# Presentation: 272996

## 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.

- 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?

- 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.

- 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

- 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”

- 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.

- 09-Sep-2003

## Preclinical Data

- What data could have been used *a priori* to protect consumers?

- 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

- 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.

- 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

- 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.

- 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.

- 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?

- 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)

- 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.

- 09-Sep-2003

## Cocaine Self-Administration Dose Response Curve

- 09-Sep-2003

## Caffeine/Ephedrine Self-Administration Dose Response Curve

- 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

- 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.

- 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

- 09-Sep-2003

## Drug Discrimination Generalization of Caffeine/Ephedrine in the Rat

- Gauvin et. al. (1993) Psychopharmacology, 110: 309-319

- 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

- 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.

- 09-Sep-2003

## Developing Herbal Products

- What can be done to increase the safety of marketed herbal products?

- 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.

- 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?

- 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

- 09-Sep-2003