This candidate wishes to systematically expand his investigative capabilities in basic and clinical psychopharmacology to become a pediatric psychopharmacologist and to explore innovative treatment strategies in content areas of Attention Deficit Disorder and Tourette's Syndrome. These content areas were chosen to accomplish two long term goals of the candidate: (1) the characterization of the drug level vs. clinical response relationship in children and (2) in vivo exploration of mechanism of drug action in children via neuroendocrine and behavioral assessment measures. Drugs of interest include pemoline, which will be studied in vivo and in vitro in a rat model as well as in hyperactive children, and pimozide and haloperidol which will be studied in children with Tourette's Syndrome. Preliminary data obtained by the candidate showing an inverse, in-phase relationship between pemoline and prolactin concentrations in hyperactive children needs further characterization both in clinical studies and in an animal model. The clinical significance of such a relationship is that it defines the time course of pemoline's effect as an indirect dopamine agonist and may correlate with clinical response to pemoline. Work to be completed over the first three project years include (1) Define the pharmacokinetic profile of pemoline in the rat, (2) Study the pharmacologic effect of reserpine and a methyl-p-tyrosine pretreatment on pemoline's action as defined by motor activity and prolactin secretion in the rat, (3) Examine the binding of high specific activity 3H pemoline in rat brain, (4) Establish whether pemoline inhibits its own metabolism in hyperactive children, (5) Characterize the relationship of pemoline level to prolactin response after both acute and three weeks of pemoline, (6) Develop a sensitive and specific RIA assay for pimozide that will accurately measure from 0.5-50 ng/ml, (7) Characterize the pharmacokinetics of pimozide in children with Tourette's. Work to be completed in years 4 and 5 of the award include (1) Characterization of the relationship between steady-state pemoline concentration and clinical response in hyperactive children in a double-blind, placebo controlled, cross-over study, and (2) Comparison of therapeutic efficacy of haloperidol and pimozide for the control of Tourette's and an estimate of the therapeutic ranges for these drugs in the pediatric age group.
| Niznik, H B; Tyndale, R F; Sallee, F R et al. (1990) The dopamine transporter and cytochrome P45OIID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins. Arch Biochem Biophys 276:424-32 |
| Sallee, F R; Pollock, B G; Perel, J M et al. (1989) Intravenous pulse loading of clomipramine in adolescents with depression. Psychopharmacol Bull 25:114-8 |
| Sallee, F R; Pollock, B G; Stiller, R L et al. (1987) Pharmacokinetics of pimozide in adults and children with Tourette's syndrome. J Clin Pharmacol 27:776-81 |
