APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance...

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1 09-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair and Professor of Psychiatry & Neuroscience, Baylor College of Medicine President – College on Problems of Drug Dependence Past President – American Academy of Addiction Psychiatry

Transcript of APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance...

Page 1: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

1 09-16-04

APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax

Thomas Kosten MDWaggoner Chair and Professor of Psychiatry & Neuroscience, Baylor College of MedicinePresident – College on Problems of Drug DependencePast President – American Academy of Addiction Psychiatry

Page 2: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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Outline of Presentation

Focus on Stimulants

Disulfiram (Antabuse)–

Dopamine & pharmacogenetics

Cocaine vaccine (Zenova-vax)–

Blocking cocaine entry into brain

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How Cocaine Alters the Brain: Dopamine Damage & Parkinsonism

Receptor Receptor

Sites of Drmcg Action at the Synapse

DopamineReuptake

Dopamine

Dopamine

Normal

Overactivity

Dopamine

Receptors

Receptor Sensitivity

DopamineReuptake

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Parkinsonian (PD) Brain Abnormalities in Cocaine Abusers

ControlControl

%ID/cc%ID/cc0.030

0.015

0.000

AmphetamineAmphetamine CocaineCocaine PDPD

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Hypodopaminergic State InDrmcg Addiction

Non Drmcg Abuser Addicted Subject

DA

DA

DA

DA DADA

DA

Reward CircuitsReward Circuits

DA

DA

DA

DA DA

DA

DADA DADA

DA

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Dopamine Agonist Therapy Reverse Craving and Attenuate Priming

Reverse stimulant induced dopamine deficiency – receptors down, transporters upD2 agonists not effective – bromocriptineIndirect agonists promisingDisulfiram: inhibit dopamine beta hydroxylase conversion of dopamine to norepinephrine

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DA and NE-responsiveNeuron

Alpha 2 and DA1receptors

Low DβH reduces DA to NE conversion

Higher Dopamine(lower NE)for

release

NE neuron

Disulfiram increases dopamine (DA) by inhibiting its conversion to norepinephrine (NE)

Presenter�
Presentation Notes�
This slide illustrates our hypothesis explaining how genetically elevated DAT expression (see data of Jacobsen and Gelernter) and genetically diminished DBH protein expression (see data of Cubells et al.) could explain greater sensitivity to cocaine-induced anxiety/paranoia. The subject illustrated here would carry low-dbh associated variants of the DBH gene, and 9-repeat (high DAT-associated) variants of the DAT gene. In NE neurons, low dbh protein expression leads to higher ratios of DA to NE, with higher baseline DA release. In the baseline state, there is a relative deficit of NE release, leading to feedback increase in catecholamine synthesis by the NE nueron, with further enhanced release of “ectopic DA.” However, the NET is an efficient scavenger of DA, so in the unstimulated state, this may not be experienced by the subject as anxiety/paranoia. In the DA neuron, higher expression of the DAT protein leads to a relative deficit of synaptic DA, leading to feedback-increased DA transmission (ie, the opposite of what is observed in DAT knockout mice). On the post-synaptic side, the brain is similarly “supersensitive” owing to the genetic increase in DAT expression. (Note that post-synaptic neurons in the PFC probably are responsive to both DA and NE, and receive both DA and NE input.) {NEXT SLIDE}�
Page 8: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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Disulfiram Effects on Acute Cocaine (2mg/kg I.N.)Disulfiram Effects on Acute Cocaine (2mg/kg I.N.) Yellow (cocaine alone),Yellow (cocaine alone), Red (disulfiram + cocaine) Red (disulfiram + cocaine)

Craving for cocaine Nervousness from cocaineCraving for cocaine Nervousness from cocaine

0

5

1015

20

25

-30 15 45 90 180Minutes

Cra

ving

DisulfiramPlaceboPlacebo Coke/DPlacebo/Placebo

0

5

10

15

20

25

-30 15 45 90 180Minutes

Ner

vous

ness

DisulfiramPlaceboPlacebo Coke/DPlacebo/Placebo

Page 9: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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Cocaine Free Urines Across 5 Disulfiram Clinical Cocaine Free Urines Across 5 Disulfiram Clinical Studies (n=337)Studies (n=337)

Study (n)

vs Naltrexone (18)

w Buprenorphine (20)w Methadone (67)

Psychotherapy (117)Match Study (115)

Meta Average

Disulfiram vs. Placebo% Cocaine Free Urines90% vs 66%

41% vs 25%35% vs 25%

55% vs 40%57% vs

45%

55% vs 40%

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Disulfiram vs. Placebo: Cocaine-free urines High cocaine use group, stratified by DBH genotype

Pink line is disulfiram (n=75) (Schottenfeld 2004)

0

1

2

3

Induction Weeks 1-2 Weeks 3-4 Weeks 5-6 Weeks 7-8 Weeks 9-10 Weeks 11-12

#co

cain

e(-

)uto

x(6

per2

wee

ks)

Placebo T-allele Disulfiram T-allele

00.5

11.5

22.5

3

Induction Weeks 1-2 Weeks 3-4 Weeks 5-6 Weeks 7-8 Weeks 9-10 Weeks 11-12

Coc

aine

-free

urin

es

Placebo CC-homozygous Disulfiram CC-homozygous

TT + CT (lower DβH): CC (higher DβH):

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Conclusions for DisulfiramDisulfiram increases cocaine-free urines more than placebo (55% vs 40%)Individuals with genetically lower plasma DBH levels (CT and TT genotypes at –1021C>T) showed the best response to disulfiram.Mechanism may be reduced craving, reduced withdrawal and increased cocaine-induced dysphoria

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Immunotherapy and Vaccines for Cocaine Dependence

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CapillaryBlood

Flow

Brain

Drugs of abuse easily enter the brain

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CapillaryBlood

Flow

Brain

Antibodies can reduce brain concentrations

Antibody holdsdrugs in

blood stream

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CocaineVaccine: What is it?

Active immunisationHapten: Cocaine derivativeCarrier protein: Cholera toxin B (rCTB)Aluminium hydroxide adjuvant

Presenter�
Presentation Notes�
Placebo contains the alhydrogel adjuvant but no protein�
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rCT B

cocaine derivative

Cocaine bound to Cholera toxin

Presenter�
Presentation Notes�
The size of the rCTB protein is in the order of 55 kd The nicotine derivatives are covalently bonded to the rCTB�
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Effects of cocaine vaccine in animals

Vaccine generated antibodies can bind modest amounts of injected cocaineNO animal toxicity. Even at several times a clinically relevant doseVaccine decreased cocaine self administration (SA) in rodents

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Safety of Vaccine & Cocaine Antibodies in Humans

Safety: no major adverse events: year FUInjection events: temperature elevations (minimal), headache (10%), sore throat (6%) Rise in antibody significant after third dose at week 4 and peaks after fifth (12 wk) dose.Decline in antibody levels from peak evident by four months after initial vaccination and drops to undetectable after 9-12 months

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Cocaine Antibody (AB) rise with 3 months of dosing Five dosing schedules: 3 to 5 doses, 100, 400, 1000 mcg

0

500

1000

1500

2000

2500

3000

day 0 day 28 day 56 day 84

300 mcg400 mcg3000 mcg500 mcg2000 mcg

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Fewer cocaine urines at higher Vaccine Dose

Vaccination makes antibodies by Week 4 (n=11)

0

10

20

30

40

50

60

1 2 3 4 5 6 7 8 9 10 11 12 13

Week

Perc

ent P

ositi

ve U

rines

500 mcg grp

2000 mcg grp

Z= -3.17, p=0.0015

Presenter�
Presentation Notes�
Greater percent positive urines n 100 mcg group Higher vaccination schedule more likely to have cocaine negative urines Groups diverge at week 4 which corresponds to when detectable antibody levels are present�
Page 21: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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Less relapse to cocaine use with high vs

low dose vaccination

(Percent of patients relapsing in each dosage group)

01020304050607080

Any use Heavy use

Low doseHigh dose

Page 22: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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Human Laboratory StudyMeg Haney –

Columbia University

Determine direct relationship between plasma antibody levels and cocaine’s subjective and cardiovascular effects

Administer smoked cocaine (0, 25, 50 mg) to non-treatment seeking, cocaine-dependent research volunteers pre-vaccine and for 12 weeks post-vaccine

Presenter�
Presentation Notes�
Brief as my previous speakers did most of this work�
Page 23: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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1

Tite

r

Weeks

Plasma Antibody (n=10)

High AntibodyLow Antibody

0 13 26 39 520

300

600

900

1200

1500

1800

2100

2400

Presenter�
Presentation Notes�
No diff as a func of vaccine dose Individ variability; about 1/2 showed strong ab response Peak about 12 wks Total dose 1440 mcg �
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79%

0 25 5500

15

30

45

60

75

90

0 255 500

Good Drug Effect

Low ABHigh AB

Sm oked C ocaine D ose (m g)

W eek 13

W eek 3

23%

49%

max = 100

Ratings (mm)

13%

Page 25: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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W eek 13

W eek 3

Low ABHigh AB

Dol

lars

/5 d

ays

0

25

50

75

100

125

150

175

Self-reported Cocaine Use

Page 26: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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Conclusions: Human cocaine administration

Current results encouraging:• Vaccine well tolerated; safe in combination with

cocaine• Reliable antibody production: 50% volunteers• Those who produced antibody showed a

substantial decrease in cocaine intoxication

Outpatient cocaine use reduced in those producing high antibody levels

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Outpatient cocaine vaccine RCT in methadone patients

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Cocaine Vaccine Study Design (methadone patients)

Double blind placebo-controlled randomised clinical trial114 methadone-maintained cocaine dependent patientsVaccinated with 5 x 360 µg TA-CD over 12 weeksUrine toxicology 3x/weekSerum antibody levels assessed at 0, 4, 8, 12 weeks

Page 29: APA Presentation Substance Abuse Pharmacotherapy: From ......109-16-04 APA Presentation Substance Abuse Pharmacotherapy: From Antabuse to Zenova-vax Thomas Kosten MD Waggoner Chair

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Mean serum antibody levels (0-12 weeks)

0

500

1000

1500

2000

0 5 10

Time (weeks)

Ant

ibod

y un

its

Mean serumantibody

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Promise of Stimulant PharmacotherapiesDisulfiram reduces stimulant abuse perhaps by increasing dopamine available in brain and reducing norepinephrinePharmacogenetic matching of patients to disulfiram treatment shows promiseNewer treatments include cocaine vaccine with efficacy support from human cocaine administration and recent placebo RCT