442-Fin-MS

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Author:
jgiantess
ID:
147191
Filename:
442-Fin-MS
Updated:
2012-04-12 03:08:23
Tags:
pharmacology
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Description:
pharmacology
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  1. Beta-Interferon (IFNB)
    • 1st-line disease modifying: reduce risk of relapse, unclear if affect progression
    • naturally occuring cytokines, produced in response to viruses, bacteria, other cytokines
    • IFNB-1a (Avonex) 30mcg im weekly, from chinese hamster ovaries. GLYCOSYLATED
    • IFNB-1b (Betaseron) 250mcg sc qod, from E. coli. NOT GLYCOSYLATED
    • IFNB-1a (Rebif) 44mcg sc x3weekly
    • aa sequencing differences, neutralising antibodies produced are different...reduced efficacy
    • MoA:
    • 1) periphery: less Th1 pro-inflamm cytokines, more Th2 anti-inflamm. Inhibits IFN-gamma, leukocye prolif, Ag presentation
    • 2) BBB: highly active. less MMP production, vascular cell adhesion molecule-1. Reduces trafficking of inflamm cells into CNS
    • 3) CNS: no evidence of direct effect because not known to enter
    • SE:
    • common: injection site rxns, flue-like sx, elevated liver test results, NAbs, migraine, menstrual disorders, decreased lymphocytes, leukopenia, spasticity...
    • less common: liver failure, depression, anaphylaxis
    • DI:
    • warf/theophylline/PHT: IFNB is CYP450 inhibitor
    • corts: increase risk of elevated ALT/AST
    • zidovudine: increased serum [zido], may need to decrease dose of zido
    • Efficacy: similar to GA (early use delayed conversion to clinically definite MS, but not impact disability)
    • RRMS: 30% reduction in relapses, change in MRI, possible ben effect on disability (IFNB-1a IM only)
    • SPMS: Europeans showed ben, NA did not. Likely not help unless RRMS.
    • PPMS: no effect, few clinical trials.
  2. Glatiramer Acetate (GA)
    • 1st-line disease modifying: reduce risk of relapse, unclear if affect progression
    • synthetic polypeptide analogue of myelin basic protein (L-amino acids E, A, K, T)
    • Copaxone 20mg sc daily
    • MoA:
    • 1) periphery: promotes Th2
    • 2) BBB: minimal
    • 3) CNS: Th2 cells enter CNS from periphery, decrease inflamm through bystander suppression
    • SE: chest pain, dyspnea, flushing, palpitations, anxiety, tachycardia, injection site reactions, lipoatrophy (persistent even after discontinued), nausea, injection-site reactions...less common are syncope, nystagmus, lymphadenopathy
    • DI: increased injectio site rxns in pts on cortsEfficacy:
    • Efficacy: similar to IFNB (early use delayed conversion to clinically definite MS, but not impact disability)
    • RRMS: 30% reduction in relapses, change in MRI
    • SPMS: no trials published
    • PPMS: no effect, few clinical trials.
  3. natalizumab
    • 2nd-line disease modifying: reduce risk of relapse, unclear if affect progression
    • monoclonal antibody
    • MoA: inhibits alpha-4-integrin, prevents adhesion of lymphocytes and monocytes to vascular endothelium -> limits infiltration into CNS
    • Tysabri monthly 300mg infusion
    • SE: NAbs (reduce efficacy and increase infusion rxns btwn 2-6 mo after initiation); infections, hypersensitivity, PML
    • PML: white matter demyelination, fatal...due to latent JC virus (polyomavirus) migrating to CNS...progressive weaness on one side, visual disturbance, changes in thinking, memory, orientation, confusion and personality changes, sx progress over days to weeks. Pts with + JCV Ab status, prior use of immunosuppressant, use nata >24mo have greatest risk (1:100)...usually 1:1000?
    • Efficacy:
    • beneficial on MRI and rediced elapse rate by 68% for RRMS, nothing for SPMS
    • rate of disability progression reduced by 42% over 2 yrs, sustained for 3 mo...grain of salt
    • addition of IFNB increase risk of PML (progressive multifocal leukoencephalopathy)
    • no head-to-head coparision with IFNB or GA
  4. fingolimod
    2nd-line disease modifying: reduce risk of relapse, unclear if affect progression
  5. mitoxantrone
    • 2nd-line disease modifying: reduce risk of relapse, unclear if affect progression
    • not licensed in Canada for MS, but used anyway
  6. corticosteroids
    • accelerate recovery from relapse
    • helps improve sx but not progression
    • oral vs IV no difference
  7. antidepressants, baclofen, oxybutynin, carbamezapine
    • symptomatic control
    • baclofen: spasticity
    • oxybutynin: urinary incontinence
    • CBMZ: trigeminal neuralgia, paroxysmal symptoms

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