Multiple Sclerosis

1. Multiple Sclerosis Meaning “many scars” Emily Harry Dr. Buynak Medicinal Chemistry 5398 Southern Methodist University April 23, 2009

2. Overview: • 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

3. Multiple Sclerosis (MS) • 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

4. Autoimmune Disease Immune system crosses the BBB and attacks the myelin sheath on neuronal cells.

5. 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.

6. Common Symptoms: • Sensory problems (numbness or tingling of a body part). • Weakness • Difficulty walking • Monocular decreased Vision • Poor coordination

7. Diagnosis: MRI scans

9. Types: • 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

10. Hypothetical view of Immune Response of MS

11. Understanding MS • 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.

12. Proposed CSF Disease Markers in MS • 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

13. Blood Brain Barrier • BBB breaks down.

14. Mineral Levels • 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.

15. Causes: • 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.

16. Environmental Evidence:

17. Therapies: • 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.

18. T-cell Therapies • Glatiramer acetate (Copaxone®) • Subcutaneous injection • 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.

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.

20. Cytokine Therapies • Interferon-ß1b (non-glycosylated with slightly different sequence than IFN-ß) • (Betaseron®) Subcutaneous • Interferon-ß1a (similar to natural human IFN-ß) • (Avonex®) intramuscular • (Rebif®) subcutaneous • Problematic toxicity levels. • Side effects include: Flu-like symptoms, injection site rxns, menstrual irregularities, decreased white blood cells, elevated liver enzymes.

21. 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

22. Immunosuppressive Therapies • Mitoxantrone (Novantrone®) • Intravenous infusion • 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.

23. 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.

24. 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

25. Azathioprine (Imuran®) • 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.

26. Oral Methotrexate (Rheumatrex®) • Bind to and inhibits dehydrofolate reductase • Started using in MS because works well in rheumatoid arthritis • Works best for hand function.

27. Pharmaceutical Corruption • 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.

28. Drugs in Trial • 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). • Neuroprotection Drugs in Phase I/II: These drugs prevent neuronal or oligodendrocyte death and promote remyelination. (Progesterone, Riluzole, talampanel, statins, minocyclin).

29. References: • 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, 201-211 • Waubant, Emmanuelle. "Emerging Disease Modifying Therapies for Multiple Sclerosis." Expert Opinion on Emerging Drugs 8 (2003): 145-61. • Walther, E.U. "Multiple Sclerosis: Side Effects of Interferon Beta Therapy and Their Management." Neurology 53 (1999): 1622-627.