| Laboratory of Clinical Investigation |
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| Irving W. Wainer, Ph.D., Senior Investigator Bioanalytical Chemistry and Drug Discovery Section |
 Dr. Irving W. Wainer graduated from Wayne State University in 1965 with a B.S. in chemistry and then received his Ph.D. degree in chemistry from Cornell University in 1970. He did postdoctoral doctoral studies in molecular biology at the University of Oregon and clinical pharmacology at Thomas Jefferson Medical School. From 1978 to 1986 he worked for the Food and Drug Administration (FDA) as a Research Chemist. His duties included the development of the FDA's program on the stereoisomeric purity of drugs. In 1986, he left the FDA to become Director of Analytical Chemistry, Clinical Pharmacokinetics Lab, and Associate Member, Pharmaceutical Division, St. Jude Children's Research Hospital in Memphis. He stayed in Memphis until 1990 when he moved to Montreal where he assumed the position of Professor and Head of the Pharmacokinetics Laboratory, Department of Oncology, McGill University. He is still an Adjunct Professor at McGill. In 1997, he moved to Georgetown University Washington, D.C. as a Professor of Pharmacology. In 2001 he moved to NIA to head the new Bioanalytical Chemistry Section in the Laboratory of Clinical Investigation.He has published over 300 scientific papers and eight books. He was founding editor of the journal Chirality and Senior Editor of the Journal of Chromatography B: Biomedical Sciences and Applications for 11 years. His awards include: co recipient with Dr. John E. Stambaugh of the "Harry Gold Award" from the American College of Clinical Pharmacologists; "Sigma Xi Science Award", FDA Sigma Xi Club; "A.J.P. Martin Medal" presented by the Chromatographic Society for contributions to the development of chromatographic science; Elected Fellow of the American Academy of Pharmaceutical Sciences; Elected Member United States Pharmacopeial Convention Committee of Revision for 1995-2000. In June 2006 he was awarded an honorary doctotate in medicine from the Medical University of Gdansk, Poland. His research interests include clinical pharmacology, bioanalytical chemistry, proteomics and the development of on-line high throughput screens for new drug discovery. |
| Research Interests: The Effect of Disease State on Drug Metabolism: We have identified a number of discordances between metabolic genotype and expressed phenotype in patients with advanced cancer and AIDS. For example, patients with extensive or fast genotypes for cytochrome P450 (CYP) 2C19 and N-acetyltransferase-2 (NAT-2) have displayed poor and slow phenotypes, respectively. In the case of CYP 2C19, this discordance was associated with metastatic disease. With AIDS patients, the discordance between NAT-2 genotype and expressed phenotype was observed during acute disease events. Treatment of the acute illness resulted in a reversion to concordance between genotype and expressed phenotype. |
| Since these observations were associated with advanced disease, we have initiated studies in patients suffering from terminal syndromes such as cancer cachexia. In particular, we have developed a direct measure of a "protolysis inducing factor" (PIF) associated with cachexia. The PIF is measured in spot urines using capillary electrophoresis (CE). The presence of PIF in urine has been correlated with clinical status and with the identification of PIF in tumor biopsies. We have also correlated the presence of PIF in urine with treatment response and clinical relapse. A longitudinal study of the use of PIF as a disease marker has been designed and will be initiated this fall. |
| Based on these results, we have initiated a study using CE coupled with mass spectrometry (CE-MS/MS) and MADI-TOF spectrometry to quantify PIF in tissues and to examine the effect of cachexia on pre- and post-translational expression of hepatic enzymes and transporters. We will also use laser capture microdissection and CE with mass spectrometry or laser induced fluorescence to study these effects in single cells. |
| Immobilized Receptors, Transporters and Enzymes: We have developed liquid chromatographic stationary phases containing immobilized receptors, enzymes and transporters as an on-line, flow system for use in new drug discovery and in the characterization of lead drug candidates. These columns can range in size from standard lc columns to micro-columns, can be used to screen complex chemical mixtures, to characterize single compounds and to screen phage libraries. The columns can be used with characterized targets such as ligand gated ion channels (nicotinic, GABA, NMDA receptors), G-protein receptors (opioid and b-adrenergic receptors), nuclear receptors (estrogen receptor and DNA unwinding binding element) drug transporters (P-glycoprotein, human organic cation and anion transporters), enzymes (cytochrome P450, phenylethanolamine N-methyltransferase, dopamine b-hydroxylase), as well as orphan receptors and other expressed proteins. In addition, the columns can be placed on-line with mass spectrometers or any other structure or activity detectors and provide real-time data. We also have data that demonstrate that this technique can give information that cannot be obtained using standard micro-titer plate approaches. For example, the immobilized nicotinic receptor column can be used to rapidly identify non-competitive inhibitors of this receptor. At the current time, non-competitive inhibitors can only be identified through functional ion-flux studies. The mechanism of non-competitive inhibitor binding in the central lumen of the nicotinic receptor has been studied and described using molecular modeling and chemometric techniques. Current research involves the use of immobilized nicotinic receptor columns to screen tobacco smoke condensates for CNS active compounds and the development of immobilized mast cell columns to study the inflammatory process. |
| Bioanalytical Chemistry: We have developed a wide variety of new and unique bioanalytical methods for the quantification of drugs in biological matrices. These methods have been applied to pharmacokinetic and clinical studies. In addition, we have begun studies in the area of proteomics for the identification of proteins in cellular matrices. These techniques will involve MADLI and ms/ms mass spectrometry. |
| Contact Information: Laboratory of Clinical Investigation Gerontology Research Center 5600 Nathan Shock Drive Baltimore, MD 21224-6825 Phone 410-558-8498 Fax 410-558-8409 E mail wainerir@grc.nia.nih.gov For more information about the Laboratory: http://www.grc.nia.nih.gov/branches/lci/bcs.htm |
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