Multiple sclerosis (MS) is a chronic, complex neurodegenerative disease targeting the CNS, and it is believed that it is an autoimmune disease in nature. This disease occur simply by: 1- Autoreactive T cells that are able break through the endothelial cells and the basement membrane. So it could pass the blood brain barrier. 2- Because this is unfamiliar environment for the T cells, the T cells and other lymphocytes begin to attack parts of the neurons, specially the proteins on the surface of the myelin, as a foreign body. 3- As a normal response for the immune system, T cells release cytokines. These cytokines do different effects, increase the degradation of the BBB. So allow more and more cells to pass and more T cells with more cytokines. Also B cells pass the BBB and make antibodies against the myelin and make more degradation on it. Macrophages are able to pass too, which will engulf that myelin. 4- after the cytokines make a great degradation on the myelin which is called neuroinflmmation. 5- The neurons has its way to fix that degradation, by oligodendrocytes which begin the process of remyelination to repair the damaged myelin. 6- But as the time pass that process of remyelination become less effective in comparison with the power of the immune cells, and over powered by the antibodies of the B cells, the cytokines of the T cells and the macrophages. (Solaro et al, 2013)

1. Faculty of Pharmacy
pharmacology
Assignment Topic: Multiple Sclerosis
Course Title: Pharmacology
Course Code: PO311
Lab Group: C1
Submitted to: DR. Ahmed Fayez
Prepared By: Menrva father Moisis – 170429

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A) Pathophysiology
Multiple sclerosis (MS) is a chronic, complex neurodegenerative disease targeting the CNS, and
it is believed that it is an autoimmune disease in nature. This disease occur simply by:
1- Autoreactive T cells that are able break through the endothelial cells and the basement
membrane. So it could pass the blood brain barrier.
2- Because this is unfamiliar environment for the T cells, the T cells and other lymphocytes
begin to attack parts of the neurons, specially the proteins on the surface of the myelin, as a
foreign body.
3- As a normal response for the immune system, T cells release cytokines. These cytokines do
different effects, increase the degradation of the BBB. So allow more and more cells to pass and
more T cells with more cytokines. Also B cells pass the BBB and make antibodies against the
myelin and make more degradation on it. Macrophages are able to pass too, which will engulf
that myelin.
4- after the cytokines make a great degradation on the myelin which is called neuroinflmmation.
5- The neurons has its way to fix that degradation, by oligodendrocytes which begin the process
of remyelination to repair the damaged myelin.
6- But as the time pass that process of remyelination become less effective in comparison with
the power of the immune cells, and over powered by the antibodies of the B cells, the cytokines
of the T cells and the macrophages. (Solaro et al, 2013)

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B) Symptoms
1) In vision: it is the first noticeable symptom of the MS, it could be noticed as following:
- Impaired vision: low ability to read small fonts. It may reaches loss of the vision in the
affected eye for days.
- Washed out color vision in the affected eye.
- General pain specially by moving the eye.
- Involuntary horizontal and vertical eye movement, which will affects the visions of the
stationary objects.
- Double vision. (Chwastiak et al, 2002).
2) Fatigue: abnormal feeling of exhaustion in making simplest every day activity. This
sensation of fatigue increases by the end of the day, after exercising, and in hot weather.
3) Sensation: one of the initial symptoms of the MS is the abnormal sensation. It begin at
arms or legs as numbness then spreads all over the body in few days.
4) Muscles: muscle spasm and contract tightly and painfully. The muscle then become
stiff and sometimes resist to move. In addition, feeling too weak to move.
5) Pain: - neuropathic pain: in face, trunk, and limbs. Feeling of burning.
- Musculoskeletal pain: increase the pressure on hips and lower back which increase the
difficulty in movement and walking.
6) Sexual problems: erectile dysfunction, lose the ability to ejaculate.
7) In bladder: frequent urinary tract infection and urination. Having sudden and urgent
need for urination which may ends with unintentionally passing urine. Difficulty in
completely emptying the bladder. Also an urgent need for urination during night
frequently.
8) Other problems:
- Difficulty in swallowing and speaking: dysphagia and dysarthria.
- Bowel problems: constipation, and more irritation.
- Anxiety and mood swings.
- Problems in attention, thinking, long term memory, and making decision.

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C) Drugs
1) Immunosuppressive (Natalizumab)
Mechanismof action it the first drug in the group of disease modifying therapies DMTs, it
is also known as the selective adhesion molecules SAM inhibitors. It acts by preventing specific
inflammatory responses which leads to developing the MS lesion. The endothelial of the blood
vessels lumen express VCAM-1 at the active site of multiple sclerosis lesion, which is bound to

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alpha4 beta1 integrin. These adhesion molecules found on the surface of the leukocytes except
the neutrophils. This binding between the VCAM-1 and the alpha4 beta1 integrin is essential for
the leukocytes adhesion and transmigration through the blood brain barrier to the brain. The
natalizumab acts by blocking the interaction between the VCAM-1 and the α4β1 integrin by
binding to the α4β1 integrin. So it inhibit the migration of leukocytes through the BBB to the
brain, and as a result the inflammation reduced. According to Smith et al (2007), the
Natalizumab also inhibit the leukocytes that is already found in the CNS, by inhibiting the
interactions between alpha 4 integrin expressing leukocytes and extracellular matrix protein,
such as osteopontin.
Side effects
1- Progressive multifocal leukoencephalopathy: an opportunistic viral infection in brain. This
PML is caused by JC virus in people with weakened immune system. This infection may lead to
sever disability or death.
2- Herpes infection: the natalizumab increases the risk of infection with varicella zoster virus or
herpes simplex, and developing meningitis or encephalitis.
3- Hepatotoxicity.
4- Hypersensitivity and antibody formation.
5- Immunosuppression/Infections.
Drug interaction
1- BCG vaccine: the live virus vaccines should not be administered with natalizumab or
generally with immunosuppressed patient. As the vaccine may lead to the disease it is
administered to prevent. Due to the enhanced replication of vaccine virus or bacteria in the case
of diminished immune competence.
2- Etanercept: Natalizumab should not be used with tumor necrosis factor modifiers, as it
increases the risk of serious infections, including multifocal leukoencephalopathy and other

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opportunistic infection. Because the TNF modifiers decrease the inflammation response of the
immune system.
3- Cortisone: cortisone is an immunosuppressant so should not be taken with Natalizumab,
because the risk of infection increases.
4- Naltrexone: the naltrexone itself may cause hepatic problems, and using it with natalizumab
may increase that risk.
2) Immunomodulator (Glatiramer acetate)
Mechanismof action the glatiramer acetate composed of 4 amino acids which is found in
the basic protein of myelin. It is an immunomodulator. It is believed to shift the T cells from Th1
T cells (proinflammatory) into Th2 T cells (regulatory) in which it can inhibit the inflammatory
response. It acts as a trap for the immune system, by giving its likeness to the myelin basic
proteins (synthetic myelin). Simply, after several times by retraining immune cells to be less
reactive against the synthetic myelin, when the immune cells see real myelin be less reactive
against it. (Neuhaus et al, 2001).
Side effects Munari et al (2003) observed that all the adverse effects of this drug is mild:
1- Local reaction: it may show aches and lump at the site of injection.

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2- General: 5% of the patients show rapid heartbeats after injection. Other side effects as fever,
anxiety.
Drug interaction
1- Natalizumab: using both drugs together may increase the risk of serious viral infection in
brain that may leads to death or sever disabilities. As the immune system become much
suppressed with the use of natalizumab to be protected against any viral infection.
2- Vaccines: may not show its best result in the presence of glatiramer acetate.

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References:
Chwastiak, L., Ehde, D.M., Gibbons, L.E., Sullivan, M., Bowen, J.D. and
Kraft, G.H., 2002. Depressivesymptoms and severity of illness in multiple
sclerosis:epidemiologic study of a large community sample. American Journal
of Psychiatry, 159(11), pp.1862-1868.
Munari, L.M., Lovati, R. and Boiko, A., 2003. Therapywith glatiramer
acetate formultiple sclerosis.Cochranedatabaseof systematicreviews, (4).
Neuhaus, O., Farina, C., Wekerle, H. and Hohlfeld, R., 2001. Mechanisms of
actionof glatirameracetate in multiple sclerosis.Neurology, 56(6), pp.702-708.
Solaro, C., Trabucco, E. and Uccelli, M.M., 2013. Painand multiple sclerosis:
pathophysiologyand treatment. Current neurology and neuroscience
reports, 13(1), p.320.
Smith, B., Carson, S., Fu, R., McDonagh, M., Dana, T., Chan, M.B.K.,
Thakurta, S. and Gibler, A., 2010. Drug class review:Disease-modifying
drugs for multiple sclerosis. FinalUpdate, 1.