Scientists at the Massachusetts Institute of Technology (MIT) and the University of  Vienna have developed a light-field laser imaging system that generates 3D movies of entire brains at a millisecond timescale to create a complete “living” brain map.  The research thereby offers a more complete picture of nervous system activity than has been previously possible.   The technique is envisioned to elucidate how entire neural circuits operate to generate behavior, thereby empowering new therapeutic strategies for neurological and psychiatric disorders.  To date the system has been used to simultaneously image the activity of every neuron in the worm Caenorhabditis elegans as well as the entire brain of a zebrafish larva.  Such an approach could help researchers learn more about the biological basis of brain disorders and monitor the reactions of the nervous system to drugs and other substances in the body.  The researchers believe that the “ability to survey activity throughout a nervous system may help pinpoint the cells or networks that are involved with a brain disorder, leading to new ideas for therapies.”  In addition, this technique may be useful for mechanistic toxicology to help determine the relevance of adverse events for human safety.

Source:  Drug Development News

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New Hypersensitivity Screen for Drugs

Posted by cdavenport on Friday Jun 22, 2012 Under Drug Safety, Immunogenicity, Preclinical, toxicity, Toxicology

Many drug hypersensitivity reactions are HLA-linked, meaning that they will occur much more often or even exclusively in individuals who have certain variants of the HLA gene.  A new study elucidates the specific mechanism leading to HLA gene-linked hypersensitivity to the drug abacavir.  These findings are applicable to other drugs and related hypersensitivity reactions.

The findings are discussed in the paper “Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire,” published last week in the scientific journal Proceedings of the National Academy of Sciences.

An interview with the authors is published in the Source cited below.

Source:  Clinical Toxicology

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Drug Safety: Tip of the Iceberg

Posted by cdavenport on Thursday Jun 7, 2012 Under Drug Safety, FDA, Post-market Surveillance, Risk Management, toxicity

The 10 drugs with the largest numbers of reports sent directly to the FDA by healthcare practitioners and consumers in 2011 in order of frequency are Pradaxa, Coumadin, Levaquin, Carboplatin, Zestril, Cisplatin, Zocor, Cymbalta, Cipro and Bactrim.  It is interesting to note that just two of these drugs were first introduced in the last decade (Pradaxa and Cymbalta), and only one in the previous year (Pradaxa), suggesting that major drug safety issues are not confined to recently approved drugs.  On one hand, this shows that FDA and manufacturer safety surveillance programs have identified these significant safety risks. On the other, it illustrates that placing warnings in product information only begins the process of managing drug safety risks.   Relative rates vs. report expectations are detailed.

These data come from QuarterWatch™ an Institute for Safe Medication Practices surveillance program that monitors all serious and fatal adverse drug events (ADEs) reported to the Food and Drug Administration through MedWatch, its adverse event reporting system.  The goal is to identify signals that may represent important new drug safety issues.


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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.


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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TigerTox: Lack of sleep correlates with Alzheimers – FierceBiomarkers #in #pharma #neuro #CNS

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Drug Labels: Toxicity or Information Overload?

Posted by cdavenport on Saturday May 28, 2011 Under Drug Safety, Risk Management, toxicity

Side effect overload on drug labels has less to do with true toxicity and drug safety than with manufacturer liability.  Examination of more than 5600 drug labels yielded over half a million side effects.  An average drug label and the more commonly prescribed drugs averaged 70 and 100 side effects, respectively.  The upper range in a single label was 525 reactions.  Information overload can overwhelm physicians, who must weigh the risks and benefits when prescribing a medication.  The Food and Drug Administration discourages such ‘over warning,’ but information overload is presently the rule rather than the exception.  Not surprisingly, medications typically used by psychiatrists and neurologists had the most complex labels, while drugs used by dermatologists and ophthalmologists had the least.  Although providing drug safety information more efficiently to both health care providers and the public is warranted, drug manufacturer liability concerns must also be addressed.

Source: Drug Discovery and Development

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Translational Toxicology: Biomarker Development

Posted by cdavenport on Monday May 16, 2011 Under Drug Safety, Renal, toxicity

Biomarker use in translational medicine is predicated upon preclinical qualification and validation – 2 distinct steps in the biomarker development process.  Prior to issue in 2009 (EMA) and 2010 (FDA, PMDA) of the renal-specific DRAFT qualification guidelines, there was no clear direction by the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA) of how companies should qualify new biomarkers for disease progression or clinical trial endpoints.  The trend in biomarker use is multivariant analysis, the tracking of subtle changes in multiple biomarkers simultaneously, often utilizing various tissue types.   While the new guidance addresses biomarker qualification, analytical validation of new biomarkers remains undefined.  This review updates the reader of the status of both qualification and validation of translational biomarkers.


Source: Drug Discovery & Development

Additional Reading:

Predictive Safety Testing Consortium: special issue of Nature Biotechnology (renal biomarkers)  (

EMA:  Qualification of novel methodologies for drug development guidance to applicants.


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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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Drug Labels May Inadequately Address Efficacy and Risk

Posted by cdavenport on Thursday Nov 25, 2010 Under Drug Safety, FDA, toxicity

FDA approval does not mean that a drug works well; it means only that the Agency deemed its benefits to outweigh its harms.  Comparative efficacy data, other than to placebo, may be missing from the label.  In 2006, the FDA revised the drug label design, adding a “highlights” section to emphasize the drug’s indications and warnings.  It also issued guidance about reporting trial results in the label and emphasized the importance of effectiveness data.  Yet some recent label updates (e.g., for Lunesta and Rozerem) are substantively unchanged.  Use of “Prescription Drug Facts Boxes,” featuring a data table of benefits and toxicities has been proposed.  Recently, the FDA’s Risk Advisory Committee recommended that the FDA adopt these boxes as the standard for their communications.  FDA leadership is deciding whether and how to use the boxes in reviews, labels, or both.  Also proposed is the generation of a standardized executive summary of FDA drug reviews.  These summaries should include data tables of the main results of the phase 3 trials, highlight reviewers’ uncertainties, and note whether drug approval was conditional upon a post-approval study.  While publication of new comparative-effectiveness results is helpful, publications generally occur post approval.  In contrast, much is known about drug effectiveness and drug safety at approval that could better guide physician and patient choice if this information was more widely disseminated.

Source: New England Journal of Medicine

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The recent approval by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) of the 7 protein biomarker panel for use in detecting drug-induced kidney damage means that the biomarkers are now qualified at the same level by all of the ICH regulatory agencies.  In a Critical Path Initiative statement, this is the first biomarker qualification decision by the PMDA and means that the panel is qualified for voluntary use in nonclinical safety studies.  Furthermore, data generated using the panel can be submitted to the PMDA on a case-by-case basis for use in monitoring drug-induced renal toxicity in humans.  The 7 biomarker panel,  composed of kidney injury molecule-1, albumin, total protein, β2-microglobulin, cystatin C, clusterin, and trefoil factor 3, can be utilized in conjuntion with the current standard renal biomarkers, serum creatine and blood-urea nitrogen.  With the exception of trefoil factor 3, the PMDA stated that the new renal biomarkers outperformed the current standard biomarkers.  The renal biomarker panel received approval in 2008 from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for limited use in nonclinical and clinical drug development.  Additional guidelines regarding biomarker qualification are expected in July 2010.

Source: ProteoMonitor and MedHealthWorld

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