Below are a variety of sample hypotheses that would be appropriate for the Sternfels Prize. You may use these as models as you form your own proposal, but remember your submission must be your own novel idea.
Simvastatin is an HMG-CoA reductase inhibitor prescribed,
along with diet changes, to lower high cholesterol and
triglyceride levels in the blood. It is known that increased
plasma concentrations of simvastatin can lead to myopathy
(muscle pain or weakness) and rhabdomyolysis
(rapid breakdown of muscle tissue).
One of the major mechanisms of simvastatin metabolism is through Cytochrome P-450 (CYP) 3A4. Drugs such as ketoconazole and ritonavir are strong inhibitors of the CYP3A4 enzyme. If a patient takes a strong CYP3A4 inhibitor concomitantly with simvastatin, the metabolism of simvastatin is inhibited and plasma levels of simvastatin and its active metabolite increase significantly, putting the patient at high risk for myopathy and rhabdomyolysis.
Given this danger, the FDA has contraindicated the concomitant use of simvastatin with any drug known to be a strong inhibitor of CYP3A4.
Terfenadine is an antihistamine that was used for
treatment of allergies. Soon after administration,
terfenadine is almost completely metabolized to its
active metabolite, fexofenadine, by CYP3A4. It is known
that terfenadine has cardiotoxic properties, while
fexofenadine does not.
While the rapid conversion of terfenadine to fexofenadine usually resulted in a safe and effective drug, this conversion was significantly slowed or stopped in patients taking inhibitors of CYP3A4 or drinking grapefruit juice. This caused prolongation of the QT interval and led to cardiac arrhythmias such as Torsades de Pointe, which can be fatal.
As such, terfenadine has since been withdrawn from the market.
The P-glycoprotein (P-gp) transporter is an efflux pump
that drives drugs and other xenobiotics out of cells
such as the enterocytes lining the lumen of the intestine.
It also facilitates transport of drugs out of the
bloodstream and into the urine and bile in the kidneys
and liver, respectively.
P-gp can be inhibited by drugs such as quinidine, leading to its inactivation. When P-gp is blocked by quinidine, the mechanism by which substrates, such as digoxin, move from the enterocytes back into the lumen of the intestine is inhibited, allowing more digoxin to cross through the enterocyte into the bloodstream. Inhibition of P-gp also leads to reduced clearance of digoxin into the urine. Together, these phenomena lead to increased concentrations of digoxin in the plasma.
Digoxin is a narrow therapeutic index drug wherein small changes in plasma concentration can quickly lead to toxicity, and the increase of digoxin in the plasma due to inhibition of P-gp can become dangerous very quickly. Potential risks include cardiac arrhythmias such as first-, second-, and third-degree heart block, atrial tachycardia, ventricular tachycardia, and ventricular fibrillation. Thus, close monitoring of patients known to be taking digoxin and an inhibitor of P-gp are imperative.
Metformin is a commonly used drug to treat Type 2 diabetes.
Plasma levels of greater than 5 g/mL have been associated
with a rare condition called lactic acidosis, a buildup
of lactic acid in the blood, which is fatal in
approximately 50% of cases. The mechanism of elimination
of metformin is excretion of the unchanged drug via the
Patients with kidney impairment have a reduced ability to excrete metformin, leading to increased levels of the drug in the plasma and putting them at higher risk for side effects such as lactic acidosis. Thus, metformin administration to patients with certain levels of kidney impairment is contraindicated.
Abacavir is a nucleoside analog, which inhibits human
immunodeficiency virus (HIV-1) reverse transcriptase
and is used in combination with other drugs to treat
HIV-1 infection. It has been reported that some patients
have severe and sometimes fatal hypersensitivity reactions
As these reactions were being investigated, it was noted that patients carrying the HLA-B*5701 allele are at a significantly higher risk for a hypersensitivity reaction. Though not all patients that have hypersensitivity reactions carry the HLA-B*5701 allele, the risk is great enough in the subpopulation of patients with the allele that administration of abacavir to patients with the HLA-B*5701 allele is contraindicated, and all patients should be screened for the presence of the allele prior to administration.