Molecular basis of drug resistance Molecular basis of drug resistance How to Explain Multidrug Resistance in Epilepsy? How to Explain Multidrug Resistance in Epilepsy? Eleonora Eleonora Aronica Aronica Department of ( Department of ( Neuro)Pathology Neuro)Pathology , AMC, University of Amsterdam , AMC, University of Amsterdam Stichting Stichting Epilepsie Epilepsie Instellingen Instellingen Nederland Nederland Nationaal Nationaal Epilepsie Epilepsie Symposium Symposium 28 May 2010 28 May 2010
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Molecular basis of drug resistance Molecular basis of drug resistance How to Explain Multidrug Resistance in Epilepsy?How to Explain Multidrug Resistance in Epilepsy?
EleonoraEleonora AronicaAronica
Department of (Department of (Neuro)PathologyNeuro)Pathology, AMC, University of Amsterdam, AMC, University of Amsterdam StichtingStichting EpilepsieEpilepsie InstellingenInstellingen NederlandNederland
NationaalNationaal EpilepsieEpilepsie SymposiumSymposium28 May 201028 May 2010
PharmacoresistancePharmacoresistance in Brain diseasesin Brain diseases
Resistance to drug treatment is a critical problem in the theraResistance to drug treatment is a critical problem in the therapy of py of many brain disordersmany brain disorders
Brain tumors: intrinsic or acquired resistance to chemotherapeutic drugs
HIV infections of the CNS: resistance to HIV protease inhibitors
Psychiatric disorders (Mood disorders and Schizophrenia): resistance to current treatments
Epilepsy: resistance to several antiepileptic drugs (AEDs) acting by different mechanisms
525 Patients525 Patients
Epilepsy Unit, Glasgow, Scotland 1984-1997
Long term follow-up of mixed population
Kwan and Brodie N Engl J. Med, 2000
333 (63%) seizure free 192 (37%) Uncontrolled
How Common Is How Common Is PharmacoresistancePharmacoresistance in Epilepsy ?in Epilepsy ?
Observational cohort studies of newly diagnosed epilepsy in adults (Kwan &
Brodie, 2000; Mohanraj & Brodie, 2006) and children (Arts et al., 2004) suggest that once a patient
has failed trials of two appropriate AEDs, the probability of achieving
seizure freedom with subsequent AED treatments is modest
1. Remitting–relapsing pattern
2. One-third: poor long-term outcome
Persistent seizures after remission
or without any remission
Seizure-free with a change of medical regimen?
01020
3040
5060
70
<50% reduction 50-99%reduction
seizure free
Luciano et al. Ann Neurol 2007;62:375–381
Likelihood of seizure remission in an adult population with refractory epilepsy. 15 % obtained a 6-month terminal seizure remission: hope of a meaningful seizure remission in this population. Callaghan et al., Ann Neurol 2007;62:382–389.
Remission after second drug failure is common but often temporary. Children who have not responded to two appropriate drugs should be carefully evaluated to maximize therapy and possibly considered for more aggressive treatments. A.T. Berg et al, Ann Neurol. 2009 May;65(5):510-9.
Remission of epilepsy after two drug failures in children: a prospective study
The application of a systematic protocol
• The number of drugs that need to be failed
• The seizure frequency
• Factors related to time
Definition of Pharmacoresistance in Epilepsy
Failure to control seizuresFailure to control seizures
Factors to be considered in the definition of Pharmacoresistance:
NeurolNeurol ClinClin 27 (2009)27 (2009)
Definition of Pharmacoresistance in Epilepsy
There was no unifying definition of There was no unifying definition of ““PPharmacoresistance ””
Definition of Pharmacoresistance in Epilepsy
Drug-responsive epilepsy
Epilepsy in which the patient receiving the current AED regimen has been seizure-free for a minimum of three times the longest pre-intervention interseizure interval or 12 months, whichever is longer.
‘‘failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom’’
Consequences of Consequences of PharmacoresistancePharmacoresistance
Shortened lifespan
Injury, hospitalization- Status epilepticus
Neuropsychological and psychiatric impairment- Cognitive impairment - Depression- Reduded quality of life
Social disability
Early age of onset
Presentation with status epilepticus
Partial seizure at diagnosis
Abnormal neurological exam
High seizure frequency prior to antiepileptic treatment
Failure of first AED
Multiple seizures after treatment
Little or no effect effect of AEDs on cortical excitability (Transcranial magnetic stimulation;Badawy et al. ANN NEUROL 2010;67:64–73)
Multidrug resistance is likely to be Multidrug resistance is likely to be multifactorialmultifactorial
Pharmacogenetics
Löscher et al., Epilepsia, 50(1):1–23, 2009
•Disease-related factors
•Drug related factors:- Loss of efficacy (tolerance)- Ineffective mechanism of action
Mechanisms of Mechanisms of PharmacoresistancePharmacoresistance in Epilepsyin Epilepsy
1.1. Changes in drug targetsChanges in drug targets(sodium, calcium, GABAa channels)
2.2. Poor penetration of drugs into the brainPoor penetration of drugs into the brain
3. 3. Intrinsic disease severityIntrinsic disease severityRogawskiRogawski and Johnson., Epilepsy and Johnson., Epilepsy CurrCurr. 2008, 8(5):127. 2008, 8(5):127--130.130.
Schmidt D, Löscher W., Epilepsy Curr. 2009, 9(2):47-52
Reduced sensitivity of drug targets
GABAA receptors
Kapur and MacDonald (1997)
Beck et al. (2007)
Antiepileptic drug resistant rats differ from drug responsive rats in GABAA receptor subunit expression in a model of temporal lobe epilepsy. Bethmann K, et al., Neurobiol Dis 2008;31:169–187..
Several major antiepileptic drugs are substrates for human PSeveral major antiepileptic drugs are substrates for human P--glycoprotein.glycoprotein.((LunaLuna--TortTortóós C, Fedrowitz M, Ls C, Fedrowitz M, Lööscher W. scher W. NeuropharmacologyNeuropharmacology 55, 2008)55, 2008)
But not of human MRP1, MRP2 or MRP5But not of human MRP1, MRP2 or MRP5 ((NeuropharmacologyNeuropharmacology 58, 2010)58, 2010)
Are AEDs substrates of multidrug transporters ?
Pgp/control Pgp/epilesy
Multidrug Transporters are Overexpressed in Epileptogenic Tissue
Phenytoin, phenobarbital , Lev, VAL, Topiramate,
Potschka and Aronica, Atlas of Epilepsies, 2010
Potschka and Aronica, Atlas of Epilepsies, 2010
Multidrug Transporters are overexpressed in epileptic brain
*
*
FCDFCD
0
50
100
150
200
250
HippocampalHippocampal SclerosisSclerosis
Control
Epilepsy
BCRP Pgp MRP2
Aronica et al., Aronica et al., EpilepsiaEpilepsia 20052005
Control (n=7)Chronic epilepsy (n=5)
Reduction of PHT
PHT
ratio
(b
rain
/pla
sma)
*
0
0.5
1
1.5
2
2.5
0
0.5
1
1.5
2
2.5
Increase of P-gp
Nor
mal
ized
o.d
.(P
-gp/
b-ac
tin)
*
van Vliet et al., Epilepsia, 2005, 2006
RambeckRambeck, et al., , et al., EpilepsiaEpilepsia, 2006, 2006
Reduced levels of Phenytoin in chronic epileptic rats
0
4
8
12
16
0 7 14 21 28 35 42 49 56 63 70
days
aver
age
num
ber o
f sei
zure
s
Selective inhibition of Pgp function by tariquidar enhanced efficacy of the AEDs phenytoin or phenobarbital (Brandt et al. 2006, van Vliet et al. 2006).
PHT+XR12 mg/kg
***
PHT+XR24 mg/kg
* ** *
PHT
**
N=6
Increased levels of phenytoin in epileptic tissue
Inhibition of Pgp function enhanced efficacy of the AEDs
= PET tracer= Pgp
Endothelial cell
1st PET scan 2nd PET scan + inibitor Pgp
PharmacoresistancePharmacoresistance in Epilepsy: A Pilot in Epilepsy: A Pilot PET Study with the PPET Study with the P--Glycoprotein Glycoprotein Substrate RSubstrate R--[[1111C]verapamilC]verapamilLanger et al., Langer et al., EpilepsiaEpilepsia, 48(9):1774, 48(9):1774––1784, 20071784, 2007
Potschka and Aronica, Atlas of Epilepsies, 2010
Clinical evidence: identification of resistance mechanisms in patients
Two successive PET scans using a Pgp substrate radiotracer with and
without pre-treatment with a Pgp inhibitor
= multidrugtransporter
= antiepilepticdrug
2
3
4
Brain capillaryendothelial cell
Pgp/control Pgp/epilepsy
Clinical Relevance and new Clinical Relevance and new strategiesstrategies
1
New New ““pharmacological targets pharmacological targets ”” or or new new AEDsAEDs which specifically which specifically target ion channels or receptors in target ion channels or receptors in their state that predominates their state that predominates
in the brain of in the brain of pharmacoresistantpharmacoresistant individuals individuals
Inhibitors of MDRInhibitors of MDR
Bypass BBB efflux transporters by alternate approaches:Bypass BBB efflux transporters by alternate approaches:
-- AED which are not substrates of MDRAED which are not substrates of MDR-- NanoparticleNanoparticle encapsulation or by local administration of encapsulation or by local administration of AEDsAEDs
Interference with the mechanisms Interference with the mechanisms involved in the regulation of involved in the regulation of PgpPgp
INTRINSIC SEVERITY AS A
DETERMINANT OF ANTIEPILEPTIC DRUG REFRACTORINESS
Clinical criteria and Biomarkers that define more severe forms of the disease that are associated with drug refractoriness.
Rogawski and Johnson, 2008The neurobiological factors which contribute to increased disease severity
could also play a role in pharmacoresistance
The Need for an Integrative ViewThe Need for an Integrative View
Schmidt D, Löscher W., Epilepsy Curr. 2009, 9(2):47-52.
NEW DEVELOPMENTS IN ANTIEPILEPTIC DRUG RESISTANCE:
AN INTEGRATIVE VIEW
Future studies are necessary to explore whether the mechanisms have any clinical relevance, and if so, to explore whether selected mechanisms might
predominate in patient subgroups
W. W. SplietSpliet ((UMCUMC, , PathologyPathology))P. van Rijen (P. van Rijen (UMCUUMCU,, NeurosurgeryNeurosurgery))
H. H. BaayenBaayen ((VUMCVUMC, , NeurosurgeryNeurosurgery))G. Scheffer, R. Scheper G. Scheffer, R. Scheper ((VUMCVUMC))
W.J W.J WadmanWadman and and E. van VlietE. van Vliet (SILS)(SILS)
H. Potschka H. Potschka ((LMU, GermanyLMU, Germany))
A. A. VezzaniVezzani ((IstitutoIstituto M. M. NegriNegri, Italy), Italy)
AcademicAcademic MedicalMedical Center, AmsterdamCenter, AmsterdamUniversity Medical University Medical CenterCenter UtrechtUtrechtVrijeVrije UniversiteitUniversiteit Medical Medical CenterCenter, Amsterdam, AmsterdamSwammerdam Institute for Life Sciences (Swammerdam Institute for Life Sciences (Center for Neuroscience)Center for Neuroscience)StichtingStichting EpilepsieEpilepsie InstellingenInstellingen NederlandNederlandInstitute of Pharmacology, Toxicology, and Pharmacy, Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig Ludwig MaximiliansMaximilians--University, Munich, GermanyUniversity, Munich, Germany
AMCAMCUMCUUMCUVUMCVUMCSILSSILSSEINSEINLMULMU
Neuropathology Neuropathology AMCAMC
SILS, CNSSILS, CNSJ. J. GorterGorter
D. D. TroostTroost, , A. Iyer, E. A. Iyer, E. ZuroloZurolo, J. , J. AninkAnink
