mycophenolate mofetil a suppression tale ד " ר יוסי רימר
TRANSCRIPT
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Mycophenolate mofetil
A suppression tale
ד"ר יוסי רימר
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Mycophenolate mofetil
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History
MPA, a product of a Penicillium fungus, was originally isolated in 1896
MPA has anti-neoplastic, anti-viral, anti-fungal and immunosuppressive activity
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Mechanism of action
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Mechanism of action
MMF prevents T and B cell proliferation by inhibiting the metabolic pathway needed for cell division.
Two major pathways lead to purine synthesis : de-novo & salvage
T and B cell depend selectivly on the de-novo pathway
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Mechanism of action
The action of MPA on IMPDH and its ability to inhibit nucleic acid synthesis was established in 1969.
There are two types of IMPDH type I & type II.
MPA inhibits both types.The inhibition is selective reversible and
non-competitive
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Mechanism of action – regulation of purine synthesisPurine synthesis is regulated by the
balance of of adenosine to guanosine nucleotides.
IMPDH inhibition causes reduction in guanosine nucleotides and excess of adenosine nucleotides.
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Mechanism of action – regulation of purine synthesis
in human lymphocytes AMP excess cause feedback inhibition of PRPP synthetase.
Excess of d ATP inhibits ribonucleotide diphosphatase reductase.
So no substrates for DNA and RNA are available.
The de-novo pathway is shuts down
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Other metabolic effects
Glycoprotein (selectines,integrines) synthesis requires GTP for manose and fructose transfer.
MPA interfere with adhesion molecules synthesis.
Depletion of GTP interfrer with G prot. Signal transduction
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T and B lymphocytes
MPA inhibits generation of Tc.MPA prevents Ab production by
polyclonal activated B cells.MPA has no effect on cytokine
production.
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Clinical trials
MMF has FDA approval since 1995MMF is equel to AZA when 1 year
survivel is measuredMPA inhibits response to PHA,PWM,
Protein A.MPA also inhibits late MLRMPA inhibits proliferation of T and B
cells
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Cytokine production
CsA and FK-506 inhibits early T activation and IL-2 production
MPA has no primary effect on IL-2Long term treatments inhibits allmost all
cytokines production.
Meaning – MPA has no influence on early activation.
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Antibody production
Ab production is inhibitedMostly primary response is inhibited
MMF inhibits primary humoral response but not secondary response
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Apoptosis in T lymphocutes
MPA doubles the amount of apoptotic cells after CD3 activation.
MOLT-4 cells showed 82-98% apoptosisWith MPA.
MPA can eliminate T cells responding to TCR activation and possibly Ag
stimulation
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Inhibition of adhesion molecules
GTP depletion inhibits fucose and manose transfer to glycoproteins.
Adhesion molecules are one class of those glycoproteins.
The transfer through the golgi apparatus is impaired due to incorrect glycosylation
GTPase regulate secretory pathways – no GTP no regulation.
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Adhesion molecules production is tempered in multiple cellular
levels
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Say NO to MPA
NO a multifunctional biological mediatorNO is synthesized from guanidino
nitrogen of L-arginine by NO-synthaseiNOS is the enzyme that regulates NO No iNOS makes apoptosis inefficient Acute graft rejection is also NO
mediated.
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MMF suppresses NO production in human
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HIV
HIV replicates in lymphocytes where GTP is depleted.
It is logical to find some anti-HIV activity when usinf MPA.
MPA has synergistic anti-HIV effect with Abacavir (Margolis 1999)
Abacavir is a guanosine analog RT inh.When no dGTP Abacavir works better
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Other infection
Hsv – MPA potentiates acyclovir and gancyclovir
EBV – MPA inhibits cellular prolifaration of EBV infected cells
HCV – MPA given to hcv+ liver transplanted had better long term surviv.
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PMA and human
disorders
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Rheumatoid Arthritis
2 DB studies preformed.Improvement seen in some patients not
responding to any treatment before.RF titers were lowerPeak effect started after 8-12 weeks and
lasted 36 weeks.
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Myasthenia gravis
1 report about successful treatment of a severe refractory MG.
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Skin disease
MMF efficacy in treating Psoriasis is well proven
Other diseases treated are:PemphigusDishidrotic eczemaIdiopathic nodular panniculitis
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Renal disaease - SLE
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SLE
“We found that the regimen of mycophenolate mofetil and prednisolone induced complete remission in 81 percent of patients and partial remission in 14 percent within 12 months. These results were similar to those obtained with our sequential regimen but were better than the response rates reported by other investigators”