1. 09-Sep-2003 Predicting human risk with animal research: lessons learned from caffeine/ephedrine combinations Richard J. Briscoe, Ph.D. Safety Pharmacology Merck Research Laboratories This presentation represents my personal opinion and does not represent the opinion of Merck & Co., Inc.

2. 09-Sep-2003 Overview Discuss the issues for marketing herbal products as pharmaceuticals using caffeine/ephedrine as an example. Preclinical data related to caffeine/ephedrine predicted safety. What could be done to reduce the problem for other herbal products?

3. 09-Sep-2003 Marketing Issues Caffeine/Ephedrine (guarana/ma-huang) combinations are one of the most widely marketed herbal product today. Until recently these products were marketed with limited regard for safety or efficacy for their claimed indications.

4. 09-Sep-2003 Marketing Issues The safety of these products has been widely challenged with numerous reports of toxicity or death. Most reports of toxicity are linked to overdose or pre-existing conditions. –If the recommended amount is good, more is better

5. 09-Sep-2003 Marketing Issues Herbal dietary supplements are not controlled or regulated by the FDA like other over-the-counter pharmaceuticals as they are under the Dietary Supplement Health and Education Act of 1994. The FDA is unable to control an herbal product unless it “presents a significant or unreasonable risk of injury”

6. 09-Sep-2003 Marketing Issues Problem –Numerous controlled clinical trials have demonstrated that caffeine/ephedrine have efficacy for weight loss. As such they are widely available. –The known pharmacology of caffeine/ephedrine alone supports the use of these products as efficacious stimulants and they are marketed as such.

7. 09-Sep-2003 Preclinical Data What data could have been used a priori to protect consumers?

8. 09-Sep-2003 Preclinical Data Establish what the major active ingredients/compounds in the herbal product are. –Guarana - caffeine and other closely related methylxanthines –Ma-Huang - ephedrine, pseudoephedrine

9. 09-Sep-2003 Preclinical Data Mechanism of action, if known, should be considered carefully for safety assessment. –Caffeine - inhibits phosphodiesterases preventing inactivation of cAMP; increases norepinephrine levels; Adenosine receptor antagonist (primary CNS stimulant effect) –Ephedrine - adrenergic receptor agonist; increased norepinephrine release in SNS.

10. 09-Sep-2003 Preclinical Data What are the known physiological effects associated with the mechanisms of action. –Caffeine - tachycardia, CNS stimulation, hypertension, mild hyperthermia –Ephedrine - tachycardia, CNS stimulation, hypertension, increase cardiac output, hyperthermia, bronchodilation

11. 09-Sep-2003 Preclinical Data For an appropriate safety evaluation –What is the dose level of the active component(s) that is proposed for use to achieve clinical efficacy –What dose level induces toxic side effects in humans and animals. –What is the bioavailability of the intended clinical route in the animal and human. –What is the metabolic pathway Important for predicting drug interactions –Need to define a safety margin.

12. 09-Sep-2003 Preclinical Data Animal studies provide data on long term high dose exposure to give indications of what organ systems are differentially affected (e.g. hepatic or renal toxicity). Human clinical trials data refines the safety profile generated in animals.

13. 09-Sep-2003 Preclinical Data As caffeine and ephedrine have been widely studied for decades, a substantial database is available to draw on for most of the information. This is not necessarily the case for many herbal products. Could animal studies have predicted the use of these products as stimulants?

14. 09-Sep-2003 Self-Administration Studies These studies are generally accepted to have high predictive validity in predicting abuse potential in humans. –If compounds are not self-administered in animals they are generally not abused in humans (LSD is not self-administered robustly in animals but is abused in humans) –If compounds are self-administered in animals they are generally abused in humans (Nomifensine is self-administered in animals but not widely abused in humans)

15. 09-Sep-2003 Caffeine/Ephedrine Self- Administration Substitution Study Tethered rats were initially trained to self- administer 0.5 mg/kg cocaine on an FR10 schedule. 3 day substitutions of either cocaine or caffeine/ephedrine at various doses were then conducted randomly. Each session was 4 hours.

16. 09-Sep-2003 Cocaine Self-Administration Dose Response Curve

17. 09-Sep-2003 Caffeine/Ephedrine Self- Administration Dose Response Curve

18. 09-Sep-2003 Self-Administration Conclusion Rats robustly self-administered caffeine/ephedrine on day 1 when substituted for cocaine. Combination did not support administration for 3 consecutive days. As animals had unlimited access to drug this was likely due to behavioral toxicity on day 2 and 3. The only rats that died from overdose in the study were in the caffeine/ephedrine groups

19. 09-Sep-2003 Drug Discrimination Studies Animal model for assessment of the subjective effects of drugs in humans. Assesses whether administration of a test drug generates interoceptive (internal or ‘subjective’) cues that are perceived by the animal to resemble those generated by another drug. Drug discrimination is widely recognized as central nervous system mediated assay.

20. 09-Sep-2003 Drug Discrimination Study: Caffeine/Ephedrine in the Rat Rats were initially trained to press levers for food reinforcement. Training drugs were then associated with one of the levers and saline with the other. Once acceptable stimulus control was established generalization tests were conducted. Gauvin et. al. (1993) Psychopharmacology, 110: 309-319

21. 09-Sep-2003 Drug Discrimination Generalization of Caffeine/Ephedrine in the Rat Gauvin et. al. (1993) Psychopharmacology, 110: 309-319

22. 09-Sep-2003 Drug Discrimination Conclusions Caffeine/Ephedrine fully generalized to both cocaine and amphetamine. This demonstrates that caffeine/ephedrine share interoceptive cues similar to cocaine and amphetamine

23. 09-Sep-2003 Does Preclinical Data Suggest Human Abuse Potential? Pharmacology of caffeine/ephedrine demonstrates clear CNS stimulant activity. Self-administration demonstrated that rats will administer caffeine/ephedrine similar to cocaine, at least initially. Drug discrimination demonstrated that caffeine/ephedrine induce a similar internal cue as cocaine.

24. 09-Sep-2003 Developing Herbal Products What can be done to increase the safety of marketed herbal products?

25. 09-Sep-2003 Developing Herbal Products If herbal products are pharmacologically active and have efficacy, why are they treated different than other pharmaceutical products? –Most consumers seem to generally believe that because it is herbal it is safe and natural. This is a dangerous situation.

26. 09-Sep-2003 Developing Herbal Products Manufactures should conform with accepted manufacturing practices to assure a uniform product with known components and strength. Safety should be carefully evaluated and clearly stated to consumers. –What are the effects of acute and chronic administration? –What drug interactions are possible or dangerous?

27. 09-Sep-2003 Developing Herbal Products Efficacy claims should be proven in controlled clinical studies. Good product stewardship should be welcomed by companies marketing these products. –Protects the health and safety of the consumer –Protects the long term viability of their business