Update on Medication Issues

1. Update on Medication Issues Scot Waterman, DVM Executive Director Racing Medication & Testing Consortium

2. 1. Penalties and the Model Rules

3. Penalties and the Model Rules • Old version: • Contained in RCI Uniform Drug Classification document • Penalties based on RCI Class of the drug • Penalties had large ranges for number of suspension days and fines • No guidance on how to treat multiple violations or other circumstantial evidence

4. Penalties and the Model Rules • Reasons for change: • Classifications based entirely on pharmacology of drug but the question really needs to be whether the drug is appropriate to see in a racehorse • Penalties should increase with repeat violations • Other licensees should participate in the penalty phase especially repeat violators • We need to define possible mitigating and aggravating circumstances

5. Flunixin (Banamine) RCI Class 4 NSAID FDA-approved for the horse Many studies in the scientific literature in the horse Regulated by rule Meloxicam RCI Class 4 NSAID Not FDA-approved for the horse No studies in the horse Not regulated by rule So, the question is why would someone use Meloxicam instead of Flunixin? Penalties and the Model Rules

6. Penalties and the Model Rules • New version: • Took all drugs in RCI Classifications and assigned them into A, B, C or D groups • Each drug was slotted based on criteria: • FDA approval…1st for horse, 2nd for any reason? • Legitimate therapeutic application? • Identified as necessary by RMTC Vet Committee? • Does an alternative exist? • What is the current RCI Classification?

7. Diclofenac (Surpass) FDA-approved? Yes, for the horse Legitimate therapeutic application? Yes, as a topical anti-inflammatory Identified as necessary? Yes Does an alternative exist? No Current RCI Class? 4 Penalty Class “C” $500 fine, loss of purse Meloxicam FDA-approved? No for horse, yes for dog, human Legitimate therapeutic application? No, no support in literature Identified as necessary? No Does an alternative exist? Yes…flunixin, bute, ketoprofen Current RCI Class? 4 Penalty Class “B” 15 day suspension, $500 fine, loss of purse Penalties and the Model Rules

8. Penalties and the Model Rules • Other new tweaks: • Penalties for owner and horse potentially • Ability to penalize veterinarian to same extent as trainer if culpability can be proven • Licensed owners to be notified of any hearings as a result of a violation whether penalized or not • Flexibility to let the penalty fit the circumstances of the case…not uniform penalties but a uniform approach to penalties

9. Penalties and the Model Rules • Mitigating and Aggravating Circumstances: • Each medication violation will have a unique set of circumstances even if the drug in question is the same • This is true of any violation…all murder defendants do not wind up with the same jail time • Given the increased public scrutiny of the sport, violations need to be investigated and resulting penalties need to be well reasoned • Alan Foreman will cover in detail tomorrow but let’s spend some time on the concentration of the drug

10. Penalties and the Model Rules • How to interpret drug concentrations: • For the most part, you can’t! • There are too many unknowns: • Dose of drug • Route of administration • Frequency of administration • Formulation of the drug • Metabolic rate of the horse • What you want is enough information to be able to make some educated guesses

11. Penalties and the Model Rules • Example: • You are given a positive lab report of acepromazine with a concentration of 25 nanograms/ml in urine • Possibilities: • Trainer was giving 25 mg once a day orally because horse is hard to handle • Horse shipped in three days ago and was given an injection to help with van ride • Horse is a basket case in the paddock so a small amount was given IV with furosemide to take the edge off • All three are legitimate scenarios for that concentration of drug…how do you try to differentiate and do you need to?

12. Penalties and the Model Rules • What kind information can help you: • Pharmacokinetics (the study of elimination of a drug over time) • Elimination curves can be produced that give you concentration vs. time • Plasma correlates much better than urine generally • Difficulties • Not every drug has been studied • Small number of horses often used • Furosemide complicates for urine • Some drugs not detectable in plasma for a long enough period of time

13. Pharmacokinetic Analysis

15. Penalties and the Model Rules • What kind information can help you: • Veterinary Records • They can be changed/created/edited to fit the story but still useful • Interviews • Get the Vet Records first, look for consistency • If positive has been reported in urine, plasma may be useful to look at

16. Penalties and the Model Rules • 25 ng/ml acepromazine in urine: • PK chart…25 mg IV single dose

17. Penalties and the Model Rules • 25 ng/ml acepromazine in urine: • Lab tests the plasma…no detectable concentration of aceproamzine • Records show horse shipped in two days ago • Trainer has one bute overage 10 years ago • Not 100% but circumstances seem to fit with a single injection for tranquilization prior to shipping • Would fit with the minimum or could even mitigate down to below the minimum since there was likely no intent to cheat

18. RMTC Administration Studies • Have 20-horse data for: • Butorphanol • Methocarbamol (Robaxin®) • Pyrilamine • Clenbuterol • Firocoxib (Equioxx®) • Glycopyrrolate • Administrations complete for: • Lidocaine, Mepivacaine, Acepromazine, Detomidine • Administrations planned for: • Dantrolene, Hydroxyzine, Fluphenazine, Xylazine, Albuterol

19. 2. Therapeutic medications—current events

20. Furosemide (Salix, Lasix) • 90+% of horses suffer from some degree of EIPH, estimated that industry cost of EIPH approaches $100 million dollars • Working theory is that increase in circulating RBCs during exercise increases blood pressure in blood vessels of lung • Furosemide thought to lower blood pressure in lungs by reducing fluid component of blood • Published science very unclear on whether this is the case

21. Furosemide (Salix, Lasix) • Lasix Perceptions • We are breeding generations of bleeders • Lasix masks the presence of other drugs • Lasix is somehow linked to soundness issues

22. Furosemide (Salix, Lasix) • SAFE Study: • Double-blinded study using horses that have never received furosemide before in actual race conditions for purse money in South Africa • Horses receiving saline instead of furosemide had increased severity of EIPH • 67.5% of horses that bled when receiving saline had improved EIPH severity scores by at least one • Conclusion…EIPH incidence and severity was improved by pre-race administration of furosemide

23. NSAIDS • One of three (phenylbutazone, flunixin, ketoprofen) can be administered 24 hours out • Must be administered with a single IV injection • Threshold concentration used to enforce • 20 ng/ml for flunixin • 10 ng/ml for ketoprofen • 5 mcg/ml for phenylbutazone • Studies indicate analgesic effect is gone by 12 hours after IV injection

24. NSAIDS • Regulatory veterinarians feel the 24-hour administration impacts their ability to perform pre-race exams • Some science seems to support, some does not • Collecting samples in some states at the time of the pre-race exam to get an idea of plasma concentrations • On the table- pushing administration out to 48 hours (similar to Canada) or reducing phenylbutazone threshold to 2 mcg/ml • Will have an answer hopefully by end of year

25. Anabolic Steroids • Model rule has been in place now for 6-18 months depending on jurisdiction • Rule has basically eliminated the use of the usual anabolic steroids • Chemists reporting no detectable anabolic agents in post-race samples • Revised rule with plasma thresholds proposed to RCI • Labs with proper instrumentation will likely switch to plasma testing

26. Anabolic Steroids Issues • The program gelding with high testosterone • Recommend a HCG Challenge Test to determine whether residual testicular tissue is present • If “positive” horse is classified for regulatory purposes as a “rig” and kept as a gelding for program • “Rig” notation is sent to lab with subsequent samples which are excused from testosterone testing • Hermaphrodites • One Standardbred mare on east coast throws fillies with internal male sex organs

27. Anabolic steroids • Starting to see “replacement” substances begin to be a problem: • High-dose clenbuterol • Ractopamine • Ethylestrenol

28. Coming Attractions • Corticosteroids • RCI Class 4 Substances • Anti-inflammatory in action • Very diverse group of drugs, wide number of uses • Some are difficult to test for and process is complicated by multiple routes of administration • Many states choose to use testing budget elsewhere, mostly due to Class 4 status • Abuse, particularly intra-articular, is significant anecdotally especially in claiming horses

29. Coming Attractions • Corticosteroids • Pennsylvania has adopted a 7-day ban on intra-articular injections • Questionable whether this can be enforced currently • RMTC is funding studies on the corticosteroids which will look to generate PK data • Also looking at dynamic markers

30. 3. RMTC Drug Testing Initiatives

31. RMTCDrug Testing Initiatives • Post-race testing in the United States: • Currently 18 laboratories conducting testing • Only 5 labs ISO 17025 accredited • 30% of samples were tested by an accredited lab in ‘08 • Funding is dramatically different state-to-state • No industry standards for US testing labs • Animal selection strategies haven’t changed in years

32. RMTCDrug Testing Initiatives • Committee formed in September 2008 • First meeting- design the best system for US Drug Testing irrespective of funding and political concerns • Consensus that we should utilize laboratory standards developed by the World Anti-Doping Association where applicable and work toward the development of a performance-based system • Other related topics discussed- next generation of lab directors, samples selection, frozen samples, harmonization nationally and internationally

33. RMTCDrug Testing Initiatives • Creation of Industry Standards for Labs: • Edited version of the Lab Standards document created by the World Anti-Doping Association has been developed by the committee • Standards rely on ISO 17025 accreditation as the first step • An external proficiency program is then conducted • Labs failing proficiency cannot conduct testing • A percentage of the laboratory budget is mandated to be directed toward research • Current QAP programs (TIP & IDTA) salvaged for 2009 via financial arrangement between RCI and RMTC

34. RMTCDrug Testing Initiatives • Creation of Industry Standards for Labs (continued): • Result will create the first set of industry standards for post-race testing labs in US • States/industry will have a document to “sell” in order to provide incremental funding for lab to meet standards • Will need funding for the industry organization that takes on the role of WADA • Standards would be a perfect fit for the idea of a national compact

35. RMTCDrug Testing Initiatives • Post-doctoral and graduate student recruitment: • Our Laboratory Directors are aging…who replaces them? • Those with research programs that are racing related could do more with capable students • Developing a comprehensive program to target individuals with pharmacology/veterinary/chemistry backgrounds to place in research positions and will also utilize racing laboratories and possibly U of A RTIP for broad racing education • Initial cost $150,000-300,000

36. RMTCDrug Testing Initiatives • Sample Collection • Is testing winners the most efficient use of testing dollars? • McKinsey Report suggested using a matrix based on odds and finish place of the horse • Possibility of collection without testing • Frozen Sample Program • Possible deterrent effect and useful for intelligence information • Program is funded for 2009 and RMTC will administer

37. RMTCDrug Testing Initiatives • Pleased with progress in a short period • Will need broad industry support to implement • Incremental funding will be needed • Industry needs to support commissions at legislative level • Will need industry organizations with sticks to use them