nnabis and epilepsy...epilepsy and public health • chronic, progressive neurological disorder...

© University of Reading 2007 w w w .rea ding.ac.u k

Sch o ol o f Ch e m istry, Fo o d Bioscie nces & Phar m acy

Cannabis and epilepsy from recreational abuse to therapeutic useB. W halley

Epilepsy and public health• Chronic, progressive neurological disorder characterised by spontaneous, recurrent seizures.

• ~ 10% of people w ill have a seizure in their lifetime of which ~ 30% w ill subsequently develop epilepsy.

• Lifetim e prevalence ~ 1%.

• Third most prevalent neurological disorder after m igraine and Parkinson’s Disease (both ~ 0.7-1.2%).

• Affects 50 m illion people worldwide and accounts for 1% of the global burden of disease.

2Banerje e & H auser, 2006

Aetiology of epilepsy• ~ 60% of cases are id iopathic (W H O , 2012)

• Remainder are crypt ogenic or secondary to insults such as hypoxia (or o ther trau ma) at birth, head trauma, drug use, stroke and CNS infection or tumour.

• Age is an independent risk fact or and febrile seizure specific to childhood

• A small m inority are due t o specifically identifiab le m o lecular/genet ic causes.

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Banerje e & H auser, 2006

Ra t e r a tio < 1= pro t ective

D isease burden and co-morbidities

• Exam ple disease burden: $15.5 billio n p er ye ar in US (CDC, 2008)

• Premature mortality is 2-3 t imes higher in epilepsy pat ients (maximum reported: 8.8).

– Significant causes: SU DEP, status epilepticus, accidents as a consequence of seizure , asp irat ion pneumonia after se izure, drug toxicity and id iosyncrat ic ADRs and suicides (Lhatoo et al, 2006)

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• Co-m orbidit ies include: – Cognit ive decline (drug and d isease-related)– Anxiety– Depression– Agitat ion, anger and emotional out bursts– Suicide (5-15x m ore like ly)– AD H D– Reproduct ive proble ms (make and female)– Inso mnia– Migraine

• Co-m orbidities m ore fre q u e nt a n d severe in re fractory pa tie n ts

Clinical need for new AEDs• Th e in tro d uct io n of n e w AEDs since 1990 o n w ards has ha d n o effect u p o n t h e

n u m b e r of p har m aco logically in tract a b le/refract ory e pile psy p a tie n ts.– Of 525 people w ith new ly diagnosed epilepsy w ith 2–16 years of follow up, 37% st ill exhibit ed seizures at the

final clinic visi t whilst the remainder were seizure free for Ʀ1 year. – Seizure-free rat e did not differ significant ly bet ween those treat ed w ith a single established drug (67%) and

those treated with a single new drug (69%). Thus, new AEDs have not reduced pharmacoresistance (Kwan & Brodie, 2000).

• New AEDs achieve some benefit via improved side-effect profiles.

• New , better t olerated and more effective AEDs are clearly required t o benefit the 15-20M people experiencing pharmacologically refractory seizures.

5h t t p:// w w w .ncbi.nlm .nih.gov

Rational drug design• How have successful drugs been discovered?

– Sere n dipity e.g. valproate, levetiracetam– Seco n d ary use of exist ing drugs e.g. phenobarbital– Scre e ning rela t e d co m p o u nds e.g. phenytoin, ethosuxim ide

• ‘me too’ drugs – Mo difica tio n of exist ing drugs e.g. oxcarbazepine, pregabalin– “Ra tio nal”/targe t orie n t ed d esign e.g. vigabatrin, tiagabine

• The least successful have come from rational/target-based development .

• Related and m odified compounds are typically only effective in epilepsies that already respond to existing treat ments.

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H istorical use of cannabis in epilepsy• 1100A D: al-Mayusi makes first writt en record of its use

for th is purpose

• C15t h: Ibn al-Badri notes “the epileptic son of the caliph's chamberlain” was treated w ith Cannabis and “it cured him completely, but he became an addict who could not for a moment be without the drug”

• C19t h: O ’Shaughnessy, McMeens, Moreau and Reynolds independent ly tested the efficacy of a crude extract against seizures.

• J.R. Reynolds, Q ueen Victoria’s personal physician said Cannabis is “the most useful agent with which I am acquainted” in the treat m ent of “attacks or violent convulsions,” which “may recur two or three times in the hour,” claiming that such at tacks “may be stopped with a full dose of hemp”

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Evidence from preclinical models• O nly whole animal models shown since

seizures and epilepsy can only be poorly modelled in vitro

• Results strongly support an overall anticonvulsant effect of plant cannabinoids and synthetic CB1R agonists.

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Co m p oun d

Spec

ies

N u m b er of discre t e con ditio ns/m o dels/desig ns D ose An t iconvulsan t N o

effe ct Proconvulsant

THC 6 31 0.25-200 mg/kg 61% 29% 10%

CBD 2 21 1-400 mg/kg 81% 19% 0%

O ther plant cannabinoids 2 7 N/A 100% 0% 0%

CB1 receptor agonists 2 55 N/A 73% 18%

2% (7% m ixed effect)

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Evidence from anecdotal use• N o m o d ern , valid h u m a n clinical trials have been conducted

• Six m o d e rn case st u dies report clinically assessed anticonvulsant effects of cannabis

• Five large surveys concluded that some individuals using ‘medical m arijuana’ do so t o control symptoms of epilepsy

• Personal correspondence w ith ~ 50 UK PWE using cannabis for control of seizures.

• O n e sm all scale clinical trial (1981) demonstrated that CBD was ant iconvulsant in 7/8 pat ients treat ed (no change in placebo group).

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Cannabidivarin (CBDV) pharmacology• Ca nna bidivarin (CBDV; also ‘cannabidivarol’) is a propyl analogue of cannabidiol (CBD).

• First iso lated from hashish in 1969 (Vo llner et al., 1969) although there is little extant evidence about pharm acological prop erties or therapeutic uses.

• Exist ing evidence of pharmacological effects:

– St im ulates recruit ment of bone marrow m esenchymal stro mal cells via a CB2 re ce p t or-d e p e n d e n t mechanism (direct effe ct o n CB2 n o t sho w n; Scut t & W illiamson, 2007)

– Differential effects at transie n t re ce p t o r p o te n tial (TRP) ch an ne ls in vitro:• Acts as an hTRPA1, hTRPV1 and hTRPV2 agonist (EC50: 0.42, 3.6 and 7.3PM respect ively) in

transfected HEK-293 cells (De Petrocellis et al, 2011a, De Petrocellis et al, 2011b)

• Acts a TRPM8 antagonist (IC50: 0.90 PM) in transfected HEK-293 cells (D e Petrocellis et al, 2011a).

• Relevance of TRP target in epilepsy unknown

• Inhib its d iacylglyce rol lip ase a (DAGLa; IC50: 16 .6PM) in vitro, th e pri mary synth etic enzym e of the endocannab ino id, 2-arachidonoylglycerol (D e Petrocellis et al, 2011a) but relevance t o epilepsy unknown.

• Re le van ce o f affin ity f or t h ese targe ts f or e pile psy re m ains u n cle ar.10

In vitro efficacy

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Efficacy vs maximal electroshock seizures and audiogenic seizures• First line in vivo, mouse models for AED screening

• Both reveal whether or not broad anticonvulsant effects are present.

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MES

A u dioge nic in DBA/2

Efficacy against acu t e PTZ a n d pilocarpin e in d uce d seizures

• PTZ (panels A-D): m odel of generalised seizure also indicat ive of efficacy against absence seizures

• Acute pilocarpine (panels E-H): model of temporal lobe seizures and status epilepticus

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• Significan t an tico nvulsan t effects against acu t e PTZ-in d uce d gen eralise d se izures

• N o sig nifica nt effect against acu t e , pil ocarp in e-in d uce d TLS/st a tus epilep t icus(in t his st u d y).

Efficacy and t olerability retained with ot her AEDs(acute PTZ)

• Safe w h e n co-a d m inist ere d?

• St u dy d rug effect re t ain e d?

• Syn ergism of effects?

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Efficacy and t olerability retained with ot her AEDs(acute pilocarpine)

• Safe when co-administered?

• Study drug effect present?

• Syn ergism of effects?

• N o t a bly, in t his m o re hig hly p o w ere d st u d y ( m o re ani m als receive d st u d y d rug), CBDV w as an tico n vulsan t against acu t e , pil ocarp in e-in d uce d TLS/st a t us epilept icus

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Tolerability and oral efficacy vs PTZ

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Acknowledgements• Collaborat ors: Dr C. W illiams, Dr G. Stephens, Dr G. W oodhall (Aston, UK), Prof.

L. Sander (NEC & UCL, UK), Prof. E. W illiamson & Prof. R. Hampson (Wake, USA).• Rese archers (past and present): Dr A. H ill, Mr N. Jones, Dr S. W eston, Dr J.

Farrimond, Dr I. Sm ith, Dr X. Wang, Dr Y. Yamasaki, Mr T. H ill, Mrs C. H ill, Mr N. Amada, Miss I. Peres, Mrs R. Hadid, Mrs A. Al-Husaini, Mr S. Akiyama, Dr A. Futamura, Miss M. Mercier, Mr S. Marshall.

Sponsors: GW Pharmaceuticals and O tsuka Pharmaceuticals for continued financial and material support.

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References• Banerjee & Hauser (2006) in Ep ilepsy: a comprehensive t ext book Lipp inco tt & W illiams (Eds: Enge l & Ped ley) Chap ter 5, pp15

• Center for D isease Control (2008) Morbidity and Mortality W e ekly Report 57; SS-6

• De Pe troce llis, Ligresti, Morie llo, Allara, Bisogno, Pe trosino, Stott & D i Marzo (2011) Effects of cannabinoids and cannabinoid-enriched cannab is extracts on TRP channe ls and endocannabino id me tabolic enzymes. Br J Pharmacol 163:1479-1494.

• De Pe troce llis, O rlando, Morie llo, Avie llo , Sto tt , Izzo & Di Marzo (2011) Cannabino id actions at TRPV channe ls: effects on TRPV3 and TRPV4 and the ir pote ntial relevance to gastrointestinal inflam mation. Acta Physiol (Oxf).

• EMEA (2000) Gu idance on Clin ical Invest igation of Medicinal Products in the Treat ment of Ep ilep tic Disorders http://www .e mea.e u.in t/pdfs/hu man/e wp/056698en.pdf

• Engel (2006) Report of the ILAE Classification Core Grou p. Epilepsia. 2006;47:1558-1568

• Farrimond, Mercier, W halley and W illiams (2011) Cannabis sat iva and the endogenous cannabino id syst em Phyto therapy Research 25(2):170-88.

• Gastaut (1970) Clin ical and e lectroencephalograph ical classification of ep ilept ic se izures Ep ilepsia 11; 102

• H ill, Jones, W illiams, Stephens & W halley (2010) Deve lop ment of mu lt i-e lectrode array screening for ant iconvu lsants in acute rat brain slices. J Neurosci Methods 185:246-256.

• H ill, W illiams, W halley and Stephens (2012) Phytocannabino ids as nove l therapeut ic agents in CNS d isorders. Pharmacology & Therapeutics 133(1):79-97.

• H ill, Mercier, H ill, Glyn, Jones, Yamasaki, Futamura, Duncan, Sto tt , St ephens, W illiams and W halley* (2012; ePub ahead of print) Cannab idivarin is ant iconvu lsant in mouse and rat in vitro and in se izure mode ls British Journal of Pharmacology

• Kwan & Brod ie (2000) Early identificat ion of refractory ep ilepsy. N Engl J Med 342(5):314–9.

• Lhat oo , Sander & To mson (2006) in Ep ilepsy: a co mprehensive t ext book Lipp inco tt & W illiams (Eds: Enge l & Ped ley) Chap ter 10, pp1

• Vo llner, Bien iek, & Korte F (1969) Hash ish. XX. Cannabid ivarin, a ne w hash ish const ituent . Tetrahedron Lett 145-147.

• W H O (2012) ht tp://www.who .int/mediacentre/factsheets/fs999/en/index.html (last accessed 06/01/2012)

• Scut t & W illiamson (2007) Cannabino ids st imu late fibrob lastic colony format ion by bone marro w ce lls ind irectly via CB2 recep tors. CalcifTissue Int 80:50-59.

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nnabis and epilepsy...epilepsy and public health • chronic, progressive neurological disorder...

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