Predicting human risk with animal research: lessons learned from caffeine/ephedrine combinations

1. 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. 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. 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. 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. 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. 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. Preclinical Data What data could have been used a priori to protect consumers?

8. 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. 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. 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. 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. 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. 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. 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. 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. Cocaine Self-Administration Dose Response Curve

17. Caffeine/Ephedrine Self-Administration Dose Response Curve

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

22. 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. 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. Developing Herbal Products What can be done to increase the safety of marketed herbal products?

25. 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. 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. 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