Harold I Perl, PhD National Institute on Drug Abuse APA 120 th Annual Convention August 3, 2012.
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...
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
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Outline of Presentation
Focus on Stimulants
Disulfiram (Antabuse)–
Dopamine & pharmacogenetics
Cocaine vaccine (Zenova-vax)–
Blocking cocaine entry into brain
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
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}�
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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
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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�
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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
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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�
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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%
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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
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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
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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
