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DISULFIRAM

A NEUROLOGICAL EXPLANATION FOR THE EFFECTIVENESS OF DISULFIRAM IN SUBSTANCE ABUSE DISORDERS Morris D. Faiman, Ph.D. University of Kansas 2/27/11 . DISULFIRAM. Pharmacological basis for the current mechanism of action of disulfiram. DISULFIRAM BIOACTIVATION.

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DISULFIRAM

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  1. A NEUROLOGICAL EXPLANATION FOR THE EFFECTIVENESS OF DISULFIRAM IN SUBSTANCE ABUSE DISORDERS Morris D. Faiman, Ph.D.University of Kansas2/27/11

  2. DISULFIRAM Pharmacological basis for the current mechanism of action of disulfiram.

  3. DISULFIRAM BIOACTIVATION

  4. Cocaine-dependent individuals also abuse alcohol Rationale: Reduce alcohol use and you reduce cocaine use as well DISULFIRAM/COCAINE STUDIES

  5. Higgins, S. T.; Budney, A. J.; Bickel, W. K.; Hughes, J. R.; Foerg, F., Disulfiram therapy in patients abusing cocaine and alcohol. Am J Psychiatry 1993, 150, (4), 675-6. Carroll, K. M.; Nich, C.; Ball, S. A.; McCance, E.; Rounsavile, B. J., Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 1998, 93, (5), 713-27. Carroll, K. M.; Nich, C.; Ball, S. A.; McCance, E.; Frankforter, T. L.; Rounsaville, B. J., One-year follow-up of disulfiram and psychotherapy for cocaine-alcohol users: sustained effects of treatment. Addiction 2000, 95, (9), 1335-49. DISULFIRAM/COCAINE STUDIES

  6. Petrakis, I. L.; Carroll, K. M.; Nich, C.; Gordon, L. T.; McCance-Katz, E. F.; Frankforter, T.; Rounsaville, B. J., Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. Addiction 2000, 95, (2), 219-28. Carroll, K. M.; Fenton, L. R.; Ball, S. A.; Nich, C.; Frankforter, T. L.; Shi, J.; Rounsaville, B. J., Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry 2004, 61, (3), 264-72 DISULFIRAM/COCAINE STUDIES

  7. Carroll, K. M.; Fenton, L. R.; Ball, S. A.; Nich, C.; Frankforter, T. L.; Shi, J.; Rounsaville, B. J., Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry 2004, 61, (3), 264-72 Key Study: Showed that disulfiram (250 mg/day) was more effective in reducing the frequency of the amount of cocaine use among non-alcohol cocaine –dependent outpatients than among the alcohol+cocaine –dependent patients. Disulfiram has a direct influence on cocaine use independently of alcohol use DISULFIRAM/COCAINE STUDIES

  8. Carroll et al. 2004. – Seminal study. Alcoholic and non alcoholic volunteers with cocaine dependence. Rationale- 85% of cocaine abusers also alcohol-dependent Reduce alcohol intake and you reduce cocaine use Non-alcoholic volunteers did better than alcoholic dependent volunteers WHY/HOW? ‘clues as to mechanism’ “REVERSEENGINEERING”

  9. Disulfiram inhibits DβH and increases brain dopamine. Cocaine also increases brain dopamine. Combination leads to higher levels of brain dopamine (Reward Mechanism) Disulfiram inhibits cocaine metabolism resulting in longer-lasting cocaine effect. PROPOSED MECHANISM OF ACTION FOR DISULFIRAM IN COCAINE DEPENDENCE

  10. CARBAMATHIONE – PARTIAL NON-COMPETITIVE NMDA ANTAGONIST. DOES NOT INHIBIT ALDH2. DISULFIRAM EFFICACY IN COCAINE DEPENDENCE INDEPENDENT OF ALCOHOL USE  KETAMINE - NMDA ANTAGONIST AND INCREASES BRAIN DOPAMINE INFORMATION AVAILABLE

  11. INCREASING BRAIN DOPAMINE PROPOSED AS ONE TREATMENT OPTION AS REPLACEMENT FOR COCAINE ACAMPROSATE : INCREASES BRAIN DOPAMINE ( FROM MICRODIALYSIS). ATTENTUATES REINSTATEMENT OF COCAINE-SEEKING BEHAVIOR IN RATS. MORE EFFECTIVE IN ALCOHOL THERAPY WHEN COMBINED WITH DISULFIRAM INFORMATION AVAILABLE

  12. Microdialysis was used to monitor the chemistry of the extracellular fluid in brain tissue of rats before and after the administration of the analytes. MICRODIALYSIS

  13. Detection of Carbamathione (1), IS 2-ABA (2), GABA (3), Glu (4), DA (5) in brain dialysate BGE: 22.5 mmol/L LTB (pH 9.2) and 20 mmol/L LDS LODs of 0.5-1.5 nM 65 x 50 µm id fused-silica capillary (50 cm effective) 10 kV for 10 min and 20 kV for 8 min 15 sec 0.7 psi injection ANALYTICAL METHOD Micellar Electrokinetic Chromatography in Conjunction with ‘Laser Induced Fluorescence’ Siri et al., Electrophoresis, 27(22):4446-55, 2006

  14. Brain microdialysis probe implanted into nucleus accumbens shell and prefrontal cortex Vascular probe implanted into the jugular vein Carbamathione administration (200, 50, 20 mg/kg i.v.) in awake Sprague Dawley rats 3 min collections at 2 µL/min EXPERIMENTS

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  16. Inhibition of disulfiram metabolism  blocks formation of carbamathione DISULFIRAM INHIBITION

  17. DISULFIRAM BIOACTIVATION

  18. Slide is not available

  19. SUMMARY DISULFIRAM BIOACTIVATION

  20. Disulfiram inhibits DβH (Goldstein) Carbamathione responsible for DA increase, not DDTC Disulfiram efficacy (cocaine, alcohol) probably involves interaction between dopaminergic / glutamatergic/GABA pathways ALDH2 inhibition is a side-effect of disulfiram and used clinically SUMMARY

  21. Disulfiram is a neuromodulator affecting dopaminergic / glutamatergic/GABA pathways via carbamathione Clinically, be careful of bioactivation inhibition Carbamathione as a drug candidate- advantages Conflict of Interest: MDF holds patents for S-methyl N,N-diethyldithiocarbamate sulfoxide (DETC-MeSO) and carbamathione. SUMMARY

  22. Dr. Swetha Kaul Dr. Todd Williams Dr. Craig Lunte Dr. Tom Prisinzano Anton Heemskerk Dr. Elinore McCance-Katz Dr. Gillian Whitaker NIDA ACKNOWLEDGEMENTS

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