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NEW DEVELOPMENTS IN TOXICOLOGICAL TESTING FOR PHP S

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NEW DEVELOPMENTS IN TOXICOLOGICAL TESTING FOR PHP S

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    1. NEW DEVELOPMENTS IN TOXICOLOGICAL TESTING FOR PHP’S DOUGLAS LEWIS, D.Sc. PRESIDENT & SCIENTIFIC DIRECTOR

    6. SYNTHESIS OF ETHYL GLUCURONIDE AND ETHYL SULFATE

    7. EtG / EtS IN URINE Confirms alcohol exposure for up to 5 days following consumption. ?-Glucuronidase from urinary tract infections destroys EtG but not EtS. Cut-offs are variable and can be set to meet client’s needs. Innocent-positives can be generated by alcohol-containing hand sanitizers and mouthwashes.

    8. EtG ANALYSIS

    9. EtS ANALYSIS

    10. Positive EtG/EtS is NOT unequivocal evidence of beverage alcohol consumption. Positive EtG/EtS requires further examination, either clinically or by using a biomarker assay with a higher exposure threshold for positivity.

    11. USE OF EtG / EtS IN URINE Determination of alcohol ingestion Window of measure = 1 - 5 days Indicates that alcohol has been consumed Primarily used for monitoring in monitored abstinence programs (professionals in recovery)

    12. PHOSPHATIDYLETHANOL IN BLOOD A direct alcohol biomarker that incorporates into cell membranes Long half-life (t1/2 = 4.4 days)--not metabolized Remains in red cell membrane for the life of the blood cell or spontaneous hydrolysis- 3 weeks Can be detected following ingestion of 200 grams of ethanol over 1 week Window of detection 3 weeks or better

    13. SYNTHESIS OF PHOSPHATIDYLETHANOL

    14. STRUCTURE OF PHOSPHATIDYLETHANOL

    15. PHOSPHATIDYLETHANOL ANALYSIS

    16. USE OF PHOSPHATIDYLETHANOL IN BLOOD Determination of longer term alcohol abuse Window of measure up to 3 weeks Indicates heavy drinking over 3 week period Identifies potential problem drinkers Could be used to screen any population that requires abstinence such as transplant recipients, professionals in recovery, individuals under court order, etc.

    17. USE OF PHOSPHATIDYLETHANOL IN BLOOD Can be performed on dried blood spots from finger stick No longer requires phlebotomy Minimally invasive Test subjects can provide specimens themselves Dried blood spots on filter paper safe and easy to store and ship, unlike tubes of blood.

    18. Dried Blood Spot Collection

    19. STRUCTURE OF ETHYL OLEATE

    20. SYNTHESIS OF FATTY ACID ETHYL ESTERS (FAEE’s)

    21. FAEE IN HAIR Potential biomarker for long-term alcohol abuse (up to 3 months) Control group: <1 drink daily Patient group: 11 + drinks daily Hair specimens collected with interview 1.5 inches in length 100 mg in mass Obtained Timeline Followback for 90 days

    22. FAEE’s MEASURED FAEE’s separated and detected by GC/MS Ethyl myristate (E14:0) Ethyl palmitate (E16:0) Ethyl palmitoleate (E16:1) Ethyl stearate (E18:0) Ethyl oleate (E18:1)

    23. FAEE IN HAIR

    24. FAEE IN HAIR

    25. CONCLUSIONS OF FAEE IN HAIR STUDY Hair FAEE’s very specific biomarkers of long term alcohol abuse Sensitivity of hair FAEE’s (60%) is not adequate to use assay to identify individuals with a history of long term alcohol abuse

    26. EtG IN HAIR Control group: teetotalers Patient group: individuals in alcohol abuse programs Hair specimens collected with interview 1.5 inches in length 100 mg in mass Obtained Timeline Followback for 90 days

    27. EtG IN HAIR ANALYSIS Hair specimens washed sequentially with hexane, methylene chloride, and methanol Hair specimens eluted with water EtG removed from water eluates by solid phase extraction EtG resolved from water eluates and identified using LC/MS/MS

    29. COMPARISON OF FAEE’s AND EtG IN HAIR AS ALCOHOL BIOMARKERS

    30. PATIENTS TESTING NEGATIVE FOR HAIR FAEE’s BUT POSITIVE FOR HAIR EtG

    31. CONCLUSIONS OF EtG IN HAIR STUDY Hair EtG very specific biomarker of long term alcohol abuse Sensitivity of hair EtG (80%) is better than any long term marker of alcohol abuse currently available This Phase I study establishes feasibility of hair EtG as a long term alcohol biomarker and paves the way for a Phase II study to characterize and validate a hair EtG production assay

    32. Hair EtG vs. Nails EtG

    33. Hair EtG v. Nail EtG

    34. Propofol Glucuronide Propofol - a widely used ultra-short acting general anesthetic agent Propofol has abuse potential Propofol’s half life very short (10 minutes) Primary metabolite- Propofol Glucuronide Propofol glucuronide kinetics very similar to EtG. Provides 2-3 day look back

    35. Propofol Glucuronide in Urine

    36. 14 Urine Specimens Collected from CRNA's after Shift Completed

    37. Propofol Glucuronide Urine propofol glucuronide cutoff set at 20 ng/mL to avoid occupational exposure Sub-therapeutic doses (50 mg) produced urine levels at 2 hours of >10,000 ng/mL Daily (14 days) sub-therapeutic doses (50 mg/day) produced levels >20ng/mL for at least 72 hours post last dose

    40. Propofol Glucuronide Propofol glucuronide also can be found in hair samples From daily sub-therapeutic study, all four participants had no detectable propofol glucuronide in hair post dosing In 350 PHP hair samples anonymized & scheduled for destruction, 2 propofol glucuronide positive cases were found

    42. Hair Propofol Glucuronide #1

    43. Hair Propofol Glucuronide #1

    44. Hair Propofol Glucuronide #2

    45. USDTL RESEARCH FUNDING NIH SBIR Grants from National Institute of Drug Abuse National Institute on Alcohol Abuse and Alcoholism

    46. Thank You For more information on the data contact me at: douglas.lewis@usdtl.com 800-235-2367

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