“Ibudilast:A Potential Therapeutic Agent for Multiple Sclerosis” ABSTRACT:Ibudilast(3-isobutyryl-2-isopropylpyrazolol,5-?pyridine) is an oral, non-selectivephosphodiesterase inhibitor which has anti-inflammatory and neuroprotectiveproperties and is currently being studied for treatment in Multiple sclerosis. INTRODUCTION:Multiplesclerosis (MS) is an autoimmune disorder of the central nervous systemcharacterized by inflammatory demyelination and progressive axonal loss. MS maymanifest as relapsing-remitting or progressive form.Ibudilast(3-isobutyryl-2-isopropyl pyrazolol,5-? pyridine) is a non-selectivephosphodiesterase inhibitor which has anti-inflammatory and neuroprotectiveproperties and is currently being studied in MS.Previouslyit was used for the treatment of bronchial asthma and cerebrovascular disorderssuch as post-stroke dizziness.
PHARMACOLOGICALPROPERTIES:Ibudiast is a pyrazolo-pyridinecompound (Figure No.1). It is a non-selective phosphodiesterase (PDE) inhibitor(most active against PDE-4 and PDE-10) and block the cleavage of cyclicadenosine monophosphate (cAMP).1 It also had LTD4 antagonist, macrophagemigration inhibitory factor inhibitor, anti-inflammatory, platelet aggregation antagonist,and vasodilator effect.2 Ibudilast is used for treatment of chronicobstructive pulmonary disease (COPD) and asthma due to these actions.3Ibudilast has also been used for ischemicstroke due to inhibition of platelet aggregation and vasodilator effect.4This effect may be due to the combination of enhancement of NO release fromendothelial cells and potentiating prostacyclin activity.
4Ibudilast has also been found tohave anti-inflammatory properties in microglia both in vitro and in vivostudies probably due to suppression of microglial production of proinflammatorycytokines (TNF alpha, IL-12) and reduces white matter lesions andastrocyteapoptosis in animal models.1,5-7PHARMACOKINETICS AND METABOLISM:Ibudilast pharmacokinetics has beenstudied in both human and animals. When Ibudilast was given to humans in asingle 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 5hours. The apparent elimination half lifewas 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 Ibudilastwithin 10 hours of dosing and is excreted mainly in urine.
Ibudilast isnegligibly excreted in urine as unchanged drug. Ibudilast was well toleratedand had similar adverse events as with placebo.8 InterestinglyIbudilast was found to be rapidly distributed in the CNS.9Ina 2-week repeat dose study of Ibudilast 20-50 mg bid in 12 healthy subjects and12 diabetics, it was well tolerated in both groups with similarpharmacokinetics. Only difference was slightly lower circulating levels of the6,7–dihydrodiol metabolite and corresponding slightly higher plasma Ibudilastlevels among diabetics.
Ibudilast pharmacokinetics was dose-proportional insingle administration or repeat dose trials. Plasma Ibudilast levels inmulti-day repeat dosing studies in rats display significant dimunition within1-2 weeks, steady-state drug levels remain stable in humans for at least twoweeks of repeat dosing.8-9IBUDILASTAND MULTIPLE SCLEROSIS:Ibudilasthas been tested in animal model of multiple sclerosis and experimentalautoimmune encephalomyelitis (EAE). In EAE, Ibudilast had shownanti-inflammatory properties and significant reduces CNS infiltration byinflammatory cells and disease severity when started early.10PRECLINICALTRIALS IN MS:Ibudilastwas evaluated in relapsing MS due to its anti-inflammatory activity.
As inacute relapse of MS, acute inflammation plays a key role which is indicated by upregulation of Th1 response (elevated IFN-? and Th1 cytokine receptors) and downregulation of Th2 response.11 Ibudilast (60mg daily for four weeks) has beenfound to shift this Th1/Th2 balance towards down-regulation of Th1 cytokinemRNA (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.11CLINICAL TRIALS IN MS:Ina phase II clinical trial of Ibudilast therapy in active relapsing MS includingrelapsing remitting MS (RRMS) and secondary progressive MS (SPMS), patientswere assigned 1:1:1 randomly into 3 groups – 30mg or 60mg of ibudilast orplacebo daily for 12 months.12 The trial found no significantdifference in cumulative active MRI lesions or annual relapse rate over 12months of treatment between the 3 groups. However, the time to first relapseand percentage of patients that were relapse-free was greater in the 60mg groupcompared to placebo.
Also there wasreduction in brain atrophy rate and proportion of lesions that converted topersistent black holes especially in the 60mg treatment group. So in this studythough there was no difference in active lesion, there was a favourable effecton preservation of brain volume and reduction in black holes. There was noreduction in relapse rate but on analysing the results over 24 months, less ExpandedDisability Status Scale (EDSS) score worsening /slowing of degenerativedisease-course was found in the 60mg group compared to placebo. Thus Ibudilastdemonstrated significant positive outcomes in three measures indicative of apotential disease-modifying effect in RRMS and SPMS — slower rates ofdisability due to nerve fiber damage, reduced brain volume loss, and a lowerrelative risk of new inflammatory lesions converting to persistent black holes,which are associated with relapses.Anothermulticenter phase II Ibudilast NeuroNEXT trial in MS (SPRINT-MS)13is undergoing. This trial will include about 250 patients who received the oraltreatment up to 100 mg/day over 96 weeks.
Primaryend 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” interms of its development as a possible treatment of progressive MS.SAFETY AND TOLERABILITY:Ibudilast is well tolerated and is being used forasthma and cerebrovascular disease since more than two decades. The adverse effects noted during clinicaltrials for MS included nausea, depression, headache and nasopharyngitis.
(59;1) CONCLUSION:Ibudilast has anti-inflammatory properties in microglia and is effectivein slowing cerebral atrophy and thus preserving brain volume inrelapsing/progressive multiple sclerosis.Ibudilast is effective, safe and a potential oraltherapeutic agent for multiple sclerosis (MS).