Transcript Southern Methodist University

Multiple Sclerosis
Meaning “many scars”
Emily Harry
Dr. Buynak
Medicinal Chemistry 5398
Southern Methodist University
April 23, 2009
Overview:
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What is it?
Symptoms
Diagnosis
Types
Trying to understand MS
Blood Brain Barrier
Mineral abnormalities
What are the causes?
Different therapies
Pharmaceutical factors that affect drug formation
Prospective drugs
Multiple Sclerosis (MS)
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Is a chronic, degenerative disease that
usually begins in young adulthood.
– More prevalent in females
– Most prevalent in Caucasians
– More prevalent in areas that are further
away from the equator
Autoimmune Disease
Immune system
crosses the BBB
and attacks the
myelin sheath on
neuronal cells.
• Normal myelinated
fibers are
demyelinated by
inflammatory process
which causes
conduction block.
Sodium ion channel
redistribution and
remyelination restore
conduction and
contribute to clinical
remission.
Common Symptoms:
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Sensory problems (numbness or tingling
of a body part).
Weakness
Difficulty walking
Monocular decreased Vision
Poor coordination
Diagnosis:
MRI scans
Types:
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Asymptomatic MS
Relapsing-remitting MS (Most common ≈80%
at the onset of the disease)
Benign relapsing MS
Primary progressive MS
Progressive relapsing MS
Secondary Progressive MS
Acute MS
Clinically Isolated Syndromes
Hypothetical view of
Immune Response of MS
Understanding MS
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Autoreactive T cells are thought to launch
inflammation and, through their release of
cytokines, to stimulate B cells to secrete
antibodies that cause demyelination.
Cytokines have proved to be toxic to
neurons and oligodendrocytes if secreted in
high concentrations over sustained period of
time.
Proposed CSF Disease
Markers in MS
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Free Light Chains
Cytokines and Cytokine Receptors
Oligoclonal Bands
Antiviral antibodies
IgG and IgM
T cells (CD4+ and CD8+)
MBP – myelin basic protein
S-100
NSE – neuron specific enolase
GFAP – Glial Fibrillary acidic protein
Neurofiliments
Neural cell adhesion molecules
CNTF - Ciliary neurotropic factor
Gliotoxin
Neopterin
Matrix metalloproteinases
Blood Brain Barrier
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BBB breaks down.
Mineral Levels
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Mn2+levels in the cerebrospinal fluid
were significantly decreased about 40%.
Cu2+ levels in CSF were increased about
30%.
This could be due to alterations in the
manganese-containing enzyme
glutamine synthetase and Cu-containing
enzyme cytochrome oxidase.
Causes:
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Believed to be both Genetic and
Environmental
Environmental Theory includes pollutants
containing free-radicals that induce damage
by the stimulation of phospholipase A2 which
enhances the release of glutamate. The Ca2+ mediated effects of glutamate receptor
activation leads to neuronal degeneration.
Viral: Activated T cells could cross the BBB
following by a microbe much like a component
of the myelin sheath.
Environmental Evidence:
Therapies:
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No positive phase III trials of
immunomodulatory
There are 4 FDA approved immunomodulating
agents for relapsing forms of MS: (Betaseron®,
Avonex®, Rebif®, and Copaxone®)
And 1 FDA approved immunosuppressing drug
for worsening MS (Novantrone®).
Other agents used that are not FDA approved
include: oral azathioprine, oral methotrexate,
intravenous cyclophosphamide, and pulses of
intravenous methylprednisolone.
T-cell Therapies
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Glatiramer acetate (Copaxone®)
– Subcutaneous injection
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Low toxicity: Side effects include injection
site rxns and immediate postinjection rxns
which include chest tightness, palpitations,
flushing, and anxiety within a few minutes
of injection.
Glatiramer acetate consists of random polymers of 4
amino acids, designed to mimic myelin basic protein, an
important component of CNS myelin. Believed to work by
activating anti-inflammatory regulatory T cells, which then
migrate into the CNS to inhibit local immune rxns.
Cytokine Therapies
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Interferon-ß1b (non-glycosylated with slightly different sequence than IFN-ß)
– (Betaseron®) Subcutaneous
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Interferon-ß1a (similar to natural human IFN-ß)
– (Avonex®) intramuscular
– (Rebif®) subcutaneous
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Problematic toxicity levels.
Side effects include: Flu-like symptoms, injection site rxns,
menstrual irregularities, decreased white blood cells,
elevated liver enzymes.
ß- interferon (IFN-ß) is an anti-inflammatory regulatory cytokine
with antiviral, antineoplastic, and immunomodulatory activity.
 Decreases cell migration into the CNS
 Inhibits T-cell proliferation and expression of cell activation
markers
 Inhibits inductible Nitric Oxide synthase
 Enhances production of the anti-inflammatory cytokine
interleukin-10 and of nerve growth factor.
Immunomodulator Interferon-ß protein in human cells
Immunosuppressive
Therapies
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Mitoxantrone (Novantrone®)
– Intravenous infusion
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Side Effects include: Nausea, hair thinning,
menstrual irregularities, infertility, decreased
white blood cells, transient discoloration of
urine and sclera.
Also, possible cardiotoxicity and therefore
can be used for only a few years.
Mitoxantrone is a
cytotoxic agent that
interferes with DNA
synthesis and repair,
and suppresses a
variety of immune
system cells. Also,
enhances suppressor
cell activity.
All these agents:
Decrease the number of attacks.
Decrease severity of attacks
Decrease the formation of new lesions
Decrease the number of contrasting-enhancing lesions
Decrease the total burden of disease.
Decrease brain atrophy
Azathioprine (Imuran®)
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Used for decade although
clinical effects are
unknown. Physicians
stopped precribing it when
IFN-ß and GA were
approved.
An immunosuppressant
that inhibits purine
synthesis.
Cheap
Toxicity is high.
Oral Methotrexate
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(Rheumatrex )
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Bind to and inhibits
dehydrofolate
reductase
Started using in MS
because works well in
rheumatoid arthritis
Works best for hand
function.
Pharmaceutical Corruption
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Azathioprine and methotrexate are rarely
prescribed because of their low cost.
Pharmaceutical companies do not want
to do the expensive phase III trials to
clearly determine their effect on MS
course when they won’t be making any
money on the drug.
Drugs in Trial
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Presently there is a cell traffic inhibition agent
in Phase III trial.
– These drugs potentially could prevent the entry of
deleterious cells into the CNS (Natalizumab and
statins).
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Neuroprotection Drugs in Phase I/II: These
drugs prevent neuronal or oligodendrocyte
death and promote remyelination.
(Progesterone, Riluzole, talampanel, statins,
minocyclin).
References:
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http://www.springerlink.com/content/ugg65l9w9ycfuejb/fulltext.pdf
Multiple sclerosis current status and strategies for the future.
Washington, D.C: National Academy P, 2001.
http://www.squidoo.com/MS_Friends
Bernhard Hemmer, Stefan Nessler, Dun Zhou, Bernd Kieseier and
Hans-Peter Hartung. Immunopathogenesis and immunotherapy of
multiple sclerosis. Nature Clinical Practice Neurology: 2006 2, 201211
Waubant, Emmanuelle. "Emerging Disease Modifying Therapies for
Multiple Sclerosis." Expert Opinion on Emerging Drugs 8 (2003): 14561.
Walther, E.U. "Multiple Sclerosis: Side Effects of Interferon Beta
Therapy and Their Management." Neurology 53 (1999): 1622-627.