencs have been modified to increase their similarity to antibody variants produced naturally in humans.
- With anti-natalizumab, there is a corresponding reduction in drug concentration and efficacy. Allergic reactions occur in the first 2 hours after drug administration but can occur weeks afterwards. Usual symptoms include fever, headache, neck pain, itching, general malaise, and joint pain.John Cunningham (1933-1970) from Milwaukee, WI had Hodgkin’s disease. He died of PML. Source: http://bmartinmd.com/2012/01/who-the-hell-was-john-cunningham.htmlThe JC Virus is a polyomavirus and is dormant in the majority of the adult population.
- EDSS=Expanded Disability Status Scale. Progression of Disability = sustained increase in disability for > 3 months on EDDS. The range of new lesions was 0 to 191! Image is from an 80 year old patient with extensive hyperintensities in the peri-ventricular region.
- The reduced risk was specific to Alzheimer’s and did not apply to vascular dementia. Ibuprofen, naproxen, and diclofenac accounted for the vast majority of prescription NSAIDs.