Lecture 36-39

Question 1

Corticosteroids (acute attacks)

Answer 1

methylprednisolone (IV or oral)

prednisone (oral)

adrenocorticotropic hormone (ACTH) (*rarely used due to cost)

corticosteroids likely act by up-regulating anti-inflammatory genes, down-regulating pro-inflammatory genes, and alleviating edema in demyelinated areas

Question 2

Interferon B1a (Avonex, Rebif) and interferon B1b (Betaseron, Extavia)

Answer 2

DMD

MOA: act in the periphery and at the BBB

Inhibition of autoreactive lymphocytes-T cells, dendritic cells (DC)

Inhibition of BBB penetration by decreasing matrix metalloproteinase (MMP)

Question 3

Clinical features of Interferon B1a (Avonex, Rebif) and interferon B1b (Betaseron, Extavia)

Answer 3

FIRST LINE DRUG

efficacy reduced by neutralizing antibodies

Flu-likesymptoms

Can pre treat with tylenol or NSAID or dose in the evening

Depression/suicidal thinking

Monitor LFT and TSH

Question 4

Glatiramer acetate (Copaxone)

Answer 4

MOA: synthetic polypeptide, mimics antigenic properties of myelin basic protein

modulation of antigen-presenting cells such as dendritic cells leading to decreased T-cell activation

FIRST LINE DRUG

Question 5

Fingolimod (Gilenya)

Answer 5

KNOW STRUCTURE*

MOA: sphingosine-1-phosphate receptor agonist

stimulation of oligodendrocyte survival, remyelination

interference with lymphocyte movement out of lymphoid organs

FIRST LINE DRUG

SE: progressive multifocal leukoencephalopathy (PML) a potentially lethal brain infection

Question 6

Natalizumab (Tysabri) humanized monoclonal

Answer 6

monoclonal antibody specific for a4 integrin

a4-integrin pairs with B1-integrin to produce ‘very late antigen’ (VLA-4)

Inhibition of VLA-4 binding to its ligand and interferes with B and T cells movement into the CNS

SECOND LINE DRUG

SE: PML
induces the development of neutralizing antibodies-allergic response

Question 7

Mitoxantrone (Novantrone)

Answer 7

3 ring structure

anthracenedione with cytotoxic activity

reduces lymphocyte numbers by causing DNA strand breaks via intercalation, and delaying DNA repair via inhibition of topoisomerase 2

SECOND LINE DRUG

first cytotoxic drug licensed for SPMS

Question 8

Teriflunomide (Aubagio)

Answer 8

cytotoxic agent that inhibits dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine biosynthesis

inhibits proliferation of peripheral lymphocytes

Question 9

Dimethyl fumarate (Tecfidera)
Diroximel fumarate (Vumerity)
Monomethyl fumarate (Bafiertam)

Answer 9

metabolized by esterases in the GI tract, blood, and tissues

Activate Nrf2-mediated cellular antioxidant responses and anti-inflammatory pathways

may promote remyelination

suppress activated T cells, dendritic cells in the periphery

SE: apparently PML

Question 10

Siponimod, Ozanimod, Ponesimod

Answer 10

sphingosine-1-phosphate (S1P) receptor agonist

same mechanism as fingolimod

Question 11

Cladribine (Mylinax)

Answer 11

KNOW STRUCTURE*

MOA:
1. taken up cells by purine nucleoside transporters
2. in cells with high ratio of deoxycytidine kinase to deoxynucleotides, cladribine is phosphorylated to the triphosphate form, 2-chloro-dATP
3. 2-chloro-dATP damages DNA and interferes with DNA metabolism, resulting in cell death–>lymphocyte depletion

Question 12

Rituximab (Rituxan, Mabthera, ZYtux)

Answer 12

TARGETS CD20 (B cell marker)

stops RRMS, effective for some PPMS patients

Question 13

Ocrelizumab (Ocrevus) aka Rituximab (Roche)

Answer 13

humanized monoclonal antibody that targets CD20 a marker for mature B cells

does not bind CD20 on stem cells or plasma cells, so that key immune functions are uperturned

decreased disease progression in PPMS

decreased relapse rate in RRMS

ADMINISTERED VIA INFUSION

Question 14

Antisense ologonucleotides

Answer 14

Experimental MS drug

target mRNA

ATL1102, an ASO targeting VLA-4–> predicted to have same outcome as natalizumab