“Ibudilast: and PDE-10) and block the cleavage of cyclic

“Ibudilast:
A Potential Therapeutic Agent for Multiple Sclerosis”

 

ABSTRACT:

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Ibudilast
(3-isobutyryl-2-isopropylpyrazolol,5-?pyridine) is an oral, non-selective
phosphodiesterase inhibitor which has anti-inflammatory and neuroprotective
properties and is currently being studied for treatment in Multiple sclerosis.

 

INTRODUCTION:

Multiple
sclerosis (MS) is an autoimmune disorder of the central nervous system
characterized by inflammatory demyelination and progressive axonal loss. MS may
manifest as relapsing-remitting or progressive form.

Ibudilast
(3-isobutyryl-2-isopropyl pyrazolol,5-? pyridine) is a non-selective
phosphodiesterase inhibitor which has anti-inflammatory and neuroprotective
properties and is currently being studied in MS.

Previously
it was used for the treatment of bronchial asthma and cerebrovascular disorders
such as post-stroke dizziness.

PHARMACOLOGICAL
PROPERTIES:

Ibudiast is a pyrazolo-pyridine
compound (Figure No.1). It is a non-selective phosphodiesterase (PDE) inhibitor
(most active against PDE-4 and PDE-10) and block the cleavage of cyclic
adenosine monophosphate (cAMP).1 It also had LTD4 antagonist, macrophage
migration inhibitory factor inhibitor, anti-inflammatory, platelet aggregation antagonist,
and vasodilator effect.2 Ibudilast is used for treatment of chronic
obstructive pulmonary disease (COPD) and asthma due to these actions.3

Ibudilast has also been used for ischemic
stroke due to inhibition of platelet aggregation and vasodilator effect.4
This effect may be due to the combination of enhancement of NO release from
endothelial cells and potentiating prostacyclin activity.4

Ibudilast has also been found to
have anti-inflammatory properties in microglia both in vitro and in vivo
studies probably due to suppression of microglial production of proinflammatory
cytokines (TNF alpha, IL-12) and reduces white matter lesions and
astrocyteapoptosis in animal models.1,5-7

PHARMACOKINETICS AND METABOLISM:

Ibudilast pharmacokinetics has been
studied in both human and animals. When 
Ibudilast was given to humans in a
single 30 mg dose and after 30 mg twice daily for 14 days, steady state was achieved by day 5
(Cmax 60ng/mL, Cmin 20ng/mL). The time to peak serum concentration (Tmax) was 5
hours. The apparent elimination half life
was 19 hours. There were no significant differences between men and women. Its metabolite,
6,7-dihydrodiol-ibudilast, had maximum concentration of about 20-50% of Ibudilast
within 10 hours of dosing and is excreted mainly in urine. Ibudilast is
negligibly excreted in urine as unchanged drug. Ibudilast was well tolerated
and had similar adverse events as with placebo.8 Interestingly
Ibudilast was found to be rapidly distributed in the CNS.9

In
a 2-week repeat dose study of Ibudilast 20-50 mg bid in 12 healthy subjects and
12 diabetics, it was well tolerated in both groups with similar
pharmacokinetics. Only difference was slightly lower circulating levels of the
6,7–dihydrodiol metabolite and corresponding slightly higher plasma Ibudilast
levels among diabetics. Ibudilast pharmacokinetics was dose-proportional in
single administration or repeat dose trials. Plasma Ibudilast levels in
multi-day repeat dosing studies in rats display significant dimunition within
1-2 weeks, steady-state drug levels remain stable in humans for at least two
weeks of repeat dosing.8-9

IBUDILAST
AND MULTIPLE SCLEROSIS:

Ibudilast
has been tested in animal model of multiple sclerosis and experimental
autoimmune encephalomyelitis (EAE). In EAE, Ibudilast had shown
anti-inflammatory properties and significant reduces CNS infiltration by
inflammatory cells and disease severity when started early.10

PRECLINICAL
TRIALS IN MS:

Ibudilast
was evaluated in relapsing MS due to its anti-inflammatory activity. As in
acute relapse of MS, acute inflammation plays a key role which is indicated by up
regulation of Th1 response (elevated IFN-? and Th1 cytokine receptors) and down
regulation of Th2 response.11  Ibudilast (60mg daily for four weeks) has been
found to shift this Th1/Th2 balance towards down-regulation of Th1 cytokine
mRNA (IFN-? and TNF?) with up-regulation of Th2 cytokine mRNA (IL-4 and IL-10)
and emerge as a potential therapeutic agent in relapsing MS.11

CLINICAL TRIALS IN MS:

In
a phase II clinical trial of Ibudilast therapy in active relapsing MS including
relapsing remitting MS (RRMS) and secondary progressive MS (SPMS), patients
were assigned 1:1:1 randomly into 3 groups – 30mg or 60mg of ibudilast or
placebo daily for 12 months.12 The trial found no significant
difference in cumulative active MRI lesions or annual relapse rate over 12
months of treatment between the 3 groups. However, the time to first relapse
and percentage of patients that were relapse-free was greater in the 60mg group
compared to placebo.  Also there was
reduction in brain atrophy rate and proportion of lesions that converted to
persistent black holes especially in the 60mg treatment group. So in this study
though there was no difference in active lesion, there was a favourable effect
on preservation of brain volume and reduction in black holes. There was no
reduction in relapse rate but on analysing the results over 24 months, less Expanded
Disability Status Scale (EDSS) score worsening /slowing of degenerative
disease-course was found in the 60mg group compared to placebo. Thus Ibudilast
demonstrated significant positive outcomes in three measures indicative of a
potential disease-modifying effect in RRMS and SPMS — slower rates of
disability due to nerve fiber damage, reduced brain volume loss, and a lower
relative risk of new inflammatory lesions converting to persistent black holes,
which are associated with relapses.

Another
multicenter phase II Ibudilast NeuroNEXT trial in MS (SPRINT-MS)13
is undergoing. This trial will include about 250 patients who received the oral
treatment up to 100 mg/day over 96 weeks.  Primary
end points of this study will focus on cerebral atrophy and safety.  This experimental oral therapy MN-166
(ibudilast) has been designated by the U.S. FDA as a “Fast Track Product” in
terms of its development as a possible treatment of progressive MS.

SAFETY AND TOLERABILITY:

Ibudilast is well tolerated and is being used for
asthma and cerebrovascular disease since more than two decades.  The adverse effects noted during clinical
trials for MS included nausea, depression, headache and nasopharyngitis.(59;1)

 

CONCLUSION:

Ibudilast has anti-inflammatory properties in microglia and is effective
in slowing cerebral atrophy and thus preserving brain volume in
relapsing/progressive multiple sclerosis.

Ibudilast is effective, safe and a potential oral
therapeutic agent for multiple sclerosis (MS).