Old Quinolones – The Dead May Rise Again
In March of 2014 an article appeared on Nature.com which is a leading science journal outlet. The article, “Unexpected link between an antibiotic, pannexin channels and apoptosis”, highlighted an unexpected discovery between an older fluoroquinolone, trovafloxacin, which was removed from clinical use due to toxicity, mainly liver toxicity, and the body’s little understood pannexin proteins.
Pannexin proteins, in part, function as a signal beacon to direct or point apoptotic activity of the immune system. Pannexin communication to the immune system allows for an “ordered’ disassembly of a cell during the apoptotic (programmed cell death) process. Basically pannexin helps control the timing in which dying cells literally fall into pieces.
Apoptosis is programmed cell death. It is a very tightly controlled, highly active and voluminous process involved in roughly 1 million cell deaths per second in the human body. It is body’s orderly response to cell changes that range from eliminating older cells, diseased cells, and even removing cells from between fingers and toes during the embryonic process. A malfunctioning apoptotic process has been implicated in a variety of diseases. In this case the researchers believed that trovafloxacin’s interference in the apoptotic process through pannexin inhibition led to its marked liver toxicity.
For those who do not know about pannexins, in very oversimplified laymen’s terms, they are a subsection of a larger family of proteins called innexins. Pannexins are glycoproteins, commonly referred to as Panx1, Panx2, and Panx3. Basically, they form channels, or as I like to think of them, small passageways between the membranes of a cell that allow the passage of small molecules.
There is some solid knowledge on the basic roles of pannexins but much of their function in the human body is quite hypothetical. Researchers believe there are very important in neuronal metabolism specifically neurochemistry involving the hippocampus. Their dysfunction can play a role in certain neurological cancers.
Antibiotic Use Still Out of Control
Despite cautions issued by a great number of organizations about the overuse of antibiotics, their use in society goes on unabated. Although many physicians are becoming more conservative in antibiotic use, I hear stories daily about antibiotics prescribed without any due diligence on the physician’s part.
Recently the FDA found that total sales of medically important antibiotics, i.e. the types that are also needed for human medicine, have increased 16% between 2009 and 2012 and comprise a whopping 70% of those that are used. In other words, those antibiotics that are deemed to be critically important or highly important by FDA are also among those increasingly sold for livestock use.
Antibiotics, Not the Benign Drug We Previously Thought
I grew up in the miracle age of penicillin. When we were kids the ‘pink liquid’ handed out by the doctor was a very common sight. I adopted a benign view of antibiotics, along with most of society and the medical community. Little did we realize the biological monster that was being created. Science is just now starting to realize what so many have long suspected, antibiotic use is destroying and permanently altering the microbiome of the human body, not to mention its biological impact on nature itself
In the U.S., antibiotic resistance caused more than two million illnesses in 2013, according to a report by the Centers for Disease Control and Prevention, and an estimated 23,000 deaths, adding up to more than $20 million in healthcare costs. We are losing the war against superbugs that we have created because of our own reckless antibiotic use.
Antibiotic use has delivered a one-two punch. It has fostered the rise of superbugs (really nothing more than bacteria that have a natural resistance to the action of antibiotics), in addition it has created long term health problems in many that are now just coming to light. As a matter of fact, many non-antibiotic pharmaceuticals contribute to the rise of super bugs. A subject that I wrote about here.
Nicole Allan wrote in The Atlantic in early 2014, “As a result, pharmaceutical companies have found antibiotics to be less worthwhile investments than drugs for chronic illnesses.” Since pharmaceutical companies are abandoning their quest for new antibiotics, researchers are looking for ways to repurpose older toxic antibiotics.
How Does Pannexin Inhibition Tie In?
Kodi S. Ravichandran, PhD, one of the authors of the “Unexpected link between an antibiotic, pannexin channels and apoptosis” paper explains the thinking quite clearly. In an interview with the University of Virginia Health System, where he is a researcher, he stated “The increase of drug resistance to antibiotics is one of the biggest threats to human health in the next 10 years. Yet the number of new antibiotics that are developed is extremely few. The reason a number of the older antibiotics have been shelved is toxicity. So perhaps if we better understand how this toxicity arises in those molecules, and by removing the bad parts and keeping the good parts, we might be able to find more usable antibiotics.”
This approach sounds good but let’s dig a little deeper. On the UVA website the synopsis of the pannexin research is a hope to use the information on how trovafloxacin blocks these channels to re-engineer it and other antibiotics in the quinolone family to lessen toxicity concerns.
Remember, there have been several members of the quinolone family removed from use because of toxicity. The main thrust of this discovery is to use the knowledge to re-engineer the previously deemed toxic quinolones. For the average person and typical medical professional this all sounds great but for those who know just how toxic the current formulary of quinolones are, it gets more controversial.
I called the University of Virginia School of Medicine, Dept. of Pharmacology and was unable to speak with Dr. Ravichandran directly but spoke to a research assistant who spoke to me on condition of anonymity. When asking me why I was inquiring, I told the person that I was interested in their pannexin research and that I might write a blog article regarding the repurposing of old quinolones. I was told that if I write an article I must leave their name out, which I honored, even though they said nothing controversial from their end. Their comments were basically a synopsis of their research.
The assistant reiterated that on the surface the research showed that surprisingly, in contrast to trovafloxacin, two other structurally related quinolone antibiotics ciprofloxacin and levofloxacin did not block PANX1-dependent dye uptake. In other words Cipro and Levaquin did not show an affinity for blocking or inhibiting pannexin. The assistant told me that “if we can re-engineer older quinolones to achieve the same level of efficacy and safety that Levaquin and Cipro have shown, the results will be ground breaking.”
Prior to calling I had read the paper thoroughly again. I politely told the assistant that I still believe that they are too quick to dismiss Levaquin and Cipro as a non-player in pannexin inhibition. Modern FQ’s interfere with apoptosis in ways that have not been clearly identified yet and have been shown to interfere with other apoptotic signaling proteins. Cancer research has shown that there is a caspase/pannexin-1-independent mechanism and current FQ’s such as Cipro and Levaquin have been found to increase activated caspase-3, a marker of apoptosis, with confirmatory apoptotic changes on electron microscopy. As a matter of fact there are diverse pro-apoptotic drugs, including topoisomerase inhibitors, kinase inhibitors, and proteasome inhibitors that induce functional activation of Panx1 channels via caspase-3. At this point the assistant was suspecting me of being something other than what I actually am and the conversation came to an abrupt but polite end, with the assistant telling me that I would have to speak to Dr. Ravichandran directly for more information. I am still waiting a call back.
It’s a Matter of Viewpoint
Obviously I pick and choose my arguments regarding FQ’s to those that are most efficacious and this was neither the time nor place. My goal was to understand their mindset behind the research and for me it was revealed. Despite boatloads of documents pointing FQ’s to be toxic on many levels, we are still fighting an enemy that has its mindset back to the days of the ‘pink liquid’. When researchers have the mindset that the current usable formulary of FQ’s is a goal to reach based on safety and efficacy then the premise of their research is flawed.
These researchers, like many others, believe their cause is just and true and in some ways it is. They are guided by the need to defeat an enemy that man is responsible for unleashing and they believe their research will save countless lives. What they do not realize is that their research may also have the unintended consequence of disabling countless lives as well.
Despite those who think that we are winning the media battle about the toxicity of FQ’s, their use in our society is increasing. Not just because of increased antibiotic use, which is problematic, but because of the broad chemical properties of the FQ’s themselves. In cancer they have found use as adjunctive therapy and several new chemotherapeutic agents are currently being developed based on the FQ pharmacore. Now because of societal factors and the lack of development of new antibiotics coupled with a new vigor of reengineering, we face yet another controversial front as researchers seek to repurpose or re-engineer FQ’s of the past.
Not that re-engineering is a bad thing; after all, many things in our society have been successfully re-engineered for the betterment of mankind, including medications. It happens all the time. Who knows, maybe we’ll get lucky and some researcher will uncover a tidbit that further helps us understand the adverse reactions these drugs inflict. But, as far as I can see, these new directions in FQ research are all based on the deadly assumption that the current FQ’s are, for the most part, safe and efficacious and that the current adverse reaction rate is an acceptable collateral outcome. That genie is hard to get back in the bottle.