Emerging Somatic Therapies for the Addicted Patient <ul><li>Horacio A. Capote, M.D. </li></ul><ul><li>MEDICAL DIRECTOR, NE...
OVERVIEW <ul><li>Functional Neuroanatomy of  Addiction </li></ul><ul><li>Pharmacotherapy </li></ul><ul><li>Immunotherapy <...
Inhibitory/Control Reward Memory/Learning Functional Neuroanatomy of Addiction
Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ,  Nat Neur...
Ventral Pallidum NA Core PFCortex VTA Basolateral Amygdala MDthalamus Extended Amygdala Central amydala BNST NA Shell Dopa...
Pharmacotherapy:  New Targets --- NK1 <ul><li>The Stress Response: Substance P (SP) </li></ul><ul><li>Neurokinin 1 (NK1) R...
Pharmacotherapy: New Targets --- NK1 <ul><li>Double-blind, placebo-controlled trial (n=50) of LY686017 </li></ul><ul><li>S...
Positive and negative affective stimuli (IAPS) Negative Positive Pharmacotherapy: New Targets --- NK1 Courtesy of  Markus ...
Attenuated fMRI responses to negative affective stimuli following treatment with LY686017  (George et al, Science 2008) Pl...
Up-regulated fMRI responses to positive affective stimuli  following treatment with LY686017  (George et al, Science 2008)...
Pharmacotherapy: New Targets --- D3 <ul><li>Dopamine D3 receptors have a limbic distribution involved in cognitive & emoti...
Pharmacotherapy: New Targets --- Dopamine Beta Hydroxylase <ul><li>SYN117 (Nepicastat) a potent, competitive, and selectiv...
Pharmacotherapy: New Targets --- Adenosine A2A  <ul><li>SYN115: Adenosine A2A receptor antagonist (phase 1) cocaine & othe...
Pharmacotherapy: New Targets --- mGluR-1  <ul><li>SYN-119 a glutamate agonist: </li></ul><ul><li>Potently and selectively ...
Pharmacotherapy : New Targets --- Glycine <ul><li>GSK 468816 Glycine (NMDA) antagonist (phase 2) nicotine dependence </li>...
Pharmacotherapy: Semi-New Targets --- Cannabinoid 1 (CB1) <ul><li>Rimonabant – a CB1 inverse agonist currently being studi...
Pharmacotherapy: Old Targets Revisited --- Opioid  <ul><li>ALKS33 opioid modulator; phase 2 imminent; metabolism not hepat...
Pharmacotherapy: Old Targets Revisited --- GABA <ul><li>CPP-109 (Vigabatrin) – irreversible GABA transaminase inhibitor (p...
Immunotherapy
Immunotherapy <ul><li>Rationale: drugs of abuse readily cross the blood brain barrier because of their small size, while a...
Immunotherapy <ul><li>Active Vaccines : </li></ul><ul><ul><li>Phase 1 (pre-clinical) cocaine, heroin, methamphetamine, nic...
Nanotechnology <ul><li>Problem:  DARPP-32  is a protein known to trigger a cascade of changes in the addicted individual. ...
Blood brain barrier (BBB) <ul><li>Dynamic interface between the body and the brain </li></ul><ul><li>Prevents entry of mor...
Nanoplex <ul><li>Gene delivery using nanoparticles </li></ul><ul><li>Electrostatic gene condensation </li></ul><ul><li>Eff...
Gold nanorod (GNR) – fluorescent siRNA Nanoplex: Optical tracking of time dependent transport across BBB using in vitro mo...
Nanoparticle mediated gene silencing: Implications in drug addiction therapy Compliments  of  Indrijat Roy, Ph.D. Gene sil...
Gene Therapy <ul><li>Problem: Chronic cocaine and amphetamine use induces Nuclear Factor Kappa B (NFKB) dependent   transc...
Gene Therapy Complements of  Scott J. Russo, M.D., Ph.D.
Gene Therapy <ul><li>Science Fiction? </li></ul><ul><li>Viral vector treatments are already undergoing clinical trials in ...
Genetically Directed Therapy <ul><li>LL genetic variant of the serotonin transporter 5'-HTTLPR will respond better to onda...
Stem Cells <ul><li>Enhance neurogenesis in the subgranular zone of the hippocampus? </li></ul><ul><li>Regenerate cirrhotic...
Nuerostimulation <ul><li>Transcranial Magnetic Stimulation (TMS) </li></ul><ul><li>Deep Brain Stimulation (DBS) </li></ul>
TMS
TMS
TMS <ul><li>Substances: </li></ul><ul><ul><li>Cocaine, Nicotine, Alcohol, Food (human) </li></ul></ul><ul><ul><li>Opioid (...
TMS <ul><li>Related Utility: </li></ul><ul><ul><li>Depression (where medications complicate treatment or are ineffective) ...
DBS
DBS <ul><li>Target: Nucleus Accumbens </li></ul><ul><li>Historical Data: Lesions, Cingulotomies, & Ablations </li></ul><ul...
DBS Ncl.   accumbens Courtesy of  Jens Kuhn, M.D.
The machine does not isolate man from the great problems of nature but plunges him more deeply into them.  ~Saint-Exupéry,...
Upcoming SlideShare
Loading in …5
×

Emerging Somatic Therapies for the Addicted Patient

4,559 views

Published on

The Presentation for The Neuroscience and Addiction Conference 2009, presented by Horacio A. Capote, M.D.

Published in: Health & Medicine, Technology
  • mirc indir
    Great Post!!! thanks for sharing such a valuable information.
    mirc indir
    en guzel forum
    turkce mirc indir
    mirc
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

Emerging Somatic Therapies for the Addicted Patient

  1. 1. Emerging Somatic Therapies for the Addicted Patient <ul><li>Horacio A. Capote, M.D. </li></ul><ul><li>MEDICAL DIRECTOR, NEUROPSYCHIATRY DIVISION </li></ul><ul><li>DENT NEUROLOGIC INSTITUTE </li></ul>
  2. 2. OVERVIEW <ul><li>Functional Neuroanatomy of Addiction </li></ul><ul><li>Pharmacotherapy </li></ul><ul><li>Immunotherapy </li></ul><ul><li>Nanotechnology </li></ul><ul><li>Gene Therapy </li></ul><ul><li>Stem Cells </li></ul><ul><li>Neurostimulation </li></ul>
  3. 3. Inhibitory/Control Reward Memory/Learning Functional Neuroanatomy of Addiction
  4. 4. Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ, Nat Neurosci , 2005, 8:1445-1449.
  5. 5. Ventral Pallidum NA Core PFCortex VTA Basolateral Amygdala MDthalamus Extended Amygdala Central amydala BNST NA Shell Dopamine GABA glutamate Circuitry Mediating Goal-directed Behavior ?? Amygdala - FEAR- motivated behaviors Nucleus Accumbens - Reward-motivated behaviors Prefrontal Cortex - Valence of stimulus Expression of motivated behavior Extended Amygdala - Stressor-induced behaviors Functional Neuroanatomy of Addiction
  6. 6. Pharmacotherapy: New Targets --- NK1 <ul><li>The Stress Response: Substance P (SP) </li></ul><ul><li>Neurokinin 1 (NK1) Receptor Antagonists Ly686017 </li></ul><ul><li>SP & NK1 (its preferred receptor) are highly expressed in brain areas involved in stress responses and drug reward ---hypothalamus, amygdala, nucleus accumbens </li></ul><ul><li>George DT </li></ul>
  7. 7. Pharmacotherapy: New Targets --- NK1 <ul><li>Double-blind, placebo-controlled trial (n=50) of LY686017 </li></ul><ul><li>Suppressed spontaneous alcohol craving </li></ul><ul><li>Improved overall wellbeing </li></ul><ul><li>Blunted cravings induced by a challenge </li></ul><ul><li>Attenuated concomitant cortisol responses </li></ul><ul><li>Attenuated responses to positive & negative visual affective stimuli as measured by BOLD fMRI </li></ul>
  8. 8. Positive and negative affective stimuli (IAPS) Negative Positive Pharmacotherapy: New Targets --- NK1 Courtesy of Markus Heilig, M.D., Ph.D. Clinical Director NIAAA/NIH
  9. 9. Attenuated fMRI responses to negative affective stimuli following treatment with LY686017 (George et al, Science 2008) Placebo LY686017 Courtesy of Markus Heilig, M.D., Ph.D. Clinical Director NIAAA/NIH Inferior frontal gyus/insula Parahippocampal gyrus Inferior frontal gyrus Middle temporal gyrus p < 0.001 p < 0.01
  10. 10. Up-regulated fMRI responses to positive affective stimuli following treatment with LY686017 (George et al, Science 2008) Placebo LY686017 Courtesy of Markus Heilig, M.D., Ph.D. Clinical Director NIAAA/NIH Anterior cingulate/ caudate Thalamus Caudate (head) Lingual gyrus Nucleus accumbens/ putamen p < 0.001 p < 0.01
  11. 11. Pharmacotherapy: New Targets --- D3 <ul><li>Dopamine D3 receptors have a limbic distribution involved in cognitive & emotional functions </li></ul><ul><li>GSK 598809 D3 antagonist (phase 1) nicotine, food, & alcohol – 4 completed studies (safety, PET, interactions w/ETOH, safety in smokers); recruiting for reward response in nicotine & eating (w/neuroimaging); soon to recruit for ETOH [Toronto, Ontario site] </li></ul><ul><li>GSK 618334 D3 antagonist (phase 1) stimulants & alcohol -- 1 safety study completed October 2007 ; recruiting for [GSK Investigational Site Harrow, Middlesex, United Kingdom] </li></ul>
  12. 12. Pharmacotherapy: New Targets --- Dopamine Beta Hydroxylase <ul><li>SYN117 (Nepicastat) a potent, competitive, and selective dopamine β-hydroxylase inhibitor (phase 1) cocaine & others </li></ul><ul><li>Dopamine β-hydroxylase is the main enzyme responsible for the conversion of dopamine into norepinephrine. The inhibition of this enzyme has been shown to raise dopamine levels in the CNS </li></ul><ul><li>UT MB-Galveston; Synosia </li></ul>
  13. 13. Pharmacotherapy: New Targets --- Adenosine A2A <ul><li>SYN115: Adenosine A2A receptor antagonist (phase 1) cocaine & other stimulants </li></ul><ul><li>A2A is largely restricted to the Nucleus Accumbens and the striatum </li></ul><ul><li>Indirectly modulates dopamine function as well as glutamine & serotonin </li></ul><ul><li>Currently recruiting for an fMRI study </li></ul><ul><li>NIDA/UT Houston; Synosis Therapeutics </li></ul>
  14. 14. Pharmacotherapy: New Targets --- mGluR-1 <ul><li>SYN-119 a glutamate agonist: </li></ul><ul><li>Potently and selectively enhances the activity of glutamate at the mGluR-1 receptor. The molecule is under evaluation (pre-clinical studies) for the treatment of drug dependency. </li></ul><ul><li>Certain drugs of abuse cause plasticity in regions of the brain associated with pleasure and reward. </li></ul><ul><li>In preclinical studies, SYN-119 has been shown to prevent or reverse these changes and so has the potential to modulate the addictive properties of drugs of abuse, facilitate withdrawal from these drugs and decrease relapse rates. </li></ul><ul><li>Synosis Therapeutics </li></ul>
  15. 15. Pharmacotherapy : New Targets --- Glycine <ul><li>GSK 468816 Glycine (NMDA) antagonist (phase 2) nicotine dependence </li></ul><ul><li>Glycine receptors regulate dopamine release in the rat nucleus accumbens. Molander A , Söderpalm B . Alcohol Clin Exp Res. 2005 Jan;29(1):17-26. </li></ul><ul><li>Cannabanoid-induced increase in relapse-like drinking is prevented by the blockade of the glycine-binding site of N-methyl-D-aspartate receptors. Alén F, Santos A, Moreno-Sanz G, González-Cuevas G, Giné E, Franco-Ruiz L, Navarro M, López-Moreno JA. Neuroscience. 2009 Jan 23;158(2):465-73. </li></ul>
  16. 16. Pharmacotherapy: Semi-New Targets --- Cannabinoid 1 (CB1) <ul><li>Rimonabant – a CB1 inverse agonist currently being studied for nicotine dependence & smoking-cessation related weight gain </li></ul><ul><li>May also decrease cocaine, alcohol, and opioid seeking behavior </li></ul><ul><li>May enhance short-term memory </li></ul><ul><li>Has a checkered past as an anti-obesity drug (safety: suicidality & neurodegeneration) </li></ul><ul><li>Beardsley PM, Sanofi-Aventis </li></ul>
  17. 17. Pharmacotherapy: Old Targets Revisited --- Opioid <ul><li>ALKS33 opioid modulator; phase 2 imminent; metabolism not hepatic; “for the treatment of alcohol dependence and other reward disorders” </li></ul><ul><li>ALKS29 (ALKS33 + Baclofen) “…may address both the compulsive and impulsive components of alcoholism” </li></ul>
  18. 18. Pharmacotherapy: Old Targets Revisited --- GABA <ul><li>CPP-109 (Vigabatrin) – irreversible GABA transaminase inhibitor (phase 2) 3 trials completed; most recent n=180 multicenter double blind placebo controlled </li></ul><ul><li>Also may have utility in weight loss, methamphetamine dependence, alcohol dependence, and alcohol detoxification </li></ul><ul><li>Catalyst Pharmaceutical Partners </li></ul>
  19. 19. Immunotherapy
  20. 20. Immunotherapy <ul><li>Rationale: drugs of abuse readily cross the blood brain barrier because of their small size, while antibodies are larger & cannot enter the brain. Thus, any substance bound to antibody is prevented from having its effect on the central nervous system. </li></ul><ul><li>Active vaccines stimulate the body to make its own antibodies---problem: small size of abused drugs prevents them from stimulating an immune response. Solution: linking substances to toxins such as cholera toxin. </li></ul><ul><li>Passive immunotherapy uses monoclonal antibodies synthesized in a laboratory & administered intravenously. (Some potential utility in overdose as well) </li></ul><ul><li>Kosten TR </li></ul>
  21. 21. Immunotherapy <ul><li>Active Vaccines : </li></ul><ul><ul><li>Phase 1 (pre-clinical) cocaine, heroin, methamphetamine, nicotine </li></ul></ul><ul><ul><li>Phase 2 (humans) </li></ul></ul><ul><ul><ul><li>cocaine (1 vaccine) TA-CD </li></ul></ul></ul><ul><ul><ul><li>nicotine (3 vaccines)NicVax, NIC-002 (Nicotine-Qbeta) , Niccine </li></ul></ul></ul><ul><li>Passive Vaccines: </li></ul><ul><ul><li>Phase 1 cocaine, methamphetamine, nicotine, phencyclidine </li></ul></ul><ul><li>Montoya I; Kosten TR </li></ul>
  22. 22. Nanotechnology <ul><li>Problem: DARPP-32 is a protein known to trigger a cascade of changes in the addicted individual. Short interference RNA (siRNA) can inhibit DARPP-32 but it is unstable and difficult to get through the blood brain barrier. </li></ul><ul><li>Solution: Nanorods, gold rod shaped nanoparticles, can safely and efficiently deliver siRNA to the brain. </li></ul><ul><li>Bonoiu AC </li></ul>
  23. 23. Blood brain barrier (BBB) <ul><li>Dynamic interface between the body and the brain </li></ul><ul><li>Prevents entry of more than 98% of molecules and 100% of macromolecules </li></ul><ul><li>Protects the brain from harmful substances and fluctuations in blood chemistry </li></ul><ul><li>Hinders brain specific delivery of therapeutics </li></ul>Function of BBB Compliments of Indrijat Roy, Ph.D. Receptor Mediated transport – Coupling of biomolecules (eg. insulin, insulin-like growth factor (IGF), leptin, transferrin) to surfaces which bind to cell receptors, are internalized and transported into brain. Strategies for overcoming BBB www.photonics.buffalo.edu The Institute for Lasers, Photonics and Biophotonics
  24. 24. Nanoplex <ul><li>Gene delivery using nanoparticles </li></ul><ul><li>Electrostatic gene condensation </li></ul><ul><li>Efficient cellular entry </li></ul><ul><li>Non-toxicity </li></ul><ul><li>High gene expression/silencing </li></ul>Compliments of Indrijat Roy, Ph.D. Gene Silencing e.g. DARPP-32 in Addictions www.photonics.buffalo.edu The Institute for Lasers, Photonics and Biophotonics
  25. 25. Gold nanorod (GNR) – fluorescent siRNA Nanoplex: Optical tracking of time dependent transport across BBB using in vitro model Compliments of Indrijat Roy, Ph.D. Confocal images of fluorescent siRNA showing enhanced staining of cells with time, thus indicating BBB transport www.photonics.buffalo.edu The Institute for Lasers, Photonics and Biophotonics
  26. 26. Nanoparticle mediated gene silencing: Implications in drug addiction therapy Compliments of Indrijat Roy, Ph.D. Gene silencing efficiency of gold nanorod (GNR)-siRNA nanoplex is higher than that obtained using commercial agent (siPORT) www.photonics.buffalo.edu The Institute for Lasers, Photonics and Biophotonics
  27. 27. Gene Therapy <ul><li>Problem: Chronic cocaine and amphetamine use induces Nuclear Factor Kappa B (NFKB) dependent transcription in the Nucleus Accumbens (Nac), increasing the number of dendritic spines on its medium spiny neurons. This structural change correlates with drug-seeking behavior and increased risk of relapse in animal models. </li></ul><ul><li>Solution: Viral-mediated gene transfer of Inhibitor of Kappa B Kinase (IKKdn) blocks the increase in dendritic spines after chronic cocaine as well as the rewarding effects of cocaine and the ability of previous cocaine exposure to increase an animal's preference for cocaine. </li></ul><ul><li>Russo SJ </li></ul>
  28. 28. Gene Therapy Complements of Scott J. Russo, M.D., Ph.D.
  29. 29. Gene Therapy <ul><li>Science Fiction? </li></ul><ul><li>Viral vector treatments are already undergoing clinical trials in epilepsy and Parkinson’s disease. </li></ul>
  30. 30. Genetically Directed Therapy <ul><li>LL genetic variant of the serotonin transporter 5'-HTTLPR will respond better to ondansetron </li></ul><ul><li>SS or SL genetic variant of the serotonin transporter 5'-HTTLPR will respond better to sertraline </li></ul><ul><li>Brown & NIAAA currently recruiting for a double-blind placebo controlled 2x2 (match, mismatch) design [estimated n=132] </li></ul><ul><li>George A Kenna, Ph.D., R.Ph. </li></ul>
  31. 31. Stem Cells <ul><li>Enhance neurogenesis in the subgranular zone of the hippocampus? </li></ul><ul><li>Regenerate cirrhotic livers? (7 trials – 2 completed, 1 terminated, 4 recruiting) </li></ul>Stem Cell: Paul Leonard/Photo Researchers
  32. 32. Nuerostimulation <ul><li>Transcranial Magnetic Stimulation (TMS) </li></ul><ul><li>Deep Brain Stimulation (DBS) </li></ul>
  33. 33. TMS
  34. 34. TMS
  35. 35. TMS <ul><li>Substances: </li></ul><ul><ul><li>Cocaine, Nicotine, Alcohol, Food (human) </li></ul></ul><ul><ul><li>Opioid (preclinical) </li></ul></ul><ul><li>Localization: </li></ul><ul><ul><li>Right Dorsolateral Prefrontal Cortex </li></ul></ul><ul><ul><li>Left Prefrontal Cortex </li></ul></ul><ul><ul><ul><li>Camprodon JA; Politi E; Uher R </li></ul></ul></ul>
  36. 36. TMS <ul><li>Related Utility: </li></ul><ul><ul><li>Depression (where medications complicate treatment or are ineffective) </li></ul></ul><ul><ul><li>Pain Management </li></ul></ul><ul><ul><ul><li>Borckardt JJ(Kings College) </li></ul></ul></ul>
  37. 37. DBS
  38. 38. DBS <ul><li>Target: Nucleus Accumbens </li></ul><ul><li>Historical Data: Lesions, Cingulotomies, & Ablations </li></ul><ul><li>Animal Data: Cocaine (Vassoler FM – BU) </li></ul><ul><li>Human Data: 28 cases [2 categories] </li></ul><ul><ul><li>Subthalamic Nucleus in Parkinson’s Dopamine Discontrol Syndrome & Pathological Gambling </li></ul></ul><ul><ul><li>Nucleus Accumbens for Alcohol, Heroine, Nicotine </li></ul></ul><ul><ul><li>Bianaca M.L. Stelten, </li></ul></ul>
  39. 39. DBS Ncl. accumbens Courtesy of Jens Kuhn, M.D.
  40. 40. The machine does not isolate man from the great problems of nature but plunges him more deeply into them.  ~Saint-Exupéry, Wind, Sand, and Stars , 1939

×