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

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?

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

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

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

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

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

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

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

In vivo tests

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

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

http://www.fda.gov/cder/index.html

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

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.

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)).

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..

http://clinicaltrials.gov/

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

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