Predicting human risk with animal research: lessons learned from caffeineephedrine 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