Current Research Areas:
Prevention of Contrast-induced Acute Kidney Injury
Contrast-induced acute kidney injury (CIAKI) is a complex syndrome of acute nephropathy occurring within 48 hours of exposure to intravascular iodinated contrast media. CIAKI is associated with an increased risk of adverse cardiovascular events, prolonged hospitalization, and short- and long-term mortality. The pathophysiology of CIAKI is poorly understood and little is known about the underlying cellular mechanisms. With the increasing use of contrast media in both diagnostic and interventional procedures, CIAKI has become the third leading cause of hospital-acquired AKI. The incidence of CIAKI remains high despite the introduction of newer and "safer" contrast media.
Although the exact mechanism of contrast-induced renal injury is unknown, vasoconstriction of the peritubular capillaries is thought to be an important component. Consequently, our current studies seek to investigate whether a class of vasodilators (Phosphodiesterase Type 5 inhibitors) which are used in the treatment of erectile dysfunction might also protect the kidney from contrast-induced damage.
Development of a Novel Conjugate of Clopidogrel
Clopidogrel is an oral antithrombotic prodrug that inhibits the platelet P2Y12 receptor upon bioactivation by members of the cytochrome P450 family. In combination with aspirin, clopidogrel is widely used in dual antiplatelet therapy to treat patients with acute coronary syndromes, especially those receiving percutaneous coronary interventions. Despite its broad use in clinical cardiology, clopidogrel has major limitations including interindividual variability, delayed onset of action, and adverse drug–drug interactions. A large body of evidence indicates that approximately 30% of Caucasians and up to 60%–70% of Asians respond poorly to clopidogrel therapy, in part due to polymorphisms in the CYP450 enzyme responsible for its bioactivation (CYP2C19). As a result, these patients are at increased risk for major adverse cardiovascular events.
In collaboration with a research team at the University of Michigan, we have generated a disulfide conjugate of the active metabolite of clopidogrel with 3-nitropyridine-2-thiol. This conjugate is readily converted to the active metabolite in the presence of glutathione through a thiol exchange reaction. Our current research is focused on characterizing the speed and effectiveness by which this drug inhibits platelet aggregation and the formation of occlusive thrombi in vivo.
Computational Modeling Approach to Predicting Proarrhythmia in Drug Discovery and Development
Drug-induced prolongation of the QT interval, resulting from the inhibition of hERG potassium channels, can result in serious ventricular arrhythmias and sudden death. These adverse effects on cardiac repolarization have directly led to the withdrawal of 14 medications from global markets. In the past decade more than $5 Billion has been spent by the pharmaceutical industry on the assessment of proarrhythmia at various stages of drug development. While this investment has eliminated the appearance of proarrhythmia in recently approved drugs, it has done so at the expense of many non-toxic drugs which may have been falsely identified as unsafe by existing testing methods.
In conjunction with scientists at Eli Lilly and Company we seek to improve the sensitivity and predictive success of existing proarrhythmia assays by establishing a quantitative systems pharmacology approach to predicting drug-induced proarrhythmia. We are utilizing data from individual cardiomyocytes, isolated hearts and whole animal preparations to establish a model which better translates in vitro findings to clinical outcomes.