Exam 3 lecture 3 Flashcards
Treatments for acute attacks of MS (relapses/exacerbations)
methylprednisolone
Prednisolone
Adrenocorticotropic hormone (ACTH)
What are DMDs for MS
Reduce relapse rates, may slow progression of disability (generally used to treat relapsing rather than progressive forms of MS)
1st line DMD for MS
Interferon B1a (avonex, rebixf)
Interferon B1b (betaseron, extavia)
Glatiramer acetate (copaxone)
Fingolimod (gilenya)
2nd line DMD for MS
Natalizumab (tysabri)
Mitoxantrone (novatrone)
New drugs for DMD of MS
Teriflumide (aubagio)
dimethyl fumarate (Tecfidera)
cladribine (mylinax)
What are primary corticosteroid treatments for acute attacks
Methylprednisolone (oral vs IV)
Prednisone (oral)
Adrenocorticotropic hormone (ACTH)
how do corticosteroids act
likely act by upregulating antiinflammatory genes downregulating pro inflammatroy and alleviating edema in demyelinating areas.
MOA of interferon B1a and interferon B1b for MS
acts in periphery and at BBB
Periphery- inhibition of autoreactive lymphocytes, T cells, Dendritic cells
BBB- Inhibition of BBB penetration by lowering matrix metalloprotenase (MMP)
clinical features of interferon B1a and B1b
first line
Efficacy reduced by neutralizing antibodies
Glatiramer acetate MOA for MS
synthetic polypeptide. mimics antigenic properties of myelin basic protein.
modulation of antigen-presenting cells such as dendritic cells, leading to lower T cell activation.
Clinical features of glatiramer acetate
1st line
delays the conversion of CIS to clinical MS
Name drugs that act only in periphery (including BBB)
Interferon-B
glatiramer acetate
natalizumab
mitoxantrone
teriflunomide
cladribine
rituximab
ATL 1102
drugs that act on periphery and CNS for MS
FIngolimod
siponimod
ozanimod
ponesimod
dimethyl fumarate
monomethyl fumarate
Drugs that act at BBB for MS
Interferon-B
Natalizumab
ATL 1102
What are drugs that act via a cytotoxic effect for MS
mitocantrone
Teriflunomide
Cladribine
Drugs that increase risk of PML for MS
Fingolimod
Natalizumab
dimethyl fumarate
Monomethyl fumarate
diroximel fumarate
Drugs that can be used to treat PPMS
Rituximab (ocrelizumab(
Drugs whos effectiveness may be limited by neutralizing antibodies
IF-B
Natalizumab
Rituximab
Recognize fingolimod structure
left long chain structure
attached to phenol ring
attached to two OH groups and an H2N group
MOA of fingolimod (MS)
sphingophosine-1-phosphate (s1P) receptor agonist
action of fingolimod on BBB (MS)
interference with lymphocyte movement out of lymphoid organs
action of fingolimod on periphery (MS)
stimulation of oligodendrocyte survival, remyelination
clinical features of fingolimod (MS)
first line
side effects include
progressive multifocal leukoencephalopathy
(PML), a potentially lethal brain infection
side effects of fingolimod
Could cause PML
what is PML
a potentially life threatening brain infection
progressive multifocal leukoencephalopathy
Natalizumab MOA (MS)
Monoclonal antibody specific for a-4 integrin
Natalizumab effect on periphery (MS)
a-4 integrin pairs with B1 integrin to produce very late antigen (VLA-4)
What does natalizumabs inhibition of VLA-4 lead to
inhibition of VLA-4 binding to its ligand leads to interference with B and T cell movement into CNS
Clinical features of Natalizumab
2nd line
a key side effect is the development of PML
- induces the development of neutralizing antibodies → allergic reactions
Mitoxantrone MOA (MS)
anthracenidone with cytotoxic activity
effect of mitoxantrone on periphery (MS)
reduces lymphocyte numbers
How does mitoxantrone reduce lymphocyte numbers
Cause DNA strand breakage by intercalation
delaying DNA repair via inhibition of topoisomerase II
Clinical features of mitocantrone
2nd line
Teriflunomide MOA (MS)
Cytotoxic agent that inhibits dihydroorotate dehydrogenase
effect of teriflunomide on periphery (MS)
Inhibits proliferation of peripheral lymphocytes (activated and T cells)
What are the fumarate drugs used to treat MS
Dimethyl fumarate
diroximal fumarate
monomethyl fumarate
Dimethyl fumarate, diroximal fumarate,
monomethyl fumarate MOA
metabolized by esterases in GI tract, blood, tissues
Dimethyl fumarate, diroximal fumarate,
monomethyl fumarate effects on periphery
activate Nrf2- mediated cellular antioxidant responses and anti-inflammatory pathways
suppresses activated T cells, dendritic cells in periphery
Dimethyl fumarate, diroximal fumarate,
monomethyl fumarate effects on BBB
may promote remyelination
side effects on Dimethyl fumarate, diroximal fumarate,
monomethyl fumarate
PML
recognize dimethyl fumarate structure
Recognize cladribine structure
(same as adenosine but has Cl attached)
Siponimod, ozanimod, ponesimod MOA
S1P receptor agonist (same as fingolimod)
Cladribine MOA
- taken up in cells by purine nucleoside transporters
- in cells with a high ratio of deoxycytidine kinase to deoxynucleotidase (e.g.
lymphocytes, monocytes), cladribine is phosphorylated to the triphosphate
form, 2-chloro-dATP. - 2-chloro-dATP damages DNA and interferes with DNA
metabolism, resulting in cell death -> lymphocyte depletion
What are antibody therapies for MS
Rituximab (ocrelizumab)
Use of rituximab (ocrelizumab)
PPMS pts
Rituximab (ocrelizumab) (MS) MOA
- humanized monoclonal antibody that targets CD20, a marker of mature B-cells
- doesn’t bind CD20 on stem cells or plasma cells, so that key immune functions
are unperturbed. - decreased disease progression in PPMS (first example)
- decreased relapse rate in RRMS
What are some experimental MS drugs
Antisense oligonucleotide (ATL 1102)
ATL 1102 MOA
ASO targeting VLA 4, predicted to have the same outcome as natalizumab
Which drug is active in both peripher and CNS
dimethyl fumarate
What is a single diagnostic feature or criteria to diagnose MS
No single feature or diagnostic criteria is sufficient to diagnose on clinical features or presentations
What are other disorders to rule out when diagnosing MS
Neuromyelitis
Optica spectrum disorder
What is DIT (!)
Dissemination in time
Time between evidence of new lesions in subsequent MRIs (30 days). Damage that has happened more than once.
What is DIS (!)
Dissemination in space
Need for more than 1 lesion to appear in atleast 2 of the 4 MS typical CNS regions (damage is in more than one place)
In summary- 1 lesion is not enough, 2 lesions at different areas of brain in different times.
What are the types of MS
CIS
RRMS
SPMS
PPMS
PRMS
define CIS (!)
Clinically isolated syndrome
descriptor of a 1st demyelinating event involving the optic nerve, cerebrum, cerebellum, brainstem or spinal cord.
most will develop MS within 20 yrs
Define RRMS (!)
most common (80-90% of diagnosis)
Consists of relapses with partial or complete remission between relapses.
most will become progressive over time
Define SPMS (!)
80% of RRMS pts will progress to SPMS.
consists of fewer relapses with continuing disability
Define PPMS (!)
10-15% of pts
progressive form from onset with minor improvements or periods of stability more common in patiets diagnosed in later years (greater than 50 years of age)
Define PRMS (!)
least common form. steadily worsening disease from onset with later, clear, acute relapses;
may be some recovery from acute attacks, but no
remission between relapses
treatment of acute attacks of MS (!)
- High dose corticosteroid treatment is 1st choice (oral vs IV setting)
- Methylprednisolone 500 mg-1000mg IV daily for 3-7 days, with or without an oral taper over 1-3 weeks
- If outpatient- oral prednisone 1250 mg every other day x 3 doses
Oral medications for MS (!)
Dimethyl fumarate
Diroximel fumarate
Fingolimod
Ozanimod
Punesimod
Siponimod
Teriflunomide
Injectible medications for MS (!)
interferon B 1a
Peginterferon beta-1 a
Interferon beta-1 b
glatiramer acetate
Infusion medications for MS (!)
Alemtuzumab
Natalizumab
Ocrelizumab (only one approved for PPMS)
