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Multiple Sclerosis Meaning “many scars” Emily Harry Dr. Buynak Medicinal Chemistry 5398 Southern Methodist University Apri...
Overview: <ul><li>What is it? </li></ul><ul><li>Symptoms </li></ul><ul><li>Diagnosis </li></ul><ul><li>Types </li></ul><ul...
Multiple Sclerosis (MS) <ul><li>Is a chronic, degenerative disease that usually begins in young adulthood. </li></ul><ul><...
Autoimmune Disease Immune system crosses the BBB and attacks the myelin sheath on neuronal cells.
<ul><li>Normal myelinated fibers are demyelinated by inflammatory process which causes conduction block. Sodium ion channe...
Common Symptoms: <ul><li>Sensory problems (numbness or tingling of a body part). </li></ul><ul><li>Weakness </li></ul><ul>...
Diagnosis: MRI scans
 
Types: <ul><li>Asymptomatic MS </li></ul><ul><li>Relapsing-remitting MS (Most common ≈80% at the onset of the disease) </l...
Hypothetical view of Immune Response of MS
Understanding MS <ul><li>Autoreactive T cells are thought to launch inflammation and, through their release of cytokines, ...
Proposed CSF Disease Markers in MS <ul><li>Free Light Chains </li></ul><ul><li>Cytokines and Cytokine Receptors </li></ul>...
Blood Brain Barrier <ul><li>BBB breaks down. </li></ul>
Mineral Levels <ul><li>Mn 2+ levels in the cerebrospinal fluid were significantly decreased about 40%. </li></ul><ul><li>C...
Causes: <ul><li>Believed to be both Genetic and Environmental </li></ul><ul><li>Environmental Theory includes pollutants c...
Environmental Evidence:
Therapies: <ul><li>No positive phase III trials of immunomodulatory </li></ul><ul><li>There are 4 FDA approved immunomodul...
T-cell Therapies <ul><li>Glatiramer acetate (Copaxone ® ) </li></ul><ul><ul><li>Subcutaneous injection </li></ul></ul><ul>...
Glatiramer acetate consists of random polymers of 4 amino acids, designed to mimic myelin basic protein, an important comp...
Cytokine Therapies <ul><li>Interferon- ß1b  (non-glycosylated with slightly different sequence than IFN-ß)   </li></ul><ul...
<ul><li>ß - interferon (IFN- ß) is an anti-inflammatory regulatory cytokine with antiviral, antineoplastic, and immunomodu...
Immunosuppressive Therapies <ul><li>Mitoxantrone (Novantrone ® ) </li></ul><ul><ul><li>Intravenous infusion </li></ul></ul...
<ul><li>Mitoxantrone is a cytotoxic agent that interferes with DNA synthesis and repair, and suppresses a variety of immun...
<ul><li>All these agents: </li></ul><ul><li>Decrease the number of attacks. </li></ul><ul><li>Decrease severity of attacks...
Azathioprine (Imuran ® ) <ul><li>Used for decade although clinical effects are unknown.  Physicians stopped precribing it ...
Oral Methotrexate (Rheumatrex ® ) <ul><li>Bind to and inhibits dehydrofolate reductase </li></ul><ul><li>Started using in ...
Pharmaceutical Corruption <ul><li>Azathioprine and methotrexate are rarely prescribed because of their low cost. </li></ul...
Drugs in Trial <ul><li>Presently there is a cell traffic inhibition agent in Phase III trial. </li></ul><ul><ul><li>These ...
References: <ul><li>http://www.springerlink.com/content/ugg65l9w9ycfuejb/fulltext.pdf </li></ul><ul><li>Multiple sclerosis...
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  • As in other autoimmune diseases, women are much more likely to get MS than men, suggesting that hormonal or genetic factors are involved. Ratio 2:1.
  • An MRI image shows multiple ovoid and confluent hyperintense lesions in the white matter surrounding the ventricles. Nine months later, the number and size of the lesions have increased demonstrate ring or peripheral enhancement, indicating the breakdown of the BBB. After the administration of gadolinium, many of the lesions demonstrate ring or peripheral enhancement, indicating the breakdown of the BBB. A parasagittal T1-weighted MRI scan shows multiple regions in which the signal is diminished in the periventricular white matter and corpus callosum. These regions correspond to the chronic lesions of MS.
  • MS lesions are typically confined to CNS white matter, and are found most frequently in periventricular areas of the brain, but are also in the optic nerves, the brain stem and the spinal cord.
  • T- and B-cell responses are primed in the peripheral lymphoid tissue by antigens that are released from the CNS or by cross-reactive foreign antigens. Dendritic cells that present neural antigens are strong stimulators of T-cell responses. After clonal expansion, T and B cells infiltrate the CNS. Clonally expanded B cells re-encounter their specific antigen, mature to plasma cells and release large amounts of immunoglobulin- (IgG) antibodies. These antibodies bind soluble or membrane-bound antigen on expressing cells. Clonally expanded CD8+ T cells also invade the brain and could encounter their specific peptide ligand, presented by glial or neuronal cells on MHC class I molecules. The recognition of specific MHC–peptide complexes on these cells prompts direct damage to expressing cells. CD4+ T cells migrate into the CNS and encounter antigens that are presented by microglial cells on MHC class II molecules. Reactivation of these cells leads to heightened production of inflammatory cytokines. These cytokines attract other immune cells, such as macrophages, which contribute to inflammation through the release of injurious immune mediators and direct phagocytic attack on the myelin sheath.
  • This is consistent with animal studies finding that EAE can be produced only by injecting myelin- specific T cells in combination with myelin-specific antibodies. Without injecting the antibodies, demyelination does not occur.
  • Activated antigen-specific T cells and B cells cross the blood–brain barrier and target self antigens expressed by oligodendrocytes and neurons. In concert with the innate immune response in the CNS, T cells and B cells cause inflammatory damage. Susceptibility of oligodendrocytes and neurons to inflammatory damage, and the capacity for CNS repair and reorganization, determines the extent and functional consequences of the inflammatory damage.
  • Manganese(II) ions function as cofactors for a number of enzymes in higher organisms, where they are essential in detoxification of superoxide free radicals. The element is a required trace mineral for all known living organisms. In larger amounts, and apparently with far greater activity by inhalation, manganese can cause a poisoning syndrome in mammals, with neurological damage which is sometimes irreversible.
  • L-lysine, L-tyrosine, L-glutamic acid, L-alanine, acetic acid and molar ratio of (1.4: 3.4: 4.2: 1.0)
  • Transcript of "Multiple_Sclerosis_EmilyHarry"

    1. 1. Multiple Sclerosis Meaning “many scars” Emily Harry Dr. Buynak Medicinal Chemistry 5398 Southern Methodist University April 23, 2009
    2. 2. Overview: <ul><li>What is it? </li></ul><ul><li>Symptoms </li></ul><ul><li>Diagnosis </li></ul><ul><li>Types </li></ul><ul><li>Trying to understand MS </li></ul><ul><li>Blood Brain Barrier </li></ul><ul><li>Mineral abnormalities </li></ul><ul><li>What are the causes? </li></ul><ul><li>Different therapies </li></ul><ul><li>Pharmaceutical factors that affect drug formation </li></ul><ul><li>Prospective drugs </li></ul>
    3. 3. Multiple Sclerosis (MS) <ul><li>Is a chronic, degenerative disease that usually begins in young adulthood. </li></ul><ul><ul><li>More prevalent in females </li></ul></ul><ul><ul><li>Most prevalent in Caucasians </li></ul></ul><ul><ul><li>More prevalent in areas that are further away from the equator </li></ul></ul>
    4. 4. Autoimmune Disease Immune system crosses the BBB and attacks the myelin sheath on neuronal cells.
    5. 5. <ul><li>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. </li></ul>
    6. 6. Common Symptoms: <ul><li>Sensory problems (numbness or tingling of a body part). </li></ul><ul><li>Weakness </li></ul><ul><li>Difficulty walking </li></ul><ul><li>Monocular decreased Vision </li></ul><ul><li>Poor coordination </li></ul>
    7. 7. Diagnosis: MRI scans
    8. 9. Types: <ul><li>Asymptomatic MS </li></ul><ul><li>Relapsing-remitting MS (Most common ≈80% at the onset of the disease) </li></ul><ul><li>Benign relapsing MS </li></ul><ul><li>Primary progressive MS </li></ul><ul><li>Progressive relapsing MS </li></ul><ul><li>Secondary Progressive MS </li></ul><ul><li>Acute MS </li></ul><ul><li>Clinically Isolated Syndromes </li></ul>
    9. 10. Hypothetical view of Immune Response of MS
    10. 11. Understanding MS <ul><li>Autoreactive T cells are thought to launch inflammation and, through their release of cytokines, to stimulate B cells to secrete antibodies that cause demyelination. </li></ul><ul><li>Cytokines have proved to be toxic to neurons and oligodendrocytes if secreted in high concentrations over sustained period of time. </li></ul>
    11. 12. Proposed CSF Disease Markers in MS <ul><li>Free Light Chains </li></ul><ul><li>Cytokines and Cytokine Receptors </li></ul><ul><li>Oligoclonal Bands </li></ul><ul><li>Antiviral antibodies </li></ul><ul><li>IgG and IgM </li></ul><ul><li>T cells (CD4+ and CD8+) </li></ul><ul><li>MBP – myelin basic protein </li></ul><ul><li>S-100 </li></ul><ul><li>NSE – neuron specific enolase </li></ul><ul><li>GFAP – Glial Fibrillary acidic protein </li></ul><ul><li>Neurofiliments </li></ul><ul><li>Neural cell adhesion molecules </li></ul><ul><li>CNTF - Ciliary neurotropic factor </li></ul><ul><li>Gliotoxin </li></ul><ul><li>Neopterin </li></ul><ul><li>Matrix metalloproteinases </li></ul>
    12. 13. Blood Brain Barrier <ul><li>BBB breaks down. </li></ul>
    13. 14. Mineral Levels <ul><li>Mn 2+ levels in the cerebrospinal fluid were significantly decreased about 40%. </li></ul><ul><li>Cu 2+ levels in CSF were increased about 30%. </li></ul><ul><li>This could be due to alterations in the manganese-containing enzyme glutamine synthetase and Cu-containing enzyme cytochrome oxidase. </li></ul>
    14. 15. Causes: <ul><li>Believed to be both Genetic and Environmental </li></ul><ul><li>Environmental Theory includes pollutants containing free-radicals that induce damage by the stimulation of phospholipase A2 which enhances the release of glutamate. The Ca 2+ -mediated effects of glutamate receptor activation leads to neuronal degeneration. </li></ul><ul><li>Viral: Activated T cells could cross the BBB following by a microbe much like a component of the myelin sheath. </li></ul>
    15. 16. Environmental Evidence:
    16. 17. Therapies: <ul><li>No positive phase III trials of immunomodulatory </li></ul><ul><li>There are 4 FDA approved immunomodulating agents for relapsing forms of MS: (Betaseron ® , Avonex ® , Rebif ®, and Copaxone ® ) </li></ul><ul><li>And 1 FDA approved immunosuppressing drug for worsening MS (Novantrone ® ). </li></ul><ul><li>Other agents used that are not FDA approved include: oral azathioprine, oral methotrexate, intravenous cyclophosphamide, and pulses of intravenous methylprednisolone. </li></ul>
    17. 18. T-cell Therapies <ul><li>Glatiramer acetate (Copaxone ® ) </li></ul><ul><ul><li>Subcutaneous injection </li></ul></ul><ul><li>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. </li></ul>
    18. 19. 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.
    19. 20. Cytokine Therapies <ul><li>Interferon- ß1b (non-glycosylated with slightly different sequence than IFN-ß) </li></ul><ul><ul><li>(Betaseron ® ) Subcutaneous </li></ul></ul><ul><li>Interferon-ß1a (similar to natural human IFN-ß) </li></ul><ul><ul><li>(Avonex ® ) intramuscular </li></ul></ul><ul><ul><li>(Rebif ® ) subcutaneous </li></ul></ul><ul><li>Problematic toxicity levels. </li></ul><ul><li>Side effects include: Flu-like symptoms, injection site rxns, menstrual irregularities, decreased white blood cells, elevated liver enzymes. </li></ul>
    20. 21. <ul><li>ß - interferon (IFN- ß) is an anti-inflammatory regulatory cytokine with antiviral, antineoplastic, and immunomodulatory activity. </li></ul><ul><li>Decreases cell migration into the CNS </li></ul><ul><li>Inhibits T-cell proliferation and expression of cell activation markers </li></ul><ul><li>Inhibits inductible Nitric Oxide synthase </li></ul><ul><li>Enhances production of the anti-inflammatory cytokine interleukin-10 and of nerve growth factor. </li></ul>Immunomodulator Interferon- ß protein in human cells
    21. 22. Immunosuppressive Therapies <ul><li>Mitoxantrone (Novantrone ® ) </li></ul><ul><ul><li>Intravenous infusion </li></ul></ul><ul><li>Side Effects include: Nausea, hair thinning, menstrual irregularities, infertility, decreased white blood cells, transient discoloration of urine and sclera. </li></ul><ul><li>Also, possible cardiotoxicity and therefore can be used for only a few years. </li></ul>
    22. 23. <ul><li>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. </li></ul>
    23. 24. <ul><li>All these agents: </li></ul><ul><li>Decrease the number of attacks. </li></ul><ul><li>Decrease severity of attacks </li></ul><ul><li>Decrease the formation of new lesions </li></ul><ul><li>Decrease the number of contrasting-enhancing lesions </li></ul><ul><li>Decrease the total burden of disease. </li></ul><ul><li>Decrease brain atrophy </li></ul>
    24. 25. Azathioprine (Imuran ® ) <ul><li>Used for decade although clinical effects are unknown. Physicians stopped precribing it when IFN- ß and GA were approved. </li></ul><ul><li>An immunosuppressant that inhibits purine synthesis. </li></ul><ul><li>Cheap </li></ul><ul><li>Toxicity is high. </li></ul>
    25. 26. Oral Methotrexate (Rheumatrex ® ) <ul><li>Bind to and inhibits dehydrofolate reductase </li></ul><ul><li>Started using in MS because works well in rheumatoid arthritis </li></ul><ul><li>Works best for hand function. </li></ul>
    26. 27. Pharmaceutical Corruption <ul><li>Azathioprine and methotrexate are rarely prescribed because of their low cost. </li></ul><ul><li>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. </li></ul>
    27. 28. Drugs in Trial <ul><li>Presently there is a cell traffic inhibition agent in Phase III trial. </li></ul><ul><ul><li>These drugs potentially could prevent the entry of deleterious cells into the CNS (Natalizumab and statins). </li></ul></ul><ul><li>Neuroprotection Drugs in Phase I/II: These drugs prevent neuronal or oligodendrocyte death and promote remyelination. (Progesterone, Riluzole, talampanel, statins, minocyclin). </li></ul>
    28. 29. References: <ul><li>http://www.springerlink.com/content/ugg65l9w9ycfuejb/fulltext.pdf </li></ul><ul><li>Multiple sclerosis current status and strategies for the future . Washington, D.C: National Academy P, 2001. </li></ul><ul><li>http://www.squidoo.com/MS_Friends </li></ul><ul><li>Bernhard Hemmer, Stefan Nessler, Dun Zhou, Bernd Kieseier and Hans-Peter Hartung. Immunopathogenesis and immunotherapy of multiple sclerosis. Nature Clinical Practice Neurology: 2006 2, 201-211 </li></ul><ul><li>Waubant, Emmanuelle. &quot;Emerging Disease Modifying Therapies for Multiple Sclerosis.&quot; Expert Opinion on Emerging Drugs 8 (2003): 145-61. </li></ul><ul><li>Walther, E.U. &quot;Multiple Sclerosis: Side Effects of Interferon Beta Therapy and Their Management.&quot; Neurology 53 (1999): 1622-627. </li></ul>
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