3. Design Issues in Human studies of Psychopharmacology
placebo controls
double blind studies

4. Variables that affect differences in response to drugs
Inheritance – genetics
gender
body weight/body fat/ etc
age
ethnicity
ethnopharmacology
personality characteristics
sensation seeking
addictive personality?

5. Ways that new drugs are developed
rediscovery of “folk remedies”
unexpected accidental observation
synthesis of known or novel compounds

6. An Example
agmatine-
appears “neuroprotective”
appears to work on GLU receptors (among other NT) as a modulatory drug
modulatory drugs – can alter activity of NT at the postsynaptic receptor

7. During ETOH Withdrawal
Ca2+
NMDAR
Glutamate
Polyamine site
During ETOH
Exposure
Glutamate and NMDAR activity initially reduced followed by compensatory increase in NMDAR sensitivity
and polyamine synthesis
During ETOH Withdrawal
Reactive increases in polyamine release, glutamate release, and NMDAR sensitivity contribute to toxicity
modulatory site

9. molecular screen
does the drug stop polyamines from increasing GLU activity?

10. a cell culture model (part of the cellular screen)
hippocampal slice

11. CP 101,606 Traxoprodil Selective type of NMDA r antagonist Pfizer
recently published for
possible effects on neuropathic pain
depression ?

12. Our novel drugs that blocks the polyamine site (JR 220) also reduced ethanol-induced neurotoxicity

13. In vivo tests

17. Stages in Testing and Marketing a Drug
Hypothesis
In vitro and in vivo animal studies
Toxicity testing
Limited human studies with healthy volunteers (limited n)
Experimental studies conducted with clinical populations
Broader clinical trials
Licensing and marketing approval
After marketing evaluation of clinical use

18. Center for Drug Evaluation and Research's (CDER)
ensures that drugs are safe and effective.

21. Steps necessary to bring a new drug to market
Screening tests using animal models
must include at least two species
Phase 1 - assessment of safety and toxicity
small n, small dose
Phase 2 - tested in limited n of patients
individuals with condition ~ few hundred patients
Phase 3 - Expanded clinical trials
usually administered to thousands

22. Phase IV - Post Marketing Surveillance Trial
Phase IV - Post Marketing Surveillance Trial. involves the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold.

23. Short-term testing in animals ranges in duration from 2 weeks to 3 months, depending on the proposed use of the substance.
Long-term testing in animals ranges in duration from a few weeks to several years. Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects. Much of this information is submitted to FDA when a sponsor requests to proceed with human clinical trials. The FDA reviews the preclinical research data and then makes a decision as to whether to allow the clinical trials to proceed (see Clinical Studies (Overview)).

24. Ethical Issues…..
consider when using placebo? What are ethical factors in admin of experimental drugs to human
length of drug approval period – good or bad..

27. What about nutritional supplements?
1994 Dietary Supplement Health and Education Act-
Saint Johns Wort

29. What about nutritional supplements?
1994 Dietary Supplement Health and Education Act
Saint Johns Wort
ephedrine- Metabolife
80 deaths, 1500 serious events