Bloodstream scavenger inhibits clotting without increased bleeding
A compound that mops up debris of damaged cells from the bloodstream may be the first in a new class of drugs designed to address one of medicine's most difficult challenges -- stopping the formation of blood clots without triggering equally threatening bleeding.
In a mouse study published online July 23, 2012, in the journal Proceedings of the National Academy of Sciences, Duke University Medical Center scientists report that the experimental compound called PAMAM G-3 actually prevents activation of the process that leads to the formation of dangerous blood clots, while avoiding any impact on the factors that are essential to normal blood clot formation.
"In the thrombosis (clotting) space, the holy grail has been to make something anti-thrombotic that doesn't significantly increase your chance of hemorrhage or bleeding," said Bruce A. Sullenger, Ph.D., director of the Duke Translational Research Institute and senior author of the study. "We think this is a promising example of a type of compound that could do that. If it can be clinically developed and exhibit the same properties in humans, clearly that would improve safety and outcome of treating patients who have thrombotic disease."
Thrombosis, the formation of blood clots in the circulatory system that form blockages, is a major cause of death in the Western world, contributing to the mortality associated with leading killers such as myocardial infarctions, stroke, and even cancer.
"If you can control thrombosis without greatly increasing hemorrhage or bleeding risk, you would address a major unmet medical need," Sullenger said. "It would have potentially major clinical implications."
The thrombosis study builds upon previous work by Sullenger and his group, which showed that the compounds called nucleic acid-binding polymers or NABPs, which include PAMAM G-3, have potent anti-inflammatory properties. Work published last year by Sullenger's lab demonstrated the polymer's potential to interrupt the inflammatory response that is the hallmark of auto-immune disorders such as lupus and multiple sclerosis.
It had been shown previously that dying and diseased cells spill nucleic acids into the bloodstream at high levels rogue bits of DNA and RNA that trigger an inflammatory immune response. Noting that any circulating nucleic acids or inorganic polyphosphates also seem to trigger the coagulation response, the researchers hypothesized that NBAPs might also be effective anti-coagulants. In test tube-based assays and experiments in two mouse models of thrombosis, the NABPs proved to be potent inhibitors of thrombosis without simultaneously triggering abnormal bleeding.
After screening several of the NABPs, which were originally developed for other biomedical applications, the team settled on PAMAM G-3 due to its combination of anticoagulant potency and low toxicity.
"We found that other [NABP] compounds were more toxic, but this particular compound, PAMAM G-3, had been purported to be less toxic in mouse models, so that's why we chose it for our further studies," said Shashank Jain, Ph.D, the study's lead author and a post-doctoral associate at Duke.
The researchers plan further work to better understand how the nucleic acids and polyphosphates are mediating the coagulation response. They will also engineer additional NABP compounds to improve potency, safety and tolerability. And of course they have their sights set on the clinic, but that is a few years away.
"Clearly we want to think about other animal models and then translating it eventually into human studies," Sullenger said. "In a variety of the major diseases, thrombosis is an important clinical problem, and the challenge is always, how do you treat it without causing bleeding problems? If you can address that critical issue, it would be a significant advance."
Journal reference: Proceedings of the National Academy of Sciences
Provided by Duke University Medical Center
- New anti-inflammatory agents silence overactive immune response Aug 15, 2011 | not rated yet | 0
- Designing drugs and their antidotes together improves patient care Oct 04, 2009 | not rated yet | 0
- Flavonoid compound found in foods and supplements shown to prevent the formation of blood clots May 08, 2012 | not rated yet | 0
- Blood cell breakthrough could help treat heart disease Apr 27, 2012 | not rated yet | 0
- New treatment for thrombosis discovered Mar 17, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
In 2008 researchers from the University of Southern Denmark showed that the drug thioridazine, which has previously been used to treat schizophrenia, is also a powerful weapon against antibiotic-resistant bacteria such as ...
Medical research May 17, 2013 | 3.7 / 5 (3) | 0 |
Scientists investigating the interaction of a group of proteins in the brain responsible for protecting nerve cells from damage have identified a new target that could increase cell survival.
Medical research May 17, 2013 | 5 / 5 (1) | 0
New findings by researchers carrying out experiments at the U.S. Department of Energy Office of Science's Advanced Photon Source (APS) help explain why some drugs that interact with two kinds of human serotonin ...
Medical research May 17, 2013 | 4 / 5 (1) | 0 |
Peptide molecules derived from the body's natural immune system can help boost the body's defence against life-threatening blood poisoning, joint University research has uncovered.
Medical research May 17, 2013 | 4 / 5 (1) | 0 |
A new Montréal study conducted by Dr. May Faraj, associate research professor at the Université de Montréal and invited scientist at the IRCM, along with her research team and medical collaborators, shows ...
Medical research May 17, 2013 | not rated yet | 0 |
The devastating effect of Alzheimer's disease on bilingual people has been thrown into focus in Canada, where the sudden loss of a second language can leave sufferers feeling like strangers in their own country.
9 minutes ago | not rated yet | 0
The hunt for an HIV vaccine has gobbled up $8 billion in the past decade, and the failure of the most recent efficacy trial has delivered yet another setback to 26 years of efforts.
1 hour ago | not rated yet | 0
Regular consumption of coffee is associated with a reduced risk of primary sclerosing cholangitis (PSC), an autoimmune liver disease, Mayo Clinic research shows. The findings were being presented at the Digestive Disease ...
9 hours ago | not rated yet | 0 |
Patients with treatment-resistant major depression saw dramatic improvement in their illness after treatment with ketamine, an anesthetic, according to the largest ketamine clinical trial to-date led by researchers from the ...
9 hours ago | 4.7 / 5 (3) | 0 |
Research presented at Digestive Disease Week (DDW) explores new methods for managing digestive health through diet and lifestyle.
9 hours ago | not rated yet | 1
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
9 hours ago | not rated yet | 0