PK/PD; Pharmacodynamic; Pharmacokinetic
Director, Center for Protein Therapeutics with research focusing on the utilization of pharmacokinetic and pharmacodynamic analyses and mathematical modeling to guide the discovery and development of new immunotherapies for cancer and autoimmunity. Research Interests and Projects: 1. Development of antibody conjugates for targeted, intra-cellular delivery of macromolecular toxins 2. Engineering monoclonal antibodies for improved pharmacokinetic properties 3. Investigation of sources of inter-individual variability in monoclonal antibody pharmacokinetics 4. Investigation of strategies to overcome the "binding site barrier" to antibody distribution in solid tumors 5. Development of improved mathematical models for predicting the disposition and effects of monoclonal antibody drugs 6. Development of new targeting strategies to optimize the safety and efficacy of intraperitoneal chemotherapy of ovarian cancers (CA118213) 7. Development of FcRn inhibitors for treatment of humoral autoimmune diseases (e.g., myasthenia gravis, autoimmune neutropenia) (AI60687) 8. Development of new strategies to treat immune thrombocytopenic purpura (HL67347) 9. Investigation of the role of FcRn in the absorption, distribution, and elimination of IgG antibodies 10. Development of antibody-based therapies to treat and prevent infection. Efforts are currently focused on prevention of infection by Treponema denticola (DE023080), S. aureus, and A. baumannii
Research interest is in the area of protein delivery and immunotherapy. Current research projects: 1. Development of lipidic nano particle containing therapeutic proteins and is supported by NHLBI/NIH. The overall goal of the project is to improve therapeutic efficacy of protein based therapies for bleeding and lysosomal disorders using a multidisciplinary approach involving Biophysics/Bioengineering, immunology and pharmacokinetics/Pharmacodynamics. 2. Re-activating Memory T Cells in the Microenvironment of Human Tumors and development of in situ vaccination. This project is supported by NCI/NIH (Dr. Bankert, PI, Balu-Iyer Co-PI). Our aim is to to rationally develop therapeutic intervention by understanding the molecular mechanism of TCR arrest. 3. Develop novel strategies to treat food allergies and autoimmune conditions using the tolerogenic properties of biomolecules. 4. Formulation and delivery of Monoclonal antibody based products: Understand and develop strategies to improve efficacy of antibody based therapeutics particularly given via sc route of administration
Dr. Bies is currently Associate Professor of Pharmaceutical Sciences at the School of Pharmacy and Pharmaceutical Sciences as well as a member of the Center for Data Sciences and Engineering at the State University of New York at Buffalo. Prior to this, Dr. Bies was Associate Professor of Medicine and Medical and Molecular Genetics at the Indiana University School of Medicine and Director of the Disease and Therapeutic Response Modeling program for the Indiana Clinical Translational Sciences Institute. He serves as: project scientist at CAMH, University of Toronto; co- North American and executive editor for the British Journal of Clinical Pharmacology; and on the editorial boards of the Journal of Pharmacokinetics and Pharmacodynamics, Clinical Pharmacology and Therapeutics:Pharmacometrics and Systems Pharmacology, Journal of Clinical Pharmacology and Biopharmaceutics and Drug Disposition. Dr. Bies is a member of AAPS, ISoP, ACCP and ASCPT. He is a board member of ISOP and section chair for the CPTR Pharmacometrics Focus Group as well the CPTR Abstract Screening Chair for AAPS. . Dr. Bies received a BSc degree in Pharmacy from the University of Toronto (1991), a Pharm.D. from the UTHSCSA and the University of Texas at Austin (1994) and a Ph.D. Pharmacology from Georgetown University in 1998. This was followed by postdoctoral training at the Center for Drug Development Sciences until 2000. His research focuses on the application of pharmacometric approaches in psychiatry, oncology, neurology and cardiovascular disease and novel methods development including machine learning approaches to model selection and optimization methods for parameter optimization in dynamic systems.
Research focus is the improvement of cancer chemotherapy by understanding the factors that contribute to interindividual variability in drug response. Dr. Blanco‘s goal is to perform translational research using a combination of approaches based on a) the analysis of biological samples from selected populations, and b) the use of informative laboratory models. A project in Dr. Blanco‘s laboratory is related to the understanding of the factors that govern interindividual variability in the metabolism and disposition of the anthracyclines doxorubicin and daunorubicin. It is possible that specific sequence variations in genes associated with the metabolism and disposition of anthracyclines may impact the risk of cardiotoxicity in some individuals. Our efforts are focused on the discovery and characterization of novel single-nucleotide polymorphisms in a family of genes involved in the metabolism of anthracyclines in liver, heart and different types of tumors (e.g. breast and lung cancer). We are investigating the extent of DNA sequence variation in these selected gene candidates among normal individuals from different ethnic groups. We will study genotype-phenotype correlations by using paired tissue-DNA-RNA samples available from my collaborators from the Pharmacogenetics of Anticancer Agents Research group, and from the Roswell Park Cancer Institute. We will expand our studies to characterize the functional effect of the genetic variants by using different in-vitro and in-vivo models (e.g. cultures of hepatocytes,cardiomyocytes, transgenic mice). Our findings are being translated into informative case-control epidemiological studies. For example, we are analyzing the distribution of candidate polymorphisms in identically treated patients who have vs. have not developed congestive heart failure (CHF) after anthracycline treatment for childhood cancer. In the future, individualizing the dosing of anthracyclines based on genetic characteristics might minimize the occurrence of adverse effects.
Research interests include: 1. Innovations in pedagogy and educational technologies. 2. Drug transport across the blood-brain barrier. Focuses on the mechanisms of drug transport across the blood-brain and blood-cerebrospinal fluid barriers. Nature designed these barriers to restrict and regulate the entry of blood borne substances into brain tissue. Essential nutrients are transported efficiently by carrier proteins expressed by the blood-brain and blood-cerebrospinal fluid barriers. However, these barriers hinder the entry of many drugs, and typically it is only highly lipophilic drugs that gain access to brain tissue via passive diffusion across the barriers. Consequently, many lead drug candidates are disqualified from further development because of poor permeability across the blood-brain barrier. There is much scientific interest in understanding brain transport processes with the goal of identifying methods, which enhance drug delivery across brain barriers. 3. Neuroinflammatory Brain Diseases. Understanding the role of neuroinflammatory processes in the progression of chronic neurodegenerative diseases. Since inflammatory processes are a common feature of many neurological diseases (viz., Alzheimer‘s disease, multiple sclerosis, HIV-1 dementia,cerebral ischemia, brain tumors and meningitis), an enhanced knowledge of inflammatory mediators and their detrimental effects on the centraln ervous system provides opportunities for the design of new pharmaceutical approaches in the management of neurological diseases.
PK/PD; Pharmacodynamic; Pharmacogenomics; Pharmacokinetic
Research interests are in theoretical, basic, and clinical aspects of the pharmacokinetics and pharmacodynamics of various immunosuppressive agents including corticosteroids, as well as drugs used to treat diabetes, inflammation, and cancer. With Drs. Richard Almon and Debra DuBois, Dr. Jusko delves into the pharmacogenomics of diverse effects of corticosteroids and has evolved advanced mathematical models of receptor/gene-mediated responses. They have characterized the effects of corticosteroids on hepatic and muscle enzymes and tissue responses and have evolved advanced PK/PD models for cascade-type processes. Dr. Jusko has developed mechanism-based pharmacokinetic, pharmacodynamic, and disease progression models and computational methods describing the action of various drugs and utilizes mathematical models of drug action to determine optimal dosage regimens diverse drugs.
Research interest areas: 1. Integrative and Systems Pharmacology of Anti-Platelet and Anti-Cancer Drugs 2. Development and experimental validation of quantitative structure-pharmacokinetic/pharmacodynamic (PK/PD) relationships (QSPR) to optimize drug design, development, and therapeutic application of anti-cancer compounds. 3. Integration of QSPR and mechanistic PD models developed with several drugs to predict in vivo PK/PD profiles of chemically related compounds. 4. Development of models of pharmacological target-mediated drug disposition and dynamics, and the experimental validation of the primary determinants of PK/PD profiles of drugs that exhibit such phenomena. 5. Development of non-deterministic models such as neural networks, alone or in combination with traditional adaptive feedback control methods, for individual optimization of complex pharmacotherapeutic regimens. 6. Incorporation of biomedical signal processing tools into PK/PD models for characterizing the pharmacology of drugs that alter spontaneous variability of signals of the cardiovascular and autonomic nervous systems
Research interests are focused in the area of drug transporters and their role in the pharmacokinetics/pharmacodynamics (PK/PD) of drugs. Studies also focus on drug transporters as therapeutic targets. Current research projects: 1. Gamma-hydroxybutyric acid (GHB) Toxicokinetics and Toxicodynamics. GHB is a drug of abuse, known as a "club drug". We are characterizing the mechanisms underlying the toxicokinetics and toxicodynamics of GHB, and evaluating methods to treat overdoses of GHB. For these studies, we are characterizing transport of GHB by Monocarboxylic Acid Transporters (MCTs), transport proteins that determine the absorption, renal clearance, and distribution of GHB throughout the body, including its distribution to the brain, the site of action. Our goal is to devise treatment strategies to treat overdoses of GHB, in order to save lives. 2. Membrane Transporters in Breast Cancer. Drug resistance is the main cause for therapeutic failure and death in breast cancer. My laboratory is interested in the discovery of new classes of compounds useful in reversing multidrug resistance (MDR) to cancer chemotherapeutic agents. One of the main causes of MDR in cancers is due to the overexpression of the efflux transport proteins, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Our current studies are evaluating various dietary components, organic isothiocyanates and flavonoids, for their effects on BCRP-mediated transport and on the efficacy and toxicity of chemotherapeutic agents. We are currently examining a new drug target in breast cancer, monocarboxylate transporters.
The Therapeutic Biomaterials Laboratory designs and engineers novel nano-scale carriers based on genetically encoded materials, lipids, and polymers for the treatment of myocardial infarction and cancer. These will target to the site of disease, respond to changes in the microenvironment, and deliver nucleic acids and drugs to subcellular compartments. Zip-code like sequences Although great advances have been made in the field of nucleic acids and drug delivery, the specificity of delivery still remains a problem. We are utilizing cutting-edge technologies to identify zip-code like sequences for more efficient delivery of therapeutic molecules for the treatment of myocardial infarction and cancer. Regeneration of Cardiac Tissue Coronary heart diseases are among the leading causes of death worldwide. After myocardial infarction, a significant number of cardiomyocytes undergo apoptosis and are replaced by non-contractile scar tissue. Our goal is to repair damaged cardiac tissue by re-establishing the muscle population with newly generated cardiomyocytes. In order to achieve this aim, we are designing novel biomaterials for reprogramming different types of cells to cardiomyocytes. Genetically Encoded materials Nanoparticulate drug carriers allow the delivery of enzymatically susceptible, highly instable, and insoluble drugs to target tissues. One of the limitations of existing drug delivery systems is insufficient and non-specific drug release in the body that leads to toxic side effects for the patient. Our lab engineers genetically encoded nanomaterials that are able to disassemble and release therapeutic drugs when exposed to disease-specific microenvironments. Please visit our lab‘s homepage for more information: http://www.acsu.buffalo.edu/~julianen/index.html
Dr. James M. O’Donnell was appointed as the eleventh Dean of the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in October 2013. He is Professor of Pharmaceutical Sciences with a joint appointment as Professor of Pharmacology and Toxicology. He received his B.S. in Psychology from Carnegie Mellon University and Ph.D. in Pharmacological and Physiological Sciences from the University of Chicago; he completed postdoctoral training in Neuropsychopharmacology at the University of Pennsylvania. Prior to joining UB, he held research or faculty positions at Los Alamos National Laboratory, Louisiana State University, University of Tennessee, and West Virginia University; at WVU, he served as Associate Dean for Research in the School of Medicine and Assistant Vice President for Health Sciences Research. His research has focused on the relationship between the neurochemical and behavioral effects of drugs, primarily those used to treat neuropsychiatric illnesses. This has involved the study of noradrenergic mechanisms in the actions of antidepressant drugs and of cyclic nucleotide phosphodiesterases as potential targets for novel antidepressant, anxiolytic, and memory-enhancing drugs. This work has been supported by the NIH, primarily the National Institute of Mental Health, and has involved collaborations with scientists at other universities and biotech and pharmaceutical companies. Dr. O’Donnell has been active in the teaching of professional and graduate students in the areas of pharmacology and neuroscience and has provided research mentorship to undergraduate, graduate, and professional students, postdoctoral fellows, and junior faculty members. He served as Director of an NIGMS-supported, T32 predoctoral training grant at the interface of behavioral and biomedical sciences. He has served on NIH review panels in the neuroscience and drug discovery areas, including founding Chair of the Pathophysiological Basis of Mental Disorders and Addictions study section, and is Associate Editor for the Journal of Pharmacology and Experimental Therapeutics. He is a member of a number of scientific and professional societies, including the American Society for Pharmacology and Experimental Therapeutics and the Society for Neuroscience, is a Fellow of the American College of Neuropsychopharmacology, and chaired the Gordon Research Conference on Cyclic Nucleotide Phosphodiesterases.
Research focus areas: Proteomics and Pharmaceutical Analysis. Major research programs in the proteomic field involve i) high-resolution and large-scale expression profiling of pathological proteomes (e.g. for cardiovascular diseases, colon cancer and infectious diseases) for the discovery of disease/therapeutic biomarkers by gel-free LC/MS methods; ii) Sensitive identification, localization and quantification of post-translational modifications in complex proteomes, with the emphases on arginine methylation and phosphorylation. Novel anti-PTM-peptides capture procedure and alternating collision induced dissociation (CID)/electron transferring dissociation (ETD) are employed to obtain abundant PTM information; iii) targeted quantification of regulatory, marker proteins for clinical study. Dr. Qu‘s lab possesses many state-of-the-art LC/MS instruments, including a high resolution/accuracy LTQ/Orbitrap XL with ETD, a highly sensitive TSQ Quantum Ultra EMR triple-quadrupole instrument, two ultra-high pressure nano-LC systems, and several HPLC instruments for pre-fraction and ion chromatography. A number of key analytical advances have been developed by his lab that greatly enhanced the proteomic coverage, sensitivity and throughput for proteomic research. As for the Pharmaceutical Analysis of small-molecule drug/markers, Dr. Qu‘s lab is focusing on the ultra-sensitive quantifications of drug, metabolites and endogenous markers (e.g. corticosteroids, di-hydroxyl-vitamin D metabolites, androgens, etc.) using a novel combination of selective enrichment and micro- or nano- LC/MS.
My laboratory is involved in clinical and translational research program in multiple sclerosis (MS) therapeutics. My laboratory has investigated the neuroimmunological and genomic mechanisms that contribute to the heterogeneity of clinical treatment responses for this chronic, disabling neurological disease. Currently, the broad focus of my MS research is to delineate the interactions among patient-specific, environmental and genetic factors that contribute to inter-individual differences in disease progression. We employ a unique multi-disciplinary approach to research by leveraging our strengths in pharmaceutical sciences and bioengineering and also through my productive collaborations with scientists from clinical disciplines such as neurologists, neuroradiologists, neuropsychologists and also from quantitative disciplines such computer science and biostatistics. Through these collaborations, our group has been able take on challenging scientific problems that could not be undertaken by any one of us individually. My multi-disciplinary research spans two inter-related areas: i) clinical research on the roles of environmental factors in MS progression and, ii) molecular and quantitative clinical pharmacology. My recent work has focused on cholesterol and lipid biomarkers in multiple sclerosis disease progression. My group has investigated other compelling environmental factors in MS including immune responses to Epstein-Barr virus exposure, vitamin D metabolism and smoking. I have the necessary expertise and record in quantitating environmental factors and surrogate markers in MS. We also have extensive experience in pharmaceutical applications of "big data" and modeling analysis of large high-dimensional data sets containing environmental factors, genetic and immunological biomarkers, quantitative neuroimaging metrics and clinical measures in MS. If you wish to support Dr. Ramanathan‘s multiple sclerosis research with a contribution, please visit his research giving form
Our research program involves the application of drug carriers for the treatment of infectious diseases and cancer. Recent past efforts have been directed toward improving the therapy of brain tumors (as well as others) by targeting tumor blood vessels. Currently we are investigating strategies in increase the perfusion and drug permeability of pancreatic cancers by compromising the ability of cells within the tumor stroma, or extracellular matrix, to maintain the very low tumor blood supply and impermeability to drugs and nanoparticles We employ a variety of experimental approaches, including high-resolution magnetic resonance imaging, liquid chromatography/mass spectrometry, confocal fluorescence microscopy and image analysis, pharmacokinetic/dynamic analysis, and molecular techniques such as quantitative RT-PCR and proteomics. With these techniques, we examine the effects of treatment upon tumor vascular permeability and drug deposition, the localization of the carrier-delivered drug within the tumor, and the molecular mechanisms involved when tumor blood vessels or tumor stroma are attacked during therapy. Additional interests of the lab that are being pursued actively include understanding the mechanisms of anti-cancer drug action and how they may be modified by changing exposure profile (time vs. concentration). Both genomic and proteomic analysis approaches are utilized in this work, but an approach of increasing importance to our research is the implementation of comprehensive proteomic investigations in order to understand in detail how tumors respond to standard-of-care drugs and new molecularly-targeted drugs.
I have the expertise, leadership, training, and motivation necessary to successfully carry out the proposed research project. I have a broad background in neuroscience and pharmacology, with specific training and expertise in behavioral, neurochemical and neurobiological analyses in animal models related to neurodegenerative and neuropsychiatric disorders, such as depression, anxiety, Alzheimer’s disease and neuropathic pain. My research includes investigation of CNS functional roles of natural polyphenols (curcumin, resveratrol and ferulic acid) and the selective phosphodiesterases (PDEs) inhibitors (PDE2, 4, 5 and 9) for treatment of neuropsychiatric and neurodegenerative disorders, in the mediation of the above diseases and the involved intracellular mechanisms. As PI or co-Investigator on the institutional- and NIH funded grants, I laid the groundwork for the proposed research by assessing the roles of PDE4 and its major subtypes (PDE4-A, B and D) in mediating antidepressant and memory-enhancing properties in aspects of behavior, biochemistry, and molecular biology. Recently, my project focused on identification of PDE2 and 9 as targets for treatment of depression, anxiety, and cognitive impairment associated with Alzheimer’s disease (AD) and in exploration of intracellular signal pathways. In addition, I successfully administered the projects collaborated with other researchers, and produced several peer-reviewed publications from these projects.