Pharmacology and Toxicology

Faculty Research Interests

ADEBOYE ADEJARE
(B.S., M.S., Iowa; Ph.D., Ohio State)
Professor of Pharmaceutical Sciences
Chair, Department of Pharmaceutical Sciences

Research Interests

My group is interested in the areas of design and syntheses of small organic molecules to probe neurodegeneration. We are also interested in in vitro models of drug absorption and ability to cross the blood brain barrier; drug targeting; pharmaceutical profiling; and chemistry of fluoroaromatic compounds. The major therapeutic ideas we focus on are N-methyl-D-aspartate (NMDA) receptor antagaonists and gamma-secretase inhibitors. These two mechanisms have been implicated in neurodegeneration as observed in stroke and Alzheimer's Disease. Our research was/is funded by the National Institutes of Health, the Office of Naval Research, and several pharmaceutical companies. These efforts have resulted in over 30 publications, a patent, and over 80 presentations at meetings, including invited presentations at national and international conferences. Several students from my group have received graduate degrees (MS and Ph.D.) and are employed in academia and the pharmaceutical industry.

Publications

A. S. Gurkan, A. Karabay, Z. Buyukbingol, A. Adejare, E. Buyukbingol, "Syntheses of Novel Indole Lipoic Acid Derivatives and Their Antioxidant Effects on Lipid Peroxidation", Archiv der Pharmazie, 2005, 338, 67-73.

A. M. Ogunbadeniyi and A. Adejare, "Synthesis of Fluorinated Phencyclidine Analogs," Journal of Fluorine Chemistry, 2002, 114, 39-42.

A. Adejare, J. Shen and A. M. Ogunbadeniyi, "Halogens Halt Aromatic Group Migration in Baeyer-Villiger Oxidation," Journal of Fluorine Chemistry, 2000, 105, 107-109.

A. Adejare, "Ionotropic NMDA Receptor Antagonists as Neuroprotective Agents," in 6th International Symposium on Pharmaceutical Sciences, Proceedings and Abstracts, Proceedings of Plenary Lectures, Ankara University, June 2000, p.70-73.

BIN CHEN
(B.S., M.S., Nanjing University of Chinese Medicine, China; Ph.D., Catholic University Leuven, Belgium)
Assistant Professor of Pharmaceutical Sciences

Light-based Tumor Targeting and Imaging

Upon absorption of a certain wavelength light, some compounds can be activated to emit fluorescence and/or generate cytotoxic reactive oxygen species. The combination of laser light and photosensitizing compounds is currently being used for the diagnosis and treatment of various diseases in clinic. My lab focuses on studying and developing this light-based technology for cancer therapy (photodynamic therapy) and imaging (photodetection).

One of my major research interests is to elucidate the mechanisms involved in photodynamic therapy. Over the past years, we have been successfully employing photodynamic therapy as a tumor vascular targeting modality. Our current research focus is on understanding how photodynamic stimulus affects tumor vascular structures and functions using various biochemical, microscopic and imaging techniques.

To achieve effective and specific tumor targeting and imaging, the photosensitizing agent should be selectively accumulated in the target tissue. We have systemically studied the distribution of some current photosensitizing agents and are trying to further improve their tumor selectivity through drug delivery system formulation and targeting moiety conjugation.

Publications

Zhou X, Pogue BW, Chen B, Demidenko E, Joshi R, Hoopes PJ, Hasan T. Pre-treatment photosensitizer dosimetry reduces variation in treatment response. Int J. Radiat Oncol Biol Phys. 2006 , 64: 1211-20.

Chen B, Pogue BW, Luna J, Hardman R, Hoopes PJ, Hasan T. Tumor vascular permeabilization by vascular-targeting photosensitization: effects, mechanism and therapeutic implications. Clin. Cancer Res. 2006, 10: 917-23.

Chen B, Pogue BW, Hasan T. Liposomal delivery of photosensitizing agents. Expert Opin Drug Deliv. 2005, 2: 477-87.   

Chen B, Pogue BW, Hoopes PJ, Hasan T. Combining vascular and cellular targeting regimens enhances the therapeutic effect of photodynamic therapy. Int J Radiat Oncol Biol Phys. 2005, 61: 1216-26.  

Chen B, Pogue BW, Zhou X, O’Hara JA, Solban N, Demidenko E, Hoopes PJ, Hasan T. Effect of tumor host microenvironment on photodynamic therapy in a rat prostate tumor model. Clin Cancer Res. 2005, 11: 720-7.    

Pogue BW, Gibbs SL, Chen B, Savellano M. Fluorescence imaging in vivo: raster scanned point-source imaging provides more accurate quantification than broad beam geometries. Tech Cancer Res Treat. 2004, 3: 15-21.   

Chen B, Pogue BW, Goodwin IA, O’Hara JA, Wilmot CM, Hutchins JE, Hoopes PJ, Hasan T. Blood flow dynamics following photodynamic therapy with verteporfin in the RIF-1 tumor. Radiat Res. 2003, 160: 452-459.   

Chen B, Busan A, Landuyt W, Ni Y, Gaspar R, Roskams T, De Witte P. Potentiation of photodynamic therapy with hypericin by mitomycin C in the RIF-1 mouse tumor model. Photochem Photobiol. 2003, 78: 278-282.   

Delaey E, Zupko I, Chen B, Derycke A, van Laar F, De Vos D, De Witte P. Comparison of hexamethylhypericin and tetrabromohypericin to hypericin for their in vivo efficacy as PDT tools. Int J Oncol. 2003, 23: 519-24.

Pogue BW, O'Hara JA, Demidenko E, Wilmot CM, Goodwin IA, Chen B, Swartz HM, Hasan T. Photodynamic therapy with verteporfin in the radiation-induced fibrosarcoma-1 tumor causes enhanced radiation sensitivity. Cancer Res. 2003, 63: 1025-33.   

Chen B, Roskams T, De Witte P. Antivascular tumor eradication by hypericin-mediated photodynamic therapy. Photochem Photobiol. 2002, 76: 509-13.

Chen B, Roskams T, De Witte P. Enhancing the antitumoral effect of hypericin-mediated photodynamic therapy by hyperthermia. Lasers Surg Med. 2002, 31: 158-63.

Chen B, Roskams T, Xu Y, Agostinis P, De Witte P. Photodynamic therapy with hypericin induces vascular damage and apoptosis in the RIF-1 mouse tumor model. Int J Cancer. 2002, 98: 284-90.

Chen B, Xu Y, Roskams T, Delaey E, Agostinis P, Vandenheede JR, De Witte P. Efficacy of antitumoral photodynamic therapy with hypericin: relationship between biodistribution and photodynamic effects in the RIF-1 mouse tumor model. Int J Cancer. 2001, 93: 275-82.

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PETER J. HARVISON
(B.S., Carnegie-Mellon; Ph.D., SUNY/Buffalo), Professor of Pharmacology and Toxicology

Chemical Toxicology: The Role of Metabolism in Bioactivation

Areas of research interest include: (a) in vivo and in vitro metabolism of drugs and environmental chemicals; (b) formation and disposition of toxic metabolites; (c) structure-toxicity relationships; and (d) assay development. One project currently in progress involves metabolic studies on a series of halogenated phenyl succinimides. Several of these compounds, originally developed as agricultural fungicides, cause selective kidney damage in rats. We are presently studying the  metabolism of two representative members of this series. Ultimately, we hope to elucidate the mechanism of toxicity of these compounds. This may provide insights into the mechanisms by which other chemicals cause kidney damage.

Publications

D. Cui, G.O. Rankin, and P.J. Harvison, "Metabolism of the nephrotoxicant N-(3,5-Dichlorophenyl)succinimide in rats: Evidence for bioactivation through alcohol-O-glucuronidation and O-sulfation", Chem. Res. Toxicol. 18, 991-1103 (2005).

D. Cui, G.O. Rankin,and P.J. Harvison, "Transamination in the metabolism of the nephrotoxicant N-(3,5-Dichlorophenyl)succinimide in rats", Drug Metab. Dispos. 33, 1765-1770 (2005).

E.L. Kennedy, R. Tchao and P.J. Harvison, "Nephrotoxic and hepatotoxic potential of imidazolidinedione-, oxazolidinedione-, and thiazolidinedione-containing analogues of N-(3,5-dichlorophenyl)succinimide (NDPS) in Fischer 344 rats", Toxicology 186, 79-91 (2003).

C.M. Henesey and P.J. Harvison, "Renal Damage, Metabolism, and Covalent Binding Following Administration of the Nephrotoxicant N-(3,5-Dichlorophenyl)succinimide (NDPS) to Male Fischer 344 Rats", Toxicology 170, 1887-200 (2002).

D. Cui and P.J. Harvison, "Determination of the Site of Glucuronidation in an N-(3,5-Dichlorophenyl)succinimide Metabolite by Electrospray Tandem Mass Spectrometry Following Derivatization to Picolinyl Esters", Rapid Commun. Mass Spectrom. 14, 1985-1990 (2000).

C.M. Henesey, G.L. Kellner-Weibel, J.B. Tarloff, and P.J. Harvison, "Comparative disposition of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide and the non-nephrotoxicant N-(3,5-difluorophenyl)succinimide in Fischer 344 rats.", Drug. Metab. Dispos. 27, 674-680 (1999).

R.J. Griffin and P.J. Harvison, "In vivo metabolism and disposition of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide in Fischer 344 rats", Drug Metab. Dispos. 26, 907-913 (1998).

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DIANE W. MOREL
(B.A. Douglass College; M.S., Ph.D. Case Western Reserve University) Associate Professor of Pharmacology and Toxicology

Oxidative/nitrative stress and cellular function in chronic disease

Oxidative/nitrative stress, an imbalance in reactive oxygen and nitrogen species (ROS/RNS) and their products and cellular antioxidant defenses, is thought to play a role in the development of chronic diseases such as ischemic heart disease and age-related macular degeneration. My research is geared to further understand the mechanisms by which oxidative and nitrative species contribute to changes in cellular function in chronic disease, and how dietary components or antioxidants may protect against these changes. Current studies are focused on vascular endothelial and smooth muscle cell function as related to ischemic heart disease, and retinal pigmented epithelial cell function in age-related macular degeneration.

Selected Publications

Beauchamp, GK, RSJ Keast, DW Morel, J Lin, J Pika, Q Han, C Lee, AB Smith and PAS Breslin. (2005) Ibuprofen-like activity in extra-virgin live oil. Nature 437:45-46.

McDevitt, TM, R Tchao, EH Harrison and DW Morel (2005) Carotenoids normally present in serum inhibit proliferation and induce differentiation of a human monocyte/macrophage cell line (U937). J. Nutrition 135:160-4.

During, A, MH Hussain, DW Morel and EH Harrison (2002) Carotenoid uptake and secretion by CaCo-2 cells: B-carotene isomer selectivity and carotenoid interactions. J. Lipid Res. 43:1086-95.

Dugas, TR, EH Harrison and DW Morel (2000)  Novel cell culture medium for use in oxidation experiments provides insights into mechanisms of endothelial cell-mediated oxidation of low density lipoprotein.  In Vitro Cellular and Developmental Biology 36:571-577.

Dugas, TR, DW Morel and EH Harrison  (1999)  Dietary Supplementation with b-carotene, but not with lycopene, inhibits endothelial cell-mediated oxidation of low density lipoprotens.  Free Rad. Biol. Med.  26:1238-44. 

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JOAN B. TARLOFF
(B.S., University of Toledo; Ph.D., Medical College of Ohio) Professor of Pharmacology and Toxicology.

Mechanisms underlying the Susceptibility of the Kidney to Injury

Areas of research interest include: (a) correlation of in vivo and in vitro expression and mechanisms of toxicant-induced injury, (b) the role of pharmacokinetic mechanisms (e.g., selective renal transport systems) in determining target organ specificity, (c) the kidney as a metabolically active organ in drug/toxicant bioactivation, and (d) the influence of disease states and pathology (e.g., hypertension, diabetes) on kidney structure and function. Many diverse chemicals, as well as long-standing diseases, impact on renal structure and function. In the case of chemicals, target organ selectivity may be due to pharmacokinetic factors that cause the kidney to accumulate and retain high concentrations of these toxicants and the ability of the kidney to metabolize these toxicants to highly reactive intermediates.

Publications

Lash, L.H. and Tarloff, J.B. editors, Toxicology of the Kidney, 3rd edition, CRC Press. 2005.

Li, Y., Bentzley, C.M., and Tarloff, J.B. Comparison of para-aminophenol cytotoxicity in rat renal epithelial cells and hepatocytes. Toxicology 209: 69-76, 2005.

Gonzalez, R.J. and Tarloff, J.B. Expression and activities of several drug-metabolizing enzymes in LLCPK1 cells. Toxicology In Vitro 18: 887-894, 2004.

Gonzalez, R.J. and Tarloff, J.B. Evaluation of hepatic subcellular fractions for Alamar blue and MTT reductase activity. Toxicology in Vitro 15: 257-259, 2001.

Tarloff, J.B.. In Vitro Assessment of Nephrotoxicity. In: In Vitro Toxicology, 2nd Edition (S.C.Gad, editor), Taylor & Francis, New York, p. 222-274, 2000.

Hallman, M.A., Tchao, R., and Tarloff, J.B. Effects of antioxidants on para-aminophenol-induced toxicity in LLC-PK₁ cells. Toxicology 156: 37-45, 2000.

Yan. Z., Nikelly, J.G., Killmer, L., and Tarloff, J.B. Metabolism of para-aminophenol by rat hepatocytes. Drug Metab. Dispos. 28: 1-7, 2000.

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RUY TCHAO
(B.S., University of Nottingham, England; Ph.D., University of Manchester, England) Professor of Pharmacology and Toxicology

Tumor cell motility and invasion

It is generally believed that tumor cell motility is one of the factors involved in tumor invasion of normal tissues and blood capillaries. The malignant nature of a tumor is characterized by its invasiveness. In this research project we are studying the role of desmosomes in the motility and invasion of several clones isolated from a squamous carcinoma cell line. Cell motility and division are studied by time lapse video microscopy, desmosomes are studied by specific antibody staining and gel electrophoresis. Drugs that induce cell differentiation will be studied in this system. Synthetic peptides that influence cell adhesion to the substrate will be studied for effects on cell motility. Finally invasiveness will be studied in an in-vitro invasion assay.

Development of in-vitro assays as alternatives to the Draize rabbit eye test

The Draize eye irritancy test has been widely criticized scientifically and for ethical use of the animals. In recent years there has been increased need for developing new and better in-vitro techniques as Draize alternatives for the evaluation of commercial products. The integrity of corneal permeability is the first physiological event to be compromised when an irritant interacts with the eye. In tissue culture we are using an epithelial cell line with similar trans-epithelial permeability to study the effect of various agents on the epithelium. The diffusion of Na-fluorescein from the apical side to the basal side of the epithelium is used as a quantitative measure of epithelial permeability. Various surfactants and commercial products are being studied in this in-vitro assay.

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SHANAZ M. TEJANI-BUTT
(B.S., M.S., University of Bombay, India; Ph.D., Medical College of Virginia). Professor of Pharmacy and Toxicology.

Unlocking the Mysteries of Depressive Illness

Exposure to stressful life events has been long associated with increased alcohol use in humans, and psychological stress is a common risk factor for both depression and alcohol abuse. Alterations in reward and motivational processes at the psychological, behavioral and the neurochemical levels may represent the defining characteristics of both depression and drug and alcohol dependency.

The Wistar-Kyoto rat strain shows greater "depressive" behavior, consumes greater amounts of alcohol and produces more stress related ulcers than other rat strains. Our laboratory has reported on several behavioral and neurochemical differences in this rat strain that may be linked to altered dopamine and/or norepinephrine transmission. Our current research is aimed at further understanding the role of the presynaptic neuron in the regulation of dopamine and norepinephrine, and their implicated roles in depression, alcohol abuse, and stress related disorders.

Publications

Yaroslavsky I, Colletti M, Jiao X & Tejani-Butt S.M.: Strain differences in the distribution of dopamine (DA2 and DA3) receptor sites in rat brain. Life Sci., 2006, in press.

Jiao X, Pare, W & Tejani-Butt S.M.: Alcohol Consumption alters dopamine transporter sites in Wistar-Kyoto rat brain. Brain Res., 175-182, 2006.

Jiao X, Pare, W & Tejani-Butt S.M.: Antidepressant drug induced alterations in dopamine transporter sites in rat brain. Prog. Neuro-Psychopharmacol. & Biol. Psychiat, 30, 30-41, 2006.

Tejani-Butt S. M, Kluczynski J & Pare W.: Strain dependent modification of behavior following antidepressant treatment. Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 27, 7-14, 2003.

Jiao X, Pare, W & Tejani-Butt S.M.: Strain differences in the distribution of dopamine transporters in rat brain.
Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 27, 913-191, 2003.

Pare W & Tejani-Butt S. M.: Chapter: Depression: Behavior and Brain: Insights from an Animal Model.
Russian Academy of Medical Sciences, 2004.

Pare W, Tejani-Butt S.M., & Kluczynski J.: The emergence test: Effects of psychotropic drugs on neophobic disposition in Wistar-Kyoto and Sprague-Dawley rats. Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 25, 1615-1628, 2001.

Zafar H.M., Shelat S, Redei E, & Tejani-Butt S.M.: Fetal alcohol exposure alters serotonin transporter sites in rat brain. Brain Res., 856, 184-192, 2000.

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