Research
The Center for Clinical Pharmacology constitutes a Division within the Department of Medicine of the University of Pittsburgh whose"raison d'etre" is translational research and education, as well as clinical service.
Center research efforts fall into four major fields of activity: Pharmacogenomics, Cardio-Renal systems, Prescribing Practices and Cardio-Behavioral studies that also incorporate an Information Technology & Biostatistics Center and a Clinical Investigation Core. Conceived of as a hybrid academic-industry, multi-disciplinary umbrella organization, the Center's mission includes the development of ideas and products with clinical application that have potential for rapid commercial transfer of technologies related to drugs. It also incorporates as a central mission to be a patient advocate for the safe and effective use of drugs through research and education.
Recent advances in science have created new opportunities in drug discovery, drug development and drug use. The Center serves as a single base of operations for leading scientists in the University's departments and divisions and the local environment to discover new drugs, develop new drugs for therapeutic indications and optimally use drugs that are already available. The Center's resources include state-of-the-art, sophisticated pharmacogenomics and drug metabolism technology and expertise, as well as advanced information technology and biostatistics capabilities.
There are two primary areas of research activity: drug discovery and drug development, each of which currently has two main areas of activity:
| Drug Discovery |
Adenosine and related analogues
Estradiol metabolites |
| Drug Development |
Pharmacogenetics
Hepatopharmacology |
Adenosine
Adenosine is a biomolecule that is involved in information storage and retrieval and cellular energy transactions (as a purine base in DNA, RNA and ATP, respectively). In addition to these cellular "housekeeping" functions, there is an increasing awareness that during times of cellular stress adenosine is importantly involved in cell-to-cell communications via specific cell surface receptors. Using an integrative and organ systems approach, Dr. Jackson is investigating the role of adenosine as one of the body's crisis management molecules during threats to physiological homeostasis. Dr. Jackson's research in this regard has led to new insights into manipulating the adenosine system for the treatment of several diseases including traumatic brain injury, acute myocardial infarction, post-surgical adhesions and cancer. Dr. Jackson's work in adenosine in myocardial infarction has resulted in phase II (AMISTAD) and phase III (AMISTAD II) clinical trials with licensing to AnazaoHealth Corporation. His work in adenosine in post-surgical adhesions has resulted in preclinical development with licensing to Xsira Pharmaceuticals.
Estradiol Metabolites
In vitro, estradiol inhibits vascular smooth muscle cell growth. Our studies show that the anti-mitogenic effects of estradiol are mediated by its downstream metabolites, in particular 2-methoxyestradiol. In this regard, our most recent studies demonstrate that 2-methoxyestradiol inhibits progression of the cell cycle from G1 to S and from G2 to M. In animal models, we find that 2-methoxyestradiol protects the cardiovascular and renal systems from disease, and this work resulted in planning of a phase I study at the University of Pittsburgh with licensing to PR Pharmaceuticals. 2-Methoxyestradiol has been cleared by the FDA for development as an orphan drug status under the trade name PulmoLar.
Pharmacogenomics
The focus of the Pharmacogenomic Drug Metabolism Group's research activities includes the study of the entire panel of pharmacologically relevant genes, the mechanisms involved in variation, how these variations interact to produce metabolic phenotypes, and how these phenotypes affect drug response (1). These same pathways are also relevant in disease risk and prognosis prediction models. The ability to identify individuals with the highest risk of developing specific diseases has important public health and clinical implications for screening, early detection, prevention and treatment.
In order to relate genotypic information on the presence or absence of mutations of genes to enzyme activity, we have developed a variety of technologies for single nucleotide polymorphism identification, including high throughput, low cost, flexible technologies. We assess expression of genes of interest using reverse transcriptase-polymerize chain reaction (RT-PCR) using TaqMan technology and are rapidly evolving to haplotype recognition using high throughput platforms.
Our technological approach is used to answer metabolic questions in the human model, each of which has potential clinical and commercial application. Our probes are now being applied in various settings where the characterization of the activities of metabolizing enzymes would provide information on selectivity and sensitivity of each enzyme's contribution to a drug's metabolism.
1. (Russ Altman "Challenges for Biomedical Informatics and Pharmacogenomics, Stanford Medical Informatics, c.2001 (http://www-smi.stanford.edu/pubs/SMI_Reports/SMI-2001-0898.pdf).
Pharmacohepatology
New insights obtained in pharmacogenomics offer an opportunity to address factors that can help a critical clinical decision. There is an urgent need to identify criteria that can aid in the clinical timing of this decision. Currently, clinical indices are either highly subjective (Child Pugh score) or insensitive (MELD score). We have the ability to evaluate the following approaches as alternative, clinically useful quantitative liver function tests: drug metabolizing enzyme activity; proteomic profile in plasma; glucagons cAPM stimulus test; and fibrosis score. Each offers an opportunity to develop proof of principle.
Pain Management in Hepatocellular Cancer (HCC): Pain management in HCC may be complicated by the tumor or anti-tumor chemotherapy by influencing disposition of potent analgesics. Studies are relating pharmacokinetics and pharmacodynamics of oxycodone therapy to in vivo measures of the effect of disease and treatment on drug metabolism.
Cardio-behavioral
Cardio-behavioral research subsumes a wide range of topics that concern the influence of social, psychological, and behavioral factors on cardiovascular disease. For example, individuals prone to depression, hostility and aggression are more likely to develop heart disease and ongoing Center research is attempting to delineate the biological mechanisms and genetic influences of such associations. In related research, Clinical Pharmacology faculty have discovered that reduced brain serotonergic functioning is related to hypertension, the metabolic syndrome, and pre-clinical atherosclerosis. Finally, the interplay between behavioral factors and cardiovascular disease can also occur in reverse, as being examined in our research on the effects of anti-hypertensive as well as cholesterol-lowering medications on cerebral blood flow, cognitive functioning and mood.
Clinical Activities
Dr. Branch is Program Director of the General Clinical Research Center, and Dr. M. Muldoon specializes in hypertension. Dr. Branch also serves as co-chair of the Pharmacy and Therapeutic Committees of UPMC. In this context, there is a structured program among the Schools of Medicine and Pharmacy and UPMC Department of Pharmacy to define local standards of medical care, to guide physicians to optimize drug therapy, and to distribute scarce resources.
The Prescribing Optimization Program of the Center for Clinical Pharmacology provides a forum and the leadership to integrate the interests of physicians, pharmacists, and administrators within an open, peer review system. This forum is facilitated by the P & T Committee at UPMC, one of the most forward-looking and effective P & T Committees in the country. Resources range from the Drug Information Service, the Drug Use in Disease State Management program (DUDSM) of the Department of Pharmacy, the Continuing Medical Education (CME), the Adverse Drug Event (ADE) reporting program in Pharmacy, and Clinical Pharmacy Service.
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