Safety pharmacology refers to the science in which experimental models are created and used to detect the potential adverse or toxic effects of medications in the treatment of disease. The Masonic Medical Research Laboratory (MMRL) works closely with pharmaceutical and biotechnology companies to design better drugs and to establish the safety of drugs under development.

Wedge preparation with floating electrodes

Masonic Medical Research Laboratory scientists have been at the forefront of this field having developed a number of models that have helped to identify drugs capable of generating cardiac arrhythmias, or abnormal rhythms of the heart.  It is important to note that some prescribed drugs for various maladies have unintended heart-related consequences. MMRL scientists have helped to identify these, thus contributing to the health and welfare of the general public. The MMRL has worked with dozens of pharmaceutical and biotechnology companies over the past 25 years to identify drugs in their pipeline that are predicted to cause serious cardiac side effects in clinical use and have worked with a number of companies to establish clinical drug safety, facilitating approval by the US Food and Drug Administration (FDA).

Canine right atria preparation

At the MMRL, we use a number of different models to establish the potential of a drug to induce cardiac arrhythmias such as atrial and ventricular tachycardias and fibrillation. Our studies have demonstrated the mechanism by which the antibiotic erythromycin when used in high doses leads to the development of a life-threatening Torsade de Pointes arrhythmia. Studies at the MMRL have also uncovered the mechanism by which the antidepressant amitriptyline leads to the development of ventricular tachycardia and fibrillation, thus identifying the mechanism underlying the life-threatening cardiac arrhythmias encountered in the clinic with the use of this drug.

We have developed several models for evaluating the effects of drugs to induce atrial fibrillation (AF) or arrhythmias capable of triggering AF, the most common arrhythmia observed in the clinic.  These models have also proved invaluable in identifying drugs that can suppress AF or prevent its induction.  Safe and effective drugs for the management of AF is today considered to be one of the greatest unmet needs facing our society, with the prevalence of AF reaching epidemic proportions. MMRL scientists have identified a combination of two drugs, ranolazine and dronedarone, which in our experimental models demonstrate remarkable synergism in the management of AF. Clinical trials are scheduled to begin in 2011.

IPS derived cardiomyocytes and native canine ventricular heart cell

Another valuable addition to the Safety Pharmacology regiment are induced pluripotent stem cells (iPS).  Our Stem Cell Center is using human fibroblasts and lymphocytes to generate iPS-derived heart cells to assess the potential adverse effects of a drug in the normal human heart.  We are also creating human models of disease by generating iPS cardiac cells from fibroblasts and lymphocytes obtained from patients with sudden death syndromes such as the long QT, short QT, Brugada and early repolarization syndromes.  These iPS-derived heart cells are then used to study the potential toxic effects of drugs in the context of these diseases as well as to uncover drugs that may be of therapeutic value in treating these syndromes. These cells also have the potential to be used in regenerative therapy, to restore function to damaged or failing hearts without fear of autoimmune rejection.

Experimental Models

The coronary-perfused left ventricular wedge preparation is used to determine if a drug can induce a prolongation of the QT interval or/and an increase in the transmural dispersion of repolarization (TDR) which correlates to the Tpeak-Tend of the transmural ECG.  An increase in Tpeak-Tend together with an increase in QT interval in the ECG are known to predispose to the development of arrhythmias in the clinic, in particular the atypical polymorphic ventricular tachycardia known as Torsade de Pointes (TdP), a potentially lethal arrhythmia.

The coronary-perfused right ventricular wedge preparation is used to establish whether a drug has the potential to induce or predispose to the Brugada syndrome, a disease known to induce a rapid polymorphic ventricular tachycardia that can be life-threatening. Potent sodium channel blockers are known to unmask the Brugada phenotype.Antidepressant drugs, both tricyclic and tetracyclic, as well as anti-epileptics and some antipsychotics have been shown to predispose to development of electrocardiographic and arrhythmic manifestations of Brugada syndrome.

Coronary-perfused atrial and the superfused pulmonary vein preparations represent models used for the detection of the ability of a drug to induce atrial fibrillation (AF) or arrhythmias capable of triggering AF, the most common arrhythmia observed in the clinic.  These models have also proved invaluable in identifying drugs that can suppress AF or prevent its induction.

Induced pluripotent stem cells (iPS):  Human fibroblasts and lymphocytes are genetically reprogrammed to generate cardiomyocytes.  These skin and blood cells transformed into heart cells are being used to generate human cardiomyocytes for safety pharmacology, to create human models of disease and for regenerative therapy, to restore better function to damaged or failing hearts.