Cardiotoxicity within SIP
As many cardiotoxic effects are rare and only occur after long-term use, identifying them in drug discovery stages is relatively difficult. The Safety Intelligence Program allows searches based on both drug class and chemical structure, so drugs with similar structures and other properties can be compared to one currently in development. SIP contains both pathological (e.g. heart failure, arrhythmic disorder) and physiological (e.g. blood pressure, ECG intervals) effects, providing insight into adverse reactions and potential underlying mechanisms.As of January 2012, there are 70,652 assertions associated with the heart in SIP, which are curated from a wide range of public data sources, including DailyMed, Medline and ToxNet. The most common cardiac effects are shown in Figure 1.
The most common pathological effects are arrhythmic disorder, caused by epinephrine (primarily in rats, humans and dogs) and ouabain (primarily in guinea pigs and dogs), myocardial infarction (caused by ergotamine and methergine – both in humans) and cardiotoxicity (caused by anthracycline and etidocaine – both in humans, among other species). The most common physiological effects are on heart rate (caused by drugs such as atazanavir and landiolol) and prolonged QT interval (caused by bepridil and sotalol).
SIP contains data for 8,588 compounds affecting the heart, the most common of which are shown in Figure 2. The compounds with the most assertions include isoprenaline, which induces toxic cardiomyopathy; doxorubicin which causes cardiotoxicity; and verapamil which adversely affects myocardial contraction.
There are fifteen species covered by the cardiac assertions, of which the main four defined are shown in Figure 3. The majority of assertions are based on studies in humans, but there are also many studies performed on rats, dogs and mice. Other species include rabbits, pigs, sheep and non-human primates.
As well as information on specific cardiac conditions, the Safety Intelligence Program can also be used to search for effects on the cardiovascular system as a whole – for example, where the published data may not have specified the effects in more detail. There are 3,681 assertions associated with cardiovascular effects, the most frequent of which are shown in Figure 4. These cover a diverse list of 1,509 compounds of which the most common include ethanol, estrogen and cocaine.