received an oral dose (10 mg to 60 mg) of PRX-00023. In addition, six subjects received a single 30 mg oral dose of Buspirone (an azapirone 5HT1A agonist).
P18
American Society for Clinical Pharmacology and Therapeutics
CLINICAL PHARMACOLOGY & THERAPEUTICS FEBRUARY 2006
PI-41
PI-43
CLINICAL NEUROENDOCRINE EFFECTS OF PRX-00023, A NOVEL 5HT1A AGONIST DISCOVERED IN-SILICO IN HEALTHY SUBJECTS. S. Donahue, MD, G. R. Iyer, PhD, S. Oshana, BS, M. Kauffman, MD, PhD, Predix Pharmaceuticals, Lexington, MA. PURPOSE: To characterize the pharmacodynamic activity of PRX-00023 following single and multiple oral PRX-00023 doses in healthy subjects. METHODS: In a single ascending dose study, 36 healthy subjects received an oral dose (10 mg to 60 mg) of PRX-00023. In addition, six subjects received a single 30 mg oral dose of Buspirone (an azapirone 5HT1A agonist). In two multiple dose studies healthy subjects received doses of 10 to 150 mg PRX-00023 QD or placebo for up to 28 days. A Profile of Mood States (POMS) survey was administered in the 28-day study. RESULTS: Following single dose administration, mean serum prolactin peak change from baseline (13-35 ng/mL) was dose dependent up to 40 mg. In addition, prolactin response with PRX-00023 observed was similar in magnitude but less variable than the response seen with the single 30 mg dose of buspirone. Following multiple dose administration, transient prolactin increases post dose were observed, but mean trough prolactin values were similar for placebo and the highest PRX-00023 dose group. Trends towards beneficial effects in POMS tension/anxiety item scores were appreciated at the 40 and 60 mg PRX-00023 doses in the 28 day study. CONCLUSIONS: PRX-00023 treatment resulted in consistent, transient induction of prolactin levels 2 to 3 hours after administration, consistent with its mechanism as a 1A agonist. This is one of the first compounds discovered by computational receptor modeling to demonstrate selective pharmacodynamic effects in humans.
GENE EXPRESSION IN HUMAN MONONUCLEAR CELLS IN RESPONSE TO REACTIVE SULFONAMIDE METABOLITES. M. J. Rieder, MD, PhD, M. J. Tucker, PhD, D. Carter, S. W. Rieder, University of Western Ontario, London Regional Genomics Centre, London, ON, Canada. BACKGROUND/AIMS: To identify genes differentially expressed in sulfamethoxazole (SMX)-sensitive and resistant individuals. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 2 volunteers: one sensitive to SMX, and one not. The cells were incubated at 37oC in a humidified CO2 atmosphere for 0, 4, or 8 hours with 100M SMX-NO, the presumed toxic nitrosometabolite of the parent SMX. At the designated times, RNA was isolated from the cells using Trizol followed by an Rneasy column. RNA quality was analyzed by an Agilent 2100 Bioanalyzer. Each sample was biotinylated and hybridized to an Affymatrix HGU133 plus 2.0 gene chip and scanned for the expression of 38,500 well characterized human genes. RESULTS: Initially 19 genes implicated in stress, apoptosis or immune activation were identified that are expressed five-fold higher in the control, but not in the sensitized individual. These include 5 heat shock proteins, TNF-␣, apoptosis-inducing kinase, MAPKKK1, ras, CD58, and a calcium membrane channel protein. CONCLUSIONS: Study of the differential gene expression by individuals exposed to toxic drug metabolites will help us to understand the mechanisms of cell death involved in adverse drug reactions.
PI-42 METHAMPHETAMINE DETECTION IN MATERNAL AND NEONATAL HAIR. F. Garcia-Bournissen, B. Rokach, G. Koren, Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, ON, Canada. BACKGROUND: Methamphetamine abuse has been gathering momentum as a serious public health problem. Evidence of chronic use, particularly during pregnancy, is hard to obtain. Methamphetamine accumulates in hair and can be detected several months after exposure. Drugs that cross the placenta can be detected in hair of newborns. METHODS: We developed a hair immunoassay for methamphetamine at Motherisk laboratory in Toronto. The aim of the study was to find evidence of methamphetamine exposure during pregnancy using hair measurements of the drug. RESULTS: Out of 1124 positive methamphetamine results, we identified 8 mother-child pairs who had methamphetamine positive hair. None of the pairs identified included mothers with negative results, but there were 2 (25%) of the neonates who had a negative methamphetamine result although the mother was positive. Mean methamphetamine values were 1.8 ng/mg of hair in the mothers and 1.08 ng/mg in the neonates. There was a trend towards correlation between maternal and fetal levels. CONCLUSION: To our knowledge, this is the first report that shows transplacental passage of methamphetamine, with accumulation in the fetal hair. We believe this provides the basis for studies to define pharmacokinetics of this drug in the mother-child couple. We have also shown that hair measurement of methamphetamine in neonates is a useful screening method to detect intra-uterus exposure. As fetal hair grows in the last trimester of pregnancy, a positive result may indicate maternal addiction.
PI-44 CORRELATION OF CYP2D6 GENOTYPE WITH RESPONSE TO OXYCODONE IN ORTHOPEDIC INJURY RELATED PAIN. A. B. Myers, MD, MSPH, J. E. Sullivan, MD, D. M. Koller, MD, MSc, S. A. Godambe, MD, PhD, M. J. Kennedy, PharmD, University of Louisville, Louisville, KY. BACKGROUND: Inter-individual variability in response and adverse effects to oxycodone in pediatric patients may be due to CYP2D6 enzyme genetic variation. Intermediate or poor metabolizer (IM, PM) genotypes have impaired oxymorphone formation and may have altered response to oxycodone. This study assessed clinical response and presence of adverse events of oxycodone treatment as a function of CYP2D6 genotype. METHODS: Randomized double blind prospective clinical trial in a tertiary care emergency department. 66 children (6-18 y) with orthopedic injuries were randomized to single dose oxycodone (0.1, 0.15 or 0.2 mg/kg). DNA was obtained via buccal swab and CYP2D6 genotype determined. Pain was assessed by Faces Pain Scale (FPS) at baseline, and 20, 40 and 60 minutes post-dose. RESULTS: Dose groups were comparable for demographics and baseline FPS scores. Each group had effective analgesia as evidenced by significant reduction of FPS scores from baseline (p ⬍ 0.001). No FPS score differences were demonstrated between dose groups at any time point. No significant adverse events occurred. One patient was a PM (mean FPS ⫽ 5.5). IM (n⫽15, FPS ⫽ 3.4 ⫾ 2.6) reported lower FPS scores than extensive metabolizers (EM) reported (n⫽36, FPS ⫽ 4.7 ⫾ 3.0). A GEE model accounted for repeated measures, and found the difference between EM and IM was non-significant (model coefficient 0.88 (-0.20, 1.97), p ⫽ 0.11). CONCLUSION: Findings suggest clinical response to oxycodone varies with CYP2D6 genotype but further study is indicated.
