Note: This is Part 2 of a two part series covering academic research with Dr. Mark Noble of the University of Rochester. Read Part 1 here.
In this article, Part 2, Dr. Noble reports to us, in his own words, disturbing Levaquin toxicity findings that he discovered. His findings became the impetus for pursuing further FQ research and our team has been working with him since.
“After discussing the potential toxicity of Levaquin and other fluoroquinolones with you, we initiated analysis of Levaquin on the precursor cells that generate the myelin–forming oligodendrocytes of the CNS. Our past studies indicate that these cells are particularly useful for detecting potential CNS vulnerabilities, as our knowledge of how to grow these cells in tissue culture is so extensive that results we obtain in a tissue culture dish are virtually always predictive of what we will find in vivo. Of greatest relevance to considering the neurotoxic effects of fluoroquinolones in a surprising number of individuals, the in vitro studies we conducted on these cells and on other cells of the central nervous system were completely predictive of the adverse effects of chemotherapeutic agents on cells of the CNS.
The results obtained in our preliminary studies are quite disturbing. Applying Levaquin to CNS precursor cells at a concentration less than that thought to occur during the patient treatment, we already found some hint of a vulnerability. As individuals taking Levaquin are also likely to be taking other compounds, we also combined this antibiotic with a variety of over-the-counter anti-inflammatory agents. We found a striking combinatorial effect when Levaquin was combined with naproxen, the active ingredient in Alleve. By itself, neither compound caused a striking reduction in cell numbers after 24 hours of exposure. When applied in combination, however, there was a greater than 65% reduction in numbers of cells, a very toxic effect at such a short exposure period. This combinatorial effect was not only seen when Levaquin was combined with the naproxen, but also was seen when Levaquin was combined with prednisone. Thus, both a steroidal anti-inflammatory agent and a non-steroidal anti-inflammatory agent are able to cause marked toxicities for CNS cells when they are applied in combination with Levaquin. These results indicate that the combination of Levaquin with other agents is going to be of particular importance to examine.
We also initiated analysis of the molecular effects of exposure to Levaquin, naproxen or a combination of the two; the studies revealed a potential mechanism of action and reinforced concerns about the importance of studying Levaquin in combination with other agents. Two of the outcomes are of particular concern. In one set of experiments we found that the combination of Levaquin and naproxen causes a dramatic (>80%) reduction in the levels of cell surface receptors that are required for normal division of the precursor cells that make myelin–forming oligodendrocytes and that also are required for normal development of neurons in the hippocampus, a part of the brain that is of central importance in learning and memory. These reductions have been shown by our previous studies to be caused by oxidative stress. In addition, we found that exposure to these compounds causes a marked elevation in two proteins that are known to be induced by oxidative stress. These proteins (called p21 and p27) are well-studied indicators of cellular stress, and are known to cause division to cease in a wide range of precursor cells. There was a 240% increase in levels of p27 and a 400% increase in levels of p21 in cells exposed to this combination of agents. Such findings provide the clues necessary to initiate an efficient analysis of the molecular mechanisms underlying Levaquin–mediated toxicity.
To put our findings on Levaquin in the context of our previous work on chemotherapeutic agents, the outcomes of the Levaquin experiments are disturbingly similar to the kinds and levels of toxicity that we initially found in our work on 5-fluorouracil. When clinically relevant drug concentrations exhibit such toxicities in vitro, this is very troublesome.”
As you can plainly see, Dr. Noble’s findings are indeed disturbing. We know that fluoroquinolones are toxic in and of themselves, but how many unsuspecting people are taking them in combination with over the counter non-steroidal anti-inflammatory agents or with prescription steroidal anti-inflammatory agents? His experiments showed anywhere from 65% to 80% damage to neurological cellular mechanisms.
The tide is turning. The toxicity profiles of these drugs are getting harder and harder to ignore.
We want to thank Dr. Noble for listening to us in the past when we approached him in 2010, and his continued work researching fluoroquinolone toxicity. Our group will continue to work closely with Dr. Noble, and other researchers in our communities’ goal of exposing the true impact that FQs are having on our society.
Stay tuned to My Quin Story as I will be sure to inform the FQ community of any pertinent developments with Dr. Noble, Dr. Golomb, Dr. Bennett, and other pertinent issues.