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.
Anti Inflammation agents for CNS
Anti-Inflammatory Agents for CNS Diseases Brian J. Piper, Ph.D., M.S. firstname.lastname@example.org 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 Compared Neurons Glia size large small action potential yes no # few manySantiago division inRamon y adulthood no* yesCajal types pyramidal (cortex) oligodendrocytes (CNS) Purkinje (cerebellum) Schwann cells (PNS) *except hippocampus & olfactory nerve
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/
Multiple Sclerosis • neurodegenerative disorder of CNS • autoimmune • Women = 1/200; Men = 1/400 • myelin > neuronsJean Martin Charcot“father of neurology” 1825 - 1893
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 MSKurtzke, J. F. (1983). Neurology, 33(11), 1444-1452.
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 < .0001Polman et al. (2006). New England Journal of Medicine, 354(9), 899-910.
Neuroinflammation & AD • COX1: ↑ in activated microglia • COX2: high levels in pyramidal neuronsMcGreer & 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 examinedVeld 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.