cardiotoxicity

High-throughput ADME Screening Technologies

Posted by cdavenport on Monday Apr 16, 2012 Under ADME, Drug Safety, Regulatory

High throughput (HT) Absorption, Distribution, Metabolism, and Excretion (ADME) screening technology is the current push from Big Pharma to be outsourced through contract research organizations (CROs).  Shifting also is the ADME regulatory emphasis; the FDA has released a draft guidance (17 Feb 2012) that includes specific wording around what needs to be done with respect to transporter drug-drug interactions (both efflux and influx).  The guidance will start to drive significant changes in how ADME screening is performed.  Two assays that are routinely being utilized in pharma are the Caco-2 cell-based assay and the PAMPA (parallel artificial-membrane permeation) assay.  As currently practiced, predictive ADME screening is made even more difficult given the variety of transport mechanisms available.  In toxicology screens (ADME-tox), however, one is not looking for altered aspects of the drug, which is generally initially unknown, but changes in known, endogenous parameters.  Thus ADME-tox lends itself more easily to HT platforms.  New platforms for high throughput ADME screening are available, and discussed in this article.

Source:  Drug Discovery and Development

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Nonclinical Cardiotoxicity Testing: Stem Cell Use

Posted by cdavenport on Thursday Oct 13, 2011 Under Cardiovascular, Drug Safety, Techniques

Prospective identification and potential amelioration of cardiotoxicity is a critical component of contemporary drug development, particularly for targeted therapies (e.g., tyrosine kinases) in oncology that are designed to inhibit critical signaling pathways shared by both the tumor cell and the cardiac myocyte (e.g., HER2 and C-Abl).  Current preclinical approaches to cardiac safety, which often focus primarily on ion channel testing (e.g., hERG), need to broaden the in vitro test menu to assess other cellular functions that are critical to cardiac cell health.  Accordingly, effective nonclinical cardiotoxicity screening programs need to be implemented earlier in the development process.

Stem-cell technologies offer induced pluripotent stem-cell-derived (iPSC) cardiac myocytes that are pure, functionally relevant (exhibit electrical profiles in culture and are amenable to patch-clamp-like studies that monitor electrical potentials and voltage-gated ion channel function), and are human in origin.  The following would comprise an effective preclinical cardiac safety testing program utilizing  iPSC-derived cardiac myocytes:

  • Determining influences on key cardiac metabolic pathways focusing on AMPK;
  • Evaluating changes in fatty acid beta-oxidation;
  • Measuring changes in mitochondrial health , reactive oxygen species production, and ATP levels;
  • Assessing drug-induced apoptosis;
  • Survey potential off-target effects using a comprehensive kinase profiling platform.

In addition to the above, the preclinical program should identify compounds that demonstrate cardio-protective effects with regard to mitochondrial health and energy homeostasis.

Glossary

ABL1 = a proto-oncogene which encodes a cytoplasmic (C-ABl) and nuclear protein tyrosine kinase.  Implicated in processes of cell differentiation, cell division, cell adhesion, and stress response.

AMPK = a metabolic sensor of cellular ATP.  Controls fatty acid oxidation and glucose uptake in skeletal muscle, heart, and liver.

ATP = adenosine-5′-triphosphate, a multifunctional nucleoside triphosphate used in cells as a coenzyme.  Responsible for intracellular energy transfer.

HER2 = “Human Epidermal growth factor Receptor 2,” a receptor required for healthy heart function.

hERG = the human Ether-à-go-go Related Gene.  Codes for a potassium ion channel protein.

 

SourceDrug Discovery and Development

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Turbulent Blood Flow may Increase Cardiovascular Risk

Posted by cdavenport on Wednesday Feb 23, 2011 Under Cardiovascular, Drug Safety, toxicity

By utilizing the basic principles of hemodynamics and hydraulics, research suggests that fluid retention is detrimental for the cardiovascular system because it increases the likelihood of turbulent blood flow, regardless of whether or not blood pressure is raised.  Increased turbulence promotes endothelial dysfunction, thereby contributing to the development of atherosclerotic cardiovascular disease.  Fluid retention induces hypertension in some individuals, increases stroke volume (the amount of blood that is ejected by the heart with each contraction) in others, and causes edema.  Some blood pressure lowering medications also increase stroke volume and cause edema but prevent heart attacks and strokes when used to treat hypertension.  For drugs that increase the risk of adverse cardiovascular events, it may be possible to reduce or neutralize the increased risk by simultaneous diuretic administration.

Source: ScienceBlog

Original Article: Clinical Hemorheology and Microcirculation (free pdf)

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