Cannabidiol in Drug Resistant Pediatric...

Weeding out the Controversy: Cannabidiol in Drug Resistant

Pediatric Epilepsy

Paige Davies, Pharm.D. PGY1 Pediatric Focused Pharmacy Resident

Seton Healthcare Family [email protected]

September 29, 2017

1

ASCENSION TEXAS

Paige Davies, Pharm.D. PGY1 Pediatric Focused Pharmacy Resident

Seton Healthcare Family

Weeding out the Controversy:

Cannabidiol in Drug Resistant

Pediatric Epilepsy

• The author has no conflicts of interest to disclose.

Conflicts of Interest

2

• Compare and contrast the properties of tetrahydrocannabinol

and cannabidiol

• Evaluate the observational and clinical literature regarding

cannabidiol use

• Discuss cannabidiol’s potential place in therapy for resistant

epilepsy

Objectives

3

• Lifetime prevalence of epilepsy: 10.2 per 1,000 (1%)

• Current epilepsy: 6.3 per 1,000 (0.6%)

Epidemiology of Pediatric Epilepsy

Syndromes

Russ SA, et al. Pediatrics. 2012;129:256-264. 4

• Benign childhood epilepsy with centrotemporal spikes

(BCECTS)

• Childhood absence epilepsy

• Juvenile myoclonic epilepsy

• Lennox-Gastaut syndrome (LGS)

• Dravet syndrome (DS)

• Infantile spasms (IS)

• Myoclonic astatic epilepsy (MAE)

Pediatric Epilepsy Syndromes

Gibbon F. Epilepsy Society. 2013. 5

AED Review

AED: antiepileptic drug 6 Appendix B

Shih. Ther Clin Risk Manag. 2013;9:285-293.

2

• Lennox-Gastaut

syndrome

- Clobazam

- Felbamate

- Rufinamide

- Lamotrigine

- Topiramate

• Dravet syndrome

- Valproic acid

- Topiramate

- Clobazam

- Stiripentol

- Avoid: lamotrigine,

carbamazepine

AEDs in LGS & DS

AED: antiepileptic drug

LGS: Lennox-Gastaut syndrome

DS: Dravet syndrome Hussain S, Sankar R. Semin Pediatr Neurol. 2011;18: 171-178. 7

• 47-85% will become seizure free with 1st AED trial

• 14% will become seizure free with trial of 2nd or 3rd AED

Efficacy of First AED in Newly

Diagnosed Epilepsy

Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

Kwan P, et al. Pharmacol Therapeut. 2001;90:21-34.

Ma MS, et al. Pediatr Neurol. 2009; 41: 22-26.

Yilmaz U, et al. Seizure. 2014; 23: 252-259. AED: antiepileptic drug 8

0

10

20

30

40

50

60

70

80

90

100

Clobazam Felbamate Rufinamide Lamotrigine Topiramate

Resp

on

der

Rate

%

Efficacy of AEDs in Lennox-Gastaut

Syndrome

VanStraten AF, Ng YT. Pediat Neuro. 2012; 47:153-161. AED: antiepileptic drug 9

0

10

20

30

40

50

60

70

80

90

100

Valproic acid Topiramate Levetiracetam CLB + STP +VPA

Resp

on

der

Rate

%

Efficacy of AEDs in Dravet Syndrome

Dressler A, et al. Epilepsy Research. 2015; 109:81-89.


CLB: clobazam

STP: stiripentol

VPA: valproic acid 10

• Uncontrolled seizures are common in LGS & DS

- LGS: 67% (1 seizure every 3 months for the past year)

- DS: 84% (1 seizure within the past year)

Drug Resistant Epilepsy

Akiyama M, et al. Epilepsia. 2010;51(6):1043-1052

Camfield P, Camfield C. Epilepsia. 2007;48(6):1128-1132..


DS: Dravet syndrome 11

• Intellectual disability

• Physical injury - Lacerations

- Fractures

- Dental trauma

- Concussions

• Decreased quality of life

• Sudden unexpected death

Potential Consequences of

Uncontrolled Seizure Activity

Camfield C, Camfield P. Seizure. 2015;27:80-83.

Russ SA, et al. Pediatrics. 2012;129:256-264. 12

3

Charlotte Figi

• Diagnosed with Dravet

syndrome at 3 months old

• Baseline of 300+ seizures per

week

• Failed 8 AEDs and the

ketogenic diet

• Collaborated with a company

in Colorado to develop a

cannabis extract, “Charlotte’s

Web Oil”

Maa E, Figi P. Epilepsia. 2014;55(6):783-786. AED: antiepileptic drug 13

Cannabinoids

∆9 tetrahydrocannabinol (THC)

Cannabidiol (CBD)

Pharmacological Actions

• Anticonvulsant

• Analgesic

• Euphoria

• Psychoactive

• Cognitive modulation

• Reduces muscle spasms

• Reduces nausea

• Anticonvulsant

• Analgesic

• Anti-inflammatory

• Antitumorigenic

• Neuroprotective

• Reduces nausea

• Immune modulation

Treated Conditions

• Migraines

• Neuropathic pain

• Nausea

• Parkinson’s

disease

• Multiple sclerosis

• CINV

• Cancer pain

Reddy DS, Golub VM. J Pharmacol Exp Ther. 2016;357:45-55. CINV: chemotherapy induced nausea and vomiting 14

CBD Anticonvulsant

THC CB1 & CB2 Anticonvulsant

& Euphoria

Cannabinoid Mechanism of Action

Block adenosine reuptake,

inhibition of TRP channels,

enhancement of

serotonergic receptors

Devinsky O, et al. Epilepsia. 2014;55(6): 791-802.

Szaflarski JP, Bebin EM. Epilepsy & Behavior. 2014; 41:277-282.

CBD: cannbidiol

CB: cannabinoid receptor

THC: tetrahydrocannabinol

TRP: transient receptor potential 15

• Cannabidiol is the component of marijuana that produces

the “high” people seek when using it recreationally.

- True

- False

Knowledge Check

16

High CBD, Low THC Products

10-83 mg/mL CBD

< 0.3% THC 100 mg/mL CBD

< 0.1% THC

CBD: cannbidiol


Recreational cannabis

3-12% THC 17

2017 Legislative Status of Cannabis in the United States

-

Appendix C

Campbell CT, et al. J Pediatr Pharmacol Ther. 2017;22(3):176-185. 18

4

2017 Legislative Status of Cannabis in the United States

• 2015: SB 339

• Legalized CBD (THC

< 0.5%) for patients with

intractable seizures who

have failed at least 2 AEDs

• Route of administration

other than inhalation

Requirements

- Physician registry

- 3 licensed dispensaries


CBD: cannabidiol

SB: senate bill


Campbell CT, et al. J Pediatr

Pharmacol Ther. 2017;22(3):176-185. 19

Observational Studies:

Surveys of Parental Opinion

on CBD Efficacy

CBD: cannabidiol 20

Observational Studies Survey Age

(years) Epilepsy syndrome (%) CBD dose

(mg/kg/day) LGS DS MAE IS Other

Porter

2013,

n=19

Facebook

group

2-16 5

68 21 N/A 6 0.5-28

Hussain

2015,

n=117

Online

forums

3-10 21 13 4 39 23 2.9-7.5

Press

2015,

n=75

Calls,

emails

0.5-18 12 17 4 N/A 67 Not reported

Aguirre-

Velazquez

2017,

n=43

Email,

Facebook

group

0.8-18 47 0 2 19 32 1-6.9

CBD: cannabidiol

DS: Dravet syndrome

IS: infantile spasms


MAE: myoclonic astatic epilepsy

N/A: not applicable

Aguirre-Velazquez CG. Neurol Res Int. 2017;2017:1-5.

Hussain SA, et al. Epilepsy & Behavior. 2015;47:138-141.

Porter BE, et al. Epilepsy & Behavior. 2013;29:574-577.

Press CA, et al. Epilepsy & Behavior. 2015;45:49-52. 21

Observational Studies Survey Age

(years)

Epilepsy syndrome

(%) CBD dose (mg/kg/day)

Reduction

in seizures,

n (%)

Complete

resolution

of seizures,

n (%)

LGS DS MAE IS Other

Porter

2013,

n=19

Facebook

group

2-16 5 68 21 N/A 6 0.5-28 16 (84%) 2 (11%)

Hussain

2015,

n=117

Online

forums

(LGS & IS)

3-10 21 13 4 39 23 2.9-7.5

100 (85%)

16 (14%)

Press

2015,

n=75

Calls and

emails to

known pts

0.5-18 12 17 4 N/A 67 Not

reported

43 (57%)

2 (0.3%)

Aguirre-

Velazquez

2017,

n=43

Email,

Facebook

group

0.8-18 47 0 2 19 32 1-6.9 35 (81%)

7 (16%)

Appendix D




Press CA, et al. Epilepsy & Behavior. 2015;45:49-52.

CBD: cannabidiol

DS: Dravet syndrome

IS: infantile spasms


MAE: myoclonic astatic epilepsy

N/A: not applicable 22

Porter Hussain Press Aguirre-

Velazquez

Negative SE

Drowsiness ++ + +

Fatigue + + +

Decreased appetite + + +

Increased appetite ++ ++

GI Symptoms +

Positive SE

Improved mood ++++ ++++ +++++

Improved sleep ++++ +++ + ++++

Improved alertness ++++ ++++ ++ +++++

Decreased self stimulation ++

Observational Studies: Side Effects

Appendix E




Press CA, et al. Epilepsy & Behavior. 2015;45:49-52.

SE: side effects GI: gastrointestinal

+ 0-20%

++ 21-40%

+++ 41-60%

++++ 61-80%

+++++ 81-100% 23

• Responder: > 50% reduction in seizure frequency

• No difference in responder rates based on seizure types

- e.g. generalized tonic-clonic, focal, absence, myoclonic

• Responder rate between epilepsy syndromes:

- Lennox-Gastaut: 8/9 (89%)

- Dravet: 3/13 (23%)

- Myoclonic astatic epilepsy: 0/3 (0%)

• Responder rate was different between families who had

moved to Colorado for treatment vs. already had

established care in Colorado

- 47% vs 22% (OR 3.16; 95% CI 1.16-8.59)

Press, 2015 - Other findings

Press CA, et al. Epilepsy & Behavior. 2015;45:49-52. 24

5

• Most parents with children using cannabis products to

aide in seizure control believe that it has a beneficial effect

• Bias

- Small sample sizes

- Voluntary response and confirmation bias

- Product and dose not standardized

• Parents know their children best

Observational Studies: Summary

25

• Many parents reported an increase in seizure frequency

with the addition of cannabidiol to their child’s therapy.

- True

- False

Knowledge Check

26

Clinical Trials

27

Epidiolex® Clinical Trials: Trial Characteristics

Design Inclusion

Criteria

Intervention

(mg/kg/day)

Duration Primary Endpoint

Devinsky

2016, n=137

Open label Epilepsy, ≥ 4

motor seizures in 4 weeks

Initial 2-5,

↑ weekly 2-5, max 25-50

12 weeks, titration

not specified

Change in motor

seizure frequency

Devinsky

2017, n=120

R, DB, PC DS, ≥ 1 AED, ≥

4 seizures in 4 weeks

20 titrated over 2

weeks, maintained for 12 weeks

Change in frequency

of convulsive seizures

GW Pharm

Jun 2016, n=171

R, DB, PC LGS,

uncontrolled on ≥ 1 AED

20 titrated over 2


% change in monthly

frequency of drop seizures

GW Pharm

Sep 2016, n=225

R, DB, PC LGS,

uncontrolled on ≥ 1 AED

20 vs 10 titrated over 2


% change in monthly

frequency of drop seizures


DS: Dravet syndrome

R: randomized

DB: double blind

PC: placebo controlled

Appendix F

Devinsky et al. Lancet Neurol. 2016;15:270-78.

Devinsky et al. N Engl J Med. 2017;376: 2011-20.

GW Pharmaceuticals. Press Releases. 28

Age, yrs.

median (range)

Epilepsy Type Current AED

mean (range)

Failed AED

mean (range)

Devinsky

2016, n=137

10.5

(0.9-26.2)

DS 20%

LGS 19%

Other 61%

3 --

Devinsky

2017, n=120

9.1 (2.5-18) DS 3 (1-5) 4 (0-26)

GW Pharm

Jun 2016, n=171

15 (2-55) LGS 3 6

GW Pharm

Sep 2016, n=225

16 (2-55) LGS 3 7

Epidiolex® Clinical Trials: Patient Characteristics

Appendix G



GW Pharmaceuticals. Press Releases



Pre/ Post

seizure

frequency per

month

CBD reduction in

monthly seizure

frequency

Placebo change

in monthly

seizure

frequency

Responder rate

(≥ 50% decrease in

seizures)

Devinsky

2016, n=137

CBD 30 15.8 36.5% 39% for motor

seizures, 37% for all seizure types

Devinsky

2017, n=120

CBD 12.4 5.9

P 14.9 14.1

38.9% 13.3% CBD 43% vs placebo

27% (OR 2; 95% CI 0.93-4.3; p=0.08)

GW Pharm

Jun 2016, n=171

-- 44% (p< 0.02) 22% --

GW Pharm

Sep 2016 n=225

-- 20- 42% (p< 0.01)

10- 37% (p< 0.01)

17% --

Epidiolex® Clinical Trials: Results

Appendix H



GW Pharmaceuticals. Press Releases LGS: Lennox-Gastaut syndrome


6

ADR (%) % Mild- Mod

of CBD ADR

% Severe of

CBD ADR

ADR with ≥ 10% incidence

*all: somnolence, decreased

appetite, diarrhea

Devinsky

2016, n=137

CBD 79% 62.5% 37.5% fatigue, convulsion

Devinsky

2017, n=120

CBD 93%

Placebo 75%

CBD 84%

Placebo 95%

CBD 16%

Placebo 5%

fatigue, convulsion, URTI,

vomiting, pyrexia, lethargy

GW Pharm

Jun 2016, n=171

CBD 86%

Placebo 69%

78% 12%

GW Pharm

Sep 2016, n=225

CBD (20) 94%

CBD (10) 84% Placebo 72%

CBD (20) 88%


CBD (20) 6%


(20) & (10) URTI

(20) pyrexia, vomiting, nasopharyngitis

10 status epilepticus

Epidiolex® Clinical Trials: ADR

Appendix I



GW Pharmaceuticals. Press Releases

ADR: adverse drug reaction

CBD: cannabidiol

URTI: upper respiratory tract infection 31

• Bias

- All funded by GW Pharmaceuticals

- Questionable application to epilepsy syndromes beyond LGS & DS

- Titration schedules not clearly defined which limits patient application

• 37-44% decrease in monthly seizure frequency

• 37-43% experienced a reduction by > 50%

• High rates of ADRs reported, even in placebo group

• Most ADRs were mild-moderate in nature

Epidiolex® Clinical Trials: Summary

32

• Clinical trials of Epidiolex® in pediatric patients with Lennox-

Gastaut and Dravet syndrome have shown a reduction in

seizure frequency in the interventional arm compared to the

placebo arm.

- True

- False

Knowledge Check

33

Drug-Drug

Interactions

34

• CBD inhibits CYP 3A4 and 2C19

• Significant changes in serum concentrations

- Clobazam

- N-desmethylclobazam

- Eslicarbazepine

- Rufinamide

- Topiramate

Drug-Drug Interactions

Gaston TE, et al. Epilepsia. 2017;XX:1-7. CBD: cannabidiol 35

• Charlotte Figi

- Completely weaned off clobazam after 1 month CBD therapy

• Porter et al.

- 12/19 (63%) were able to discontinue at least 1 AED while on CBD

• Clobazam 5/12 (42%)

• Valproic acid 5/12 (42%)

• Stiripentol 3/12 (25%)

Drug-Drug Interactions: A benefit?

Maa E, Figi P. Epilepsia. 2014;55(6):783-786.

Porter BE, et al. Epilepsy & Behavior. 2013;29:574-577. AED: antiepileptic drug

CBD: cannabidiol 36

7

Other Dilemmas

37

Success of

CBD oil in

reducing

seizures

AED Discontinuation

Belief that

“natural”

products are

safer and

healthier

Abrupt AED

discontinuation

without

physician

knowledge


CBD: cannabidiol 38

• If hospitalized, asked to stop use of CBD oil

• Will this cause the patient’s seizures to become uncontrolled?

• Will the serum concentration of other AEDs decrease

resulting in loss of seizure control?

Unfair Expectations

AED: antiepileptic drugs

CBD: cannabidiol 39

Hope from

positive

results

Extrapolations

Stigma

surrounding

cannabis

products

Initiation of

therapy without

physician

knowledge

• Is this appropriate for anyone with uncontrolled epilepsy?

40

Looking ahead…

• New drug application currently in progress • Expected to be completed in October

• Future plans: • Expanding products to include other cannabinoid products

• Research for other indications

• Autism spectrum disorders

• Rett Syndrome

• Neonatal hypoxic ischemic encephalopathy

• Glioblastoma

• Partial onset epilepsy

41

• Who: LGS or DS patients

• What: add on therapy

• When: after trial and failure of at least 2 AEDs

• How:

- Initiate at 2.5 mg/kg/day divided into 2 doses

- Increase by 2.5 mg/kg/day every 2 days

- Up to a maximum dose of 20 mg/kg/day as tolerated

Clinical Application of Epidiolex®


CBD: cannabidiol

LGS: Lennox-Gastaut syndrome 42

8

Charlotte Figi Today

43

• Dr. Ronda Machen, Pharm.D., RD, BCPPS, BCNSP

• Dr. Carolyn Ragsdale, Pharm.D., BCPS, BCPPS

• Dr. Eimeira Padilla-Tolentino, Pharm.D., PhD

• Dr. Thanhhao Ngo, Pharm.D., BCPPS

THANK YOU!

Acknowledgements

44

ASCENSION TEXAS

Paige Davies, Pharm.D.

PGY1 Pediatric Focused Pharmacy Resident

Seton Healthcare Family

Weeding out the Controversy:

Cannabidiol in Drug Resistant

Epilepsy

9

Appendix A: Abbreviations

AED Antiepileptic drug

ADR Adverse drug reactions

BCECTS Benign childhood epilepsy with centrotemporal spikes

CB1, CB2 Cannabinoid receptor 1 & 2

CBD Cannabidiol

CINV Chemotherapy induced nausea and vomiting

CLB Clobazam

DB Double blind

DS Dravet syndrome

GI Gastrointestinal

IS Infantile spasms

LGS Lennox-Gastaut syndrome

MAE Myocolonic astatic epilepsy

PC Placebo controlled

R Randomized

SB Senate bill

SE Side effects

STP Stiripentol

THC Tetrahydrocannabinol

TRP channels Transient receptor potential channels

URTI Upper respiratory tract infection

VPA Valproic acid

10

Appendix B: AED Review

Appendix C: 2017 Legislative Status of Cannabis in the United States

11

Appendix D: Observational Studies

Appendix E: Observational Studies: Side Effects

12

Appendix F: Epidiolex® Clinical Trials: Trial Characteristics

Appendix G: Epidiolex® Clinical Trials: Patient Characteristics

13

Appendix H: Epidiolex® Clinical Trials: Results

Appendix I: Epidiolex® Clinical Trials: ADR

14

Appendix J: Bibliography

Aguirre-Velázquez C. Report from a Survey of Parents Regarding the Use of Cannabidiol (Medicinal cannabis) in Mexican Children with Refractory Epilepsy. Neurology Research International. 2017;2017:1-5. doi:10.1155/2017/2985729.

Campbell C, Phillips M, Manasco K. Cannabinoids in Pediatrics. The Journal of Pediatric Pharmacology and Therapeutics. 2017;22(3):176-185. doi:10.5863/1551-6776-22.3.176.

Camfield P, Camfield C. Long-term Prognosis for Symptomatic (Secondarily) Generalized Epilepsies: A Population-based Study. Epilepsia. 2007;48(6):1128-1132. doi:10.1111/j.1528-1167.2007.01072.x.

Camfield C, Camfield P. Injuries from seizures are a serious, persistent problem in childhood onset epilepsy: A population-based study. Seizure. 2015;27:80-83. doi:10.1016/j.seizure.2015.02.031.

Devinsky O, Cilio M, Cross H et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802. doi:10.1111/epi.12631.

Devinsky O, Marsh E, Friedman D et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. The Lancet Neurology. 2016;15(3):270-278. doi:10.1016/s1474-4422(15)00379-8.

Devinsky O, Cross J, Laux L et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. New England Journal of Medicine. 2017;376(21):2011-2020. doi:10.1056/nejmoa1611618.

Dressler A, Trimmel-Schwahofer P, Reithofer E et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome – Comparison with various standard antiepileptic drug regimen. Epilepsy Research. 2015;109:81-89. doi:10.1016/j.eplepsyres.2014.10.014.

Fidelia Cascini, Carola Aiello, GianLuca Di Tanna. Increasing Delta-9-Tetrahydrocannabinol (∆-9-THC) Content in Herbal Cannabis Over Time: Systematic Review and Meta-Analysis. Current Drug Abuse Reviews. 2012;5(1):32-40. doi:10.2174/1874473711205010032.

Gaston T, Bebin E, Cutter G, Liu Y, Szaflarski J. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586-1592. doi:10.1111/epi.13852.

Gibbon F.Childhood epilepsy syndromes. Epilepsy Society. 2013. Available at: https://www.epilepsysociety.org.uk/childhood-epilepsy-syndromes#.WbHVnU2ouUk.

GW Pharmaceuticals. GW Pharmaceuticals Announces Second Positive Phase 3 Trial Of Epidiolex (Cannabidiol) In The Treatment Of Lennox-Gastaut Syndrome.; 2016. Available at: http://ir.gwpharm.com/releasedetail.cfm?ReleaseID=990804.

GW Pharmaceuticals. GW Pharmaceuticals Announces Positive Phase 3 Pivotal Trial Results For Epidiolex (Cannbidiol) In The Treatment Of Lennox-Gastaut Syndrome.; 2017. Available at: http://ir.gwpharm.com/releasedetail.cfm?ReleaseID=977117.

Hussain S, Zhou R, Jacobson C et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox–

15

Gastaut syndrome. Epilepsy & Behavior. 2015;47:138-141. doi:10.1016/j.yebeh.2015.04.009.

Kwan P, Brodie M. Early Identification of Refractory Epilepsy. New England Journal of Medicine. 2000;342(5):314-319. doi:10.1056/nejm200002033420503.

Kwan P, Sills G, Brodie M. The mechanisms of action of commonly used antiepileptic drugs. Pharmacology & Therapeutics. 2001;90(1):21-34. doi:10.1016/s0163-7258(01)00122-x.

Ma M, Ding Y, Ying W, Fang F, Ding C, Zou L. Effectiveness of the First Antiepileptic Drug in the Treatment of Pediatric Epilepsy. Pediatric Neurology. 2009;41(1):22-26. doi:10.1016/j.pediatrneurol.2009.01.010.

Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783-786. doi:10.1111/epi.12610.

Press C, Knupp K, Chapman K. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy & Behavior. 2015;45:49-52. doi:10.1016/j.yebeh.2015.02.043.

Porter B, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior. 2013;29(3):574-577. doi:10.1016/j.yebeh.2013.08.037.

Reddy D, Golub V. The Pharmacological Basis of Cannabis Therapy for Epilepsy. Journal of Pharmacology and Experimental Therapeutics. 2016;357(1):45-55. doi:10.1124/jpet.115.230151.

Russ S, Larson K, Halfon N. A National Profile of Childhood Epilepsy and Seizure Disorder. PEDIATRICS. 2012;129(2):256-264. doi:10.1542/peds.2010-1371.

Shih J, Tatum, Rudzinski L. New drug classes for the treatment of partial onset epilepsy: focus on perampanel. Therapeutics and Clinical Risk Management. 2013:285. doi:10.2147/tcrm.s37317.

Szaflarski J, Martina Bebin E. Cannabis, cannabidiol, and epilepsy — From receptors to clinical response. Epilepsy & Behavior. 2014;41:277-282. doi:10.1016/j.yebeh.2014.08.135.

VanStraten A, Ng Y. Update on the Management of Lennox-Gastaut Syndrome. Pediatric Neurology. 2012;47(3):153-161. doi:10.1016/j.pediatrneurol.2012.05.001.

Yılmaz Ü, Yılmaz T, Dizdarer G, Akıncı G, Güzel O, Tekgül H. Efficacy and tolerability of the first antiepileptic drug in children with newly diagnosed idiopathic epilepsy. Seizure. 2014;23(4):252-259. doi:10.1016/j.seizure.2013.12.001.

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