Preclinical r&d services

MYOCARDIAL INFARCTION

Acute myocardial infarction is a major cause of mortality and morbidiy in industrialized societies. The major challenge for the medical industry is to develop innovative treatment to reduce the size of myocardial infarction (Ferdinandy et al, Pharmacol Rev, 2007)

Pharmahungary is a technology leader CRO in the measurement of the size of myocardial infarction in different preclinical models of myocardial infarction. Infarct size is a gold standard end-point of preclinical and clinical studies of cardioprotection against myocardial ischemia and reperfusion injury. Infarct size is measured by a proprietary “infarctsize” system developed in-house by Pharmahungary (see www.infarctsize.com, Infarctsize™ is a trademark of Pharmahungary). The system consists of a high-throughput, precision slicing hardware as well as an image analyzer & documentation software designed for the special needs of fast and reproducible measurement and documentation of myocardial infarct size.

The following acute and chronic myocardial infarction models are available in rodents and large animals:

  • ex vivo global ischemia and reperfusion-induced infarction
  • ex vivo coronary occlusion and reperfusion-induced infarction
  • in vivo coronary occlusion and reperfusion-induced infarction
  • in vivo permanent coronary occlusion-induced infarction and heart failure
  • in vivo coronary occulsion and reperfusion-induced chronic infarction and heart failure

Pre-screening of cardioprotective drugs are available in cardiac myocyte assays (including stem cell-derived cardiac myocyte assays) subjected to simulated ischemia/reperfusion.

HEART FAILURE

About 5 million people in the U.S. have heart failure. Heart failure diminishes quality of life and it contributes to 300,000 deaths each year. The treatment of heart failure is a major challenge for drug and medical device development.

The following acute heart failure models are available:

  • heart failure induced by acute coronary occlusion
  • heart failure induced by acute coronary occlusion and reperfusion
  • heart failure induced by cardiotoxic agents

The following chronic heart failure models are available:

  • heart failure induced by permanent chronic coronary occlusion
  • chronic heart failure induced by coronary occlusion and reperfusion-induced infarction
  • heart failure induced by cardiotoxic agents
  • cardiotoxic agent-induced heart failure model
  • salt and volume overload-induced heart failure
  • transverse aortic constriction-induced heart failure
  • chronic pacing-induced heart failure

CARDIOPROTECTION & RISK FACTORS

Endogenous cardioprotection, influence of the presence of risk factors:

“Ischemic preconditioning” is a well-described adaptive response in which brief exposure to ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic injury. Moreover, brief cycles of ischemia/reperfusion applied following a longer period of ischemia also confer cardioprotection against the consequences of myocardial ischemia/reperfusion, a phenomenon called “ischemic postconditioning.” The discovery of these two major forms of endogenous cardioprotective mechanisms has encouraged the exploration of new ways to protect the ischemic/reperfused myocardium, but still has not led to a translation into clinical therapies.

Most experimental studies on cardioprotection have been undertaken with animal models, in which ischemia/reperfusion is imposed in the absence of other disease processes. However, ischemic heart disease in humans is a complex disorder caused by or associated with known cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, insulin resistance, atherosclerosis, and heart failure; additionally, ageing is an important moderating factor. In these conditions, the pathological processes are associated with fundamental molecular alterations that affect cardioprotective signalling in the myocardium. Therefore, to develop cardioprotective drugs, there is a critical need to study myocardial infarction in the presence of risk factors to maximize the likelihood of successfully developing rational approaches to therapeutic protection for the majority of patients with ischemic heart disease who are aged and/or have modifying comorbid conditions (Ferdinandy et al, Pharmacol Rev, 2007; Ovize et al, Cardiovascular Research, 2010).

The following endogenous cardioprotection models are available:

  • classic preconditioning models ex vivo and in vivo
  • delayed preconditioning models in vivo
  • postconditioning models ex vivo and in vivo
  • remote conditioning models

Cardioprotective drugs are tested in combined disease models: e.g. myocardial infarction and stroke with risk factors and co-morbidities such as hyperlipidemia and diabetes, and co-treated with widely used antihyperlipidemic or anti-anginal drugs.

HIDDEN CARDIOTOXICITY

What is hidden (latent, occult) cardiotoxicity and the hiddentox™ testing platform?

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since our original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as e.g. metabolic diseases like hyperlipidemia and diabetes) and their medications (e.g. nitrate tolerance, statins, etc.) may interfere with cardiac ischemic tolerance and endogenous cardioprotective signaling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to:

 

1. drug-induced enhancement of deleterious signaling due to ischemia/reperfusion injury and/or the presence of risk factors

2. inhibition of cardioprotective survival signalling pathways

 

These considerations led to a novel concept of ‘hidden cardiotoxicity’, defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues (Ferdinandy et al, Eur Heart Journal, 2019).

Therefore, we developed novel cardiac safety testing platform hiddentox™ involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.

Pharmahungary can test the hidden cardiotoxic effects of your compounds by our hiddentox™ service platform. The following test systems are available:

  • interaction of the test compound with ischemia/reperfusion and cardioprotection by ischemic preconditioning, postconditioning or remote conditioning in the presence of absence of different co-morbidities or co-medications. In vitro and in vivo models are available (Brenner et al, Cells, 2020; Makkos et al, Front Physiol, 2020)