Tag Archives: Mitochondrial DNA

Are Damaged Mitochondria Causing Autoimmune Diseases?

Fluoroquinolone toxicity looks and feels a lot like multiple autoimmune diseases including rheumatoid arthritis, lupus, MS, thyroid autoimmune diseases, and others. Some people have proposed that fluoroquinolone toxicity is its own autoimmune disease, but the auto-antibodies have not yet been identified and thus it is not treated as an independent autoimmune disease. In some people, fluoroquinolones have triggered a recognized autoimmune disease, as you can read about in Michelle’s Story of fluoroquinolone-induced lupus, JMR’s story of fluoroquinolone-induced thyroid autoimmune diseases, and I know a couple people with fluoroquinolone-induced MS.

I have always wondered what the connections are between fluoroquinolone toxicity and autoimmune diseases, whether or not fluoroquinolones are truly triggering autoimmune diseases generally, and what the mechanism is behind the connection.

A recent article in Scientific American, Brain’s Dumped DNA May Lead to Stress, Depression: New research suggests genetic material from the mitochondria can trigger an immune response throughout the body provides some interesting connections (and, dare I say, answers). The article points out that mitochondrial DNA, when it is released from mitochondria, can cause inflammation and an immune response:

“But how was this inflammation triggered by mitochondrial DNA leaking out of cells? A 2010 Nature paper provided the answer: In it researchers demonstrated the way mitochondrial DNA, when released into the blood after an injury, mobilized a pro-inflammatory immune response. Because of mitochondria’s bacterial origin and its circular DNA structure, immune cells think it’s a foreign invader.  When circulating mitochondrial DNA binds to a particular receptor, TLR9, on immune cells, they respond as if they were reacting to a foreign invader such as a flu virus or an infected wound. The immune cells release chemicals called cytokines telling other white blood cells they need to report for duty at sites of infection, inflammation or trauma.”

Multiple studies have shown that fluoroquinolones disrupt the replication and reproduction cycles of mitochondrial DNA (mtDNA) and deplete mtDNA. Of course they do – mitochondria are descendants of bacteria and drugs that affect bacterial DNA have similar effects on mtDNA. The way that fluoroquinolones work is that they disrupt the DNA and RNA replication cycles for bacteria (and mitochondria).

When mitochondrial DNA is released via fluoroquinolones (or a variety of other pharmaceuticals and environmental toxins that also damage mitochondria) the immune system attacks it because it appears to the immune system to be bacterial DNA. This attack of loose mtDNA can lead to an immune-system over-response, and even trigger an autoimmune disease.

The Scientific American article also notes that:

“The genetic cast-offs are not just inert cellular waste. “This circulating mitochondrial DNA acts like a hormone,” says Martin Picard, a psychobiologist at Columbia University, who has been studying mitochondrial behavior and the cell-free mitochondrial DNA for the better part of the last decade. Ejection of mitochondrial DNA from the cell mimics somewhat adrenal glands’ release of cortisol in response to stress, he says. Certain cells produce the circulating mitochondrial DNA and, as with the adrenal glands, its release is also triggered by stress.”

To emphasize – “circulating mitochondrial DNA acts like a hormone” that “mimics somewhat adrenal glands’ release of cortisol in response to stress.” So many people suffering from fluoroquinolone toxicity are in vicious cycles of chronic stress and anxiety that are wreaking further havoc on their health. The post, “Cellular Stress, Chronic Stress, and Fluoroquinolone Toxicity” goes into more detail about the connections between stress and anxiety and fluoroquinolone toxicity.

Fluoroquinolones aren’t the only toxins that damage mtDNA. The list of pharmaceuticals that damage mtDNA include all bactericidal antibiotics (including fluoroquinolones) (1), statins (2), chemotherapy drugs (3), acetaminophen (4), metformin (a diabetes drug) (5), and others. The environmental pollutants that have been shown to damage mitochondria include rotenone, cyanide, lipopolysaccharide, PAH quinones, arsenic, and many others (6).

I would bet quite a bit that the rise in autoimmune diseases corresponds with the rise in production of pharmaceuticals, pesticides, herbicides, and other chemicals that are toxic to mitochondria. The Scientific American article, Brain’s Dumped DNA May Lead to Stress, Depression: New research suggests genetic material from the mitochondria can trigger an immune response throughout the body, provides some valuable connections that point in that direction, and I would love to see more research on the topic.

 

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Ciprofloxacin Depletes Exosomal DNA

Journal of Extracellular Vesicles, “Biological properties of extracellular vesicles and their physiological functions”

The study, “Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA” published in Nature, found that, “ciprofloxacin induced the release of both DNA (mitochondrial and chromosomal sequences) and DNA-binding proteins on the exofacial surfaces of small extracellular vesicles referred to in this paper as exosomes.” And, “Our results reveal for the first time that prolonged low-dose ciprofloxacin exposure leads to the release of DNA associated with the external surface of exosomes.”

In the discussion section of “Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA” the authors expand on their findings:

“Exposure of Jurkat cells to ciprofloxacin has been shown to induce oxidative stress, production of reactive oxygen species, mitochondrial dysfunction, inhibition of the respiratory chain and decrease of mitochondrial membrane potential leading to mitophagy47. Our MS analysis has also confirmed the above biological processes in Jurkat cells. Importantly, the presence of ciprofloxacin has been reported to lead to the loss of mtDNA28, 29 and an aneuploidy caused by the genotoxic stress of Jurkat cells30, 48. Genotoxic stress response has been shown to induce the release of nucleosomes by leukemic myeloid cells49. In the present study, mitochondrial damage of ciprofloxacin-exposed Jurkat cells has been evidenced by the abundance of mtDNA, and the nucleoid protein FEN1, as well as numerous other mitochondrial proteins in the secreted vesicles. Ciprofloxacin inhibits both the bacterial DNA gyrase and the mammalian topoisomerase II enzymes responsible for proper DNA replication50. Given that ciprofloxacin mainly inhibits the mitochondrial isoform of mammalian topoisomerase II29, its presence induces mtDNA fragmentation as well as subsequent gradual decrease in mtDNA content29.”

And also note that:

“We found that the exosomal DNA release-inducing effect was not solely observed in the case of Jurkat cells as we also detected ciprofloxacin-induced release of exofacial EV DNA in the case of the pancreatic cancer cell line MiaPaCa. These results demonstrate that DNA-associated EVs may be released from various types of cells after long-term ciprofloxacin exposure.”

These findings are interesting, and I think consequential and explanatory.

But, I am guessing that most people reading this need some more information about what the excerpts above mean. I know I did (and I had to read it about five times).

First, understanding “Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA” requires a little knowledge of what extracellular vesicles and exosomes are.

Extracellular vesicles (EVs) are “lipid bilayer-delimited particles that are naturally released from a cell and, unlike a cell, cannot replicate. EVs range in diameter from near the size of the smallest physically possible unilamellar liposome (around 20-30 nanometers) to as large as 10 microns or more, although the vast majority of EVs are smaller than 200 nm. They carry a cargo of proteins, nucleic acids, lipids, metabolites, and even organelles from the parent cell. Most cells that have been studied to date are thought to release EVs, including some bacterial, fungal, and plant cells that are surrounded by cell walls. A wide variety of EV subtypes have been proposed, defined variously by size, biogenesis pathway, cargo, cellular source, and function, leading to a historically heterogenous nomenclature including terms like exosomes and ectosomes.” (Source)

Exosomes are a subtype of extracellular vesicles. “Exosomes are best defined as extracellular vesicles that are released from cells upon fusion of an intermediate endocytic compartment, the multivesicular body (MVB), with the plasma membrane.” (Source) More information (that’s only basic if you have a heavy science background) about exosomes can be found in “Q&A: What are exosomes, exactly?

Basically, they’re molecules secreted from cells that affect other cells (sometimes positively, sometimes negatively).

Here’s a series of videos that give a really high-level, shiny and high-production-value explanation of exosomes and extracellular vesicles:

Additionally, here are some interesting tidbits about extracellular vesicles (EVs) and exosomes gathered from various articles:

“In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored.” (Source)

“EVs alone regulated the expression of numerous genes related to inflammation and signaling.” (Source)

“EVs are carriers of pathogen-associated and damage-associated molecular patterns, cytokines, autoantigens and tissue-degrading enzymes. In addition to a possible role in the pathogenesis of a number of inflammatory conditions, such as infections and autoimmune diseases, EVs, including microvesicles (also known as microparticles), exosomes and apoptotic vesicles, have therapeutic potential and might be used as biomarkers for inflammatory diseases.” (Source)

“another significant role of EVs has emerged in the removal of unwanted molecular material as a means for cell maintenance.” (Source)

“This report is the first show that numbers of blood-derived EVs are elevated in patients suffering from CFS/ME, indicating their potential involvement in disease pathogenesis. This promising finding may not only provide insights into the mechanisms involved in the disease but also shows that EVs may be useful for early diagnosis of illness. Moreover, isolation of circulating EVs coupled to our prototype for their detection by LFIA may constitute a powerful diagnostic tool, which can be performed in a single step and in minutes. We concluded that EVs may play a critical role in CFS/ME. Studies with larger sample size, outcome measures and different study designs (i.e. cross-sectional vs. longitudinal cohorts) are now urgently needed. These studies should stratify subgroups according to illness onset and progression, and assess patients at baseline and following induction of post-exertional malaise (PEM), using the 2-day cardiopulmonary exercise test (CPET).” (Source)

“Mast cells, being capable of both degranulation and subsequent recovery, have recently attracted substantial attention as also being rich sources of secreted extracellular vesicles (including exosomes and microvesicles).” (Source)

Both extracellular vesicles and exosomes contribute to processes that are related to many illnesses (including multi-symptom chronic illnesses like ME/CFS and autoimmune diseases, as well as cancer), as well as some of the processes behind those diseases such as inflammation, mast cell activation, cellular signaling and communication, etc. Neither extracellular vessicles nor exosomes are bad though – they are neither good nor bad. They are a natural function, and their relationship to these disease processes may be to spread the disease or prevent the disease, depending on many more factors than I can even begin to fathom.

I surmise and assume though, that removal and depletion of DNA from exosomes, is not a healthy or productive thing to do. And as this study showed, ciprofloxacin, and probably other fluoroquinolones, remove/deplete DNA from exosomes.

Can the removal of DNA from exosomes trigger inflammation? Can the depletion of DNA from exosomes change the inter-cellular communication in ways that trigger illnesses? Extracellular vesicles and exosomes are involved with the immune system, so can depletion of DNA from exosomes trigger immune dysregulation or autoimmune diseases? In depleting DNA from exosomes, does ciprofloxacin trigger disease? We know that ciprofloxacin can trigger multi-symptom chronic illness – is the depletion of exosomal DNA the mechanism through which it “floxes” people?

I don’t know the answers to those questions, and I doubt that the scientists who know much more about cellular processes than I do know those answers either. But “Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA” raises some really interesting questions, and provides some interesting and insightful links for those of us who are exploring what occurs in the body of a “floxed” person.

Sources*:

Nature, “Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA

BMC Biology, “Q&A: What are exosomes, exactly?

Journal of Extracellular Vesicles, “Biological properties of extracellular vesicles and their physiological functions

Cellular and Molecular Life Sciences, “Critical role of extracellular vesicles in modulating the cellular effects of cytokines.

Nature Reviews. Rheumatology., “Emerging role of extracellular vesicles in inflammatory diseases.

Journal of Extracellular Vesicles, “Circulating extracellular vesicles as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis: an exploratory pilot study

Seminars in Cell and Developmental Biology, “Mast cell secretome: Soluble and vesicular components.

*I found these sources through the post “Nature’s Quinolones: The 4Qs” on FluoroquinoloneThyroid.com – you should check it out – it’s great.

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Mitochondria, Neuropathy, HIV, and Fluoroquinolones

Mitochondria and Peripheral Neuropathy – Article out of Johns Hopkins

I highly recommend reading this article –

Feet First? Old Mitochondria Might Be Responsible For Neuropathy In The Extremities

It’s a fascinating article out of Johns Hopkins Medicine.

It goes over the connection between mitochondrial damage and peripheral neuropathy.

As an explanation as to how dysfunctional mitochondrial lead to peripheral neuropathy, the article notes that:

“He and his colleagues suspected that the reason (for peripheral neuropathy) might lie within mitochondria, the parts of cells that generate energy. While mitochondria for most cells in the body have a relatively quick turnover — replacing themselves every month or so — those in nerve cells often live much longer to accommodate the sometimes long journey from where a cell starts growing to where it ends. The nerve cells that supply the feet are about 3 to 4 feet long in a person of average height, Hoke explains. Consequently, the mitochondria in these nerve cells take about two to three years to travel from where the nerve originates near the spine to where it ends in the foot.”

Peripheral Neuropathy and HIV/AIDS

It is also noted in the Johns Hopkins article that peripheral neuropathy is “a condition that often accompanies other diseases including HIV/AIDS.”  I wonder, is peripheral neuropathy in HIV/AIDS patients caused by the disease, or the treatment for the disease?  In Mitochondria as a Target of Environmental Toxicants, it is noted that:

“Another example is the nucleoside reverse transcriptase inhibitors (NRTIs) that are used to combat human immunodeficiency virus (HIV) infection. NRTIs act by inhibiting the reverse transcriptase activity required for viral replication. They have been highly successful in treating adults and in preventing transmission of HIV from pregnant mothers to their children, but unfortunately many NRTIs also inhibit the mtDNA polymerase γ. This has resulted mtDNA depletion- and mutation-mediated mitochondrial toxicity, and even death, in patients and in animal models (Benhammou et al., 2007; Blanche et al., 1999; Chan, 2007; Claessens et al., 2003; Divi et al., 2010; Kohler and Lewis, 2007). Similar effects have been observed with nucleoside analogs intended for other viruses as well (McKenzie et al., 1995). Thus, chemicals that damage mtDNA or alter its copy number can have very serious health consequences.”

Pharmaceuticals and Mitochondrial Damage / Peripheral Neuropathy

I think that the article out of Johns Hopkins is great, and I greatly appreciate the research that has been done.  However, I suspect that the researchers missed an opportunity in not noting that drugs that deplete mitochondrial DNA are responsible for many cases of mitochondria related peripheral neuropathy.

The damage to mitochondria done by NRTIs is well documented.

Other drugs, including fluoroquinolone antibiotics – Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and Floxin/ofloxacin – are also well-documented as being destructive to mitochondria AND causing peripheral neuropathy.

In the article, Calcium Signals Are Affected by Ciprofloxacin as a Consequence of Reduction of Mitochondrial DNA Content in Jurkat Cells, it is noted that ciprofloxacin, a fluoroquinolone depletes mitochondrial DNA content.  It is also noted in the article, Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells, that ciprofloxacin treated cells show a loss of mitochondrial DNA.

Though Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells was published in 1996, it was not until 2013 that the FDA added the risk of permanent peripheral neuropathy to the warning labels for fluoroquinolones.   The case study, Permanent Peripheral Neuropathy: A Case Report on a Rare but Serious Debilitating Side-Effect of Fluoroquinolone Administration illustrates the severity of peripheral neuropathy brought on by (the mitochondrial damage done by) fluoroquinolones.

It is also noted in the FDA’s April 27, 2013 Pharmacovigilance Review, “Disabling Peripheral Neuropathy Associated with Systemic Fluoroquinolone Exposure,” that the mechanism for action through which fluoroquinolones induce peripheral neuropathy is mitochondrial toxicity. The report says:

“Ciprofloxacin has been found to affect mammalian topoisomerase II, especially in mitochondria. In vitro studies in drug-treated mammalian cells found that nalidixic acid and ciprofloxacin cause a loss of motichondrial DNA (mtDNA), resulting in a decrease of mitochondrial respiration and an arrest in cell growth. Further analysis found protein-linked double-stranded DNA breaks in the mtDNA from ciprofloxacin-treated cells, suggesting that ciprofloxacin was targeting topoisomerase II activity in the mitochondria.”

Conclusion

I really do appreciate the research described in Feet First? Old Mitochondria Might Be Responsible For Neuropathy In The Extremities.  Experiments, analysis and scientific documentation are needed.  But synthesis of existing information is needed too.

Drugs that deplete mitochondrial DNA are leading to peripheral neuropathy.  Perhaps the Johns Hopkins study is the piece of the puzzle that is missing from widespread recognition of this.

We shall see.

Study Finds that Ciprofloxacin Depletes Mitochondrial DNA

DNA replication fluoroquinolone Topoisomerase Interrupter

This post contains quotes from the article “Delayed Cytotoxicity and Cleavage of Mitochondrial DNA in Ciprofloxacin-Treated Mammalian Cells” that was published in Molecular Pharmacology in 1996.  It’s a good article.  It’s an interesting and damning article.  It’s a difficult article.  It would be nice if more people read it, and I wish that its implications were better understood and explored by research scientists and regular people alike.

Direct quotes from the article are in bold and italicized.  My commentary follows each quote.

“The loss in mtDNA was associated with a delayed loss in mitochondrial function. Here, we report that the 4-quinolone drug ciprofloxacin is cytotoxic to a variety of cultured mammalian cell lines at concentrations that deplete cells of mtDNA.”

Ciprofloxacin depletes mitochondrial DNA in mammalian cells.  It’s right there in black and white.  I have no idea why it didn’t strike anyone as alarming when it was published in 1996.  It sure is alarming now.

It should be noted that, “There is indeed experimental evidence that prolonged injury to mitochondria, such as that which typifies oxidative injury to mitochondrial DNA or to components of the electron transport chain (ETC), has to cross a certain threshold (or a number of thresholds) before cell damage or cell death becomes manifest.” (source)  And that mitochondrial damage is linked to “symptoms such as fatigue, muscle pain, shortness of breath, and abdominal pain can easily be mistaken for collagen vascular disease, chronic fatigue syndrome, fibromyalgia, or psychosomatic illness.” (source)  Mitochondrial dysfunction has been linked to multiple diseases of modernity including autoimmune diseases, neurodegenerative diseases, autism and “mysterious” diseases such as fibromyalgia and ME/CFS.

Also, as I’ve pointed out before, the FDA has noted in their internal documents that fluoroquinolones are toxic to mitochondria, and that mitochondrial damage is linked to many diseases, including neurodegenerative diseases.  More information about that can be found in the post, “FLUOROQUINOLONE ANTIBIOTICS DAMAGE MITOCHONDRIA – FDA DOES LITTLE

“Resistance was not due to a decrease in cellular drug accumulation, suggesting that ciprofloxacin cytotoxicity is caused by the loss of mtDNA-encoded functions.  Analysis of mtDNA from ciprofloxacin-treated cells revealed the presence of site-specific, double-stranded DNA breaks.”

Consequences?  Implications?  What happens when cytotoxicity is induced by DNA breaks?

“These results suggest that ciprofloxacin may be causing cytotoxicity by interfering with a mitochondrial topoisomerase Il-like activity, resulting in a loss of mtDNA.”

Many assert that fluoroquinolones only affect bacterial topoisomerases.  It turns out that mitochondrial topoisomerases are affected too.  Fluoroquinolones should be used as prudently and cautiously as all other topoisomerase interrupting drugs.  All the other topoisomerase interrupting drugs are chemo drugs that are only used to treat cancers.  To prescribe a drug that depletes mitochondrial DNA and affects human topoisomerases in order to treat urinary tract infections and traveler’s diarrhea is absurd, short-sighted and wrong.

It should also be noted that, “Our data suggest that chemicals or genetic mutations that impair topoisomerases, and possibly other components of the transcription elongation machinery that interface with topoisomerases, have the potential to profoundly affect expression of long ASD (autism spectrum disorder) candidate genes. Length-dependent impairment of gene transcription, particularly in neurons and during critical periods of brain development, may thus represent a unifying cause of pathology in many individuals with ASD and other neurodevelopmental disorders.” (source)

The team of scientists who wrote that last quote are looking at whether or not fluoroquinolones turn on genes that are related to autism.  The results of their exploration have not yet been published.

What is known though, is that topoisomerases are really important.  Duh–they’re the enzymes responsible for proper DNA and RNA replication—did someone think they were optional?  Interrupting topoisomerases with drugs is a really, really, really bad idea.

“Studies have also suggested that 4-quinolones may interfere with cell growth by inhibiting mammalian mtDNA replication (6, 11). Castora et al. (11) found that the 4-quinolone drugs nalidixic acid and oxolinic acid inhibited mtDNA replication in isolated rat liver mitochondria. These investigators inferred that this effect might be mediated by the inhibition of a mitochondrial topoisomerase II activity related to the bacterial enzyme DNA gyrase.”

Naladixic acid is the backbone of all fluoroquinolone antibiotics.  The quote speaks for itself.

 “We recently demonstrated that the 4-quinolone drugs nalidixic acid and ciprofloxacin cause a selective loss of mtDNA in drug-treated mammalian cells (6). The loss of mtDNA was associated with a decrease in mitochondrial respiration and an arrest in cell growth. These results suggested that inhibition of mammalian cell proliferation by 4-quinolone drugs might be caused by the selective depletion of mtDNA, resulting in compromised mitochondrial activity. We now report that ciprofloxacin causes a delayed cytotoxicity in cultured mammalian cells at concentrations that deplete cells of mtDNA.”

DELAYED CYTOTOXICITY!  When someone says that you “shouldn’t” be experiencing an adverse reaction to a fluoroquinolone weeks, months or even years after you took the drug, show them this.  Delayed cytotoxicity and mtDNA depletion–they’re right there.  Fluoroquinolones are NASTY drugs.  Why they are used frivolously is beyond my comprehension.

“We previously demonstrated that ciprofloxacin induces a selective depletion of mtDNA in mammalian cells. The depletion of mtDNA preceded a decrease in mitochondrial respiration and cell growth, suggesting that mtDNA was a primary target of drug action (6). Studies have recently shown that some cultured mammalian and avian cells can survive in the absence of mtDNA-encoded functions if the growth medium is supplemented with pyrimidines, pyruvate, and elevated concentrations of glucose (21-23). Cells deficient in mtDNA rely exclusively on glycolysis for energy.”

Hmmmmm…. So do our cells need/want more glucose??

And, again, I’d like to point out the clearly stated, “ciprofloxacin induces a selective depletion of mtDNA in mammalian cells.”

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“The apparent decrease in mtDNA cleavage at higher drug concentrations is reminiscent of the effect of DNA intercalating anticancer drugs on nuclear topoisomerase II enzymes (29, 30). Intercalating anticancer drugs such as 2-methyl-9-hydroxyellipticinium and Adriamycin have been shown to stimulate topoisomerase II cleavage at low concentrations but inhibit cleavage at high drug concentrations.”

Fluoroquinolones are chemo drugs.  All topoisomerase interrupters are chemo drugs.  Don’t give people chemo drugs to treat sinus infections.  It’s not a difficult notion.

http://www.collective-evolution.com/2014/10/15/fda-allows-chemo-drugs-prescribed-antibiotics/

http://www.hormonesmatter.com/cipro-levaquin-avelox-fluoroquinolones-chemo-drugs/

“The non-exonuclease-treated DNA contained both linear and nicked circular forms of mtDNA but did not contain closed circular supercoiled mtDNA (Fig. 8, lane A), suggesting that ciprofloxacin induces single- as well as double stranded protein-linked breaks in the mtDNA.”

Thanks for breaking my DNA, Bayer.

“The current results indicate that ciprofloxacin is not cytotoxic unless cells are continuously exposed to drug for a minimum of three or four cell doublings. In comparison, drugs that target nuclear topoisomerase II trigger an apoptotic type of cell killing, even after a short 2-hr drug exposure.”

Interesting.  What is the time-frame for cell doubling?  And I don’t think that the question has been definitively answered as to whether or not fluoroquinolones are stored in lipids, continuously exposing cells to damage, or not.

“Another possibility is that the growth inhibitory and cytotoxic effects of ciprofloxacin are caused by the inhibition of an essential mitochondrial function or functions. This is supported by the following observations: First, treatment of mammalian cells with ciprofloxacin results in a selective depletion of mtDNA, leading to a decrease in mitochondrial respiration (6). These mitochondrial events precede the drug induced loss in cell growth and viability (Ref. 6 and current results). Second, cells become resistant to ciprofloxacin when they are grown under conditions that do not require mtDNA encoded functions. Third, ciprofloxacin induces the formation of site-specific, protein-linked breaks in mtDNA, indicating the presence of a drug-sensitive mitochondrial topoisomerase Il-like activity.”

Given the connections between ciprofloxacin and mitochondrial damage–depleting mtDNA and decreasing mitochondrial respiration, and the connections between mitochondrial damage and multiple chronic, multi-symptom illnesses, it is not absurd to make the assertion that ciprofloxacin, and other fluoroquinolones, can cause those diseases (autoimmune diseases, neurodegenerative diseases, fibromyaligia, autism, ME/Chronic Fatigue Syndrome, etc.).

The article, “Mitochondria Resuscitation: The Key to Healing Every Disease” by Chris D. Meletis, N.D. is a succinct and illustrative look at how mitochondria are related to multiple areas of health.

It’s nice and dandy that “cells become resistant to ciprofloxacin when they are grown under conditions that do not require mtDNA encoded functions” but human beings don’t have a bunch of cells that live in petri dishes that can grow without requiring our mitochondrial DNA functions.  I wonder what happens when human cells attempt to adapt to resist ciprofloxacin and adapt by ceasing to require mtDNA encoded functions.  I bet you a buck that no one knows the answer to that question.

Cipro breaks mitochondrial DNA.  WHY WASN’T THIS REPORT PAID ATTENTION TO?  All of the results in it warrant fluoroquinolones being taken off of the market until further investigation can be done.  This is absurd.  I know that there are cases where fluoroquinolones can save lives, I get that, and I’m usually decently reasonable about not calling for their removal from the market.  But this article spooked me severely.  We, collectively, have NO CLUE what the consequences of depleting our mitochondrial DNA are.

“Neither cell growth nor viability seems to be affected until cells have undergone three or four cell doublings in the presence of ciprofloxacin (Ref. 6 and current results). During this time span, the content of mtDNA decreases >90%, suggesting that drug is causing a loss in cell growth and viability by interfering with mtDNA replication.”

Nasty drugs – but if you metabolize them fast enough, they’re less nasty – apparently.

“Ciprofloxacin, as well as several other 4-quinolone drugs, can cause significant unwinding of DNA”

It’s what they’re designed to do.  They’re topoisomerase interrupters.  The mechanism of action for ciprofloxacin is, “The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.” (source)  It doesn’t take a rocket scientist to realize that drugs that inhibit the DNA and RNA replication, transcription, repair and recombination are dangerous.  I hate the FDA for allowing these dangerous drugs to be used as antibiotics.  It’s ludicrous.

Delayed Cytotoxicity and Cleavage of Mitochondrial DNA in Ciprofloxacin-Treated Mammalian Cells” is not a hopeful article.  It is, frankly, a terrifying article.  More than 20 million prescriptions for fluoroquinolones are given out in Americans each year for the last couple decades, and that’s only a small portion of the prescriptions given worldwide.  What have we done to our collective mitochondrial DNA??  What are the consequences of depleting our mitochondrial DNA?  No one knows the answers to those questions.

Anyone who thinks that people aren’t sick with the diseases related to mitochondrial poisoning, isn’t looking very hard.  People are sick.  They’re in pain (peripheral neuropathy is thought to be caused by mitochondrial malfunctions), they’re depressed and suffering from even worse psychiatric disorders, they have heart conditions and metabolic disorders (source), ME/Chronic Fatigue Syndrome, autism, and many other misunderstood, chronic illnesses.  There are many potential culprits for the sorry state of human health in the 21st century, but fluoroquinolones aren’t even on the list according to most people.

FLUOROQUINOLONES DEPLETE MITOCHONDRIAL DNA, LEAD TO MITOCHONDRIAL DYSFUNCTION AND ALSO OBLITERATE THE MICROBIOME!

I’ll keep screaming it until I’m heard.

Back in 1992 it was noted that, “the interaction (of fluoroquinolones) with DNA is still of great concern because of the possible long-term genotoxicity of quinolone compounds, which are increasingly adopted as first-choice antibiotics for the treatment of many infections, and because it addresses the real mechanism of action of this class of molecules.”  (source)

I really wish that these warnings had been heeded.  Sadly, they’ve been ignored.

Our poor mitochondrial DNA.  I hope that mtDNA recovers and that the situation isn’t as dire as I suspect.  But the truth is, no one knows.  No one has a clue what the consequences of depleting mtDNA through unnecessary use of topoisomerase interrupting drugs are.

Floxies certainly know that the consequences of fluoroquinolones can involve a massive amount of pain and suffering.  It’s not okay.

Bayer, Johnson & Johnson, the FDA and everyone else involved with frivolously prescribing these drugs should be ashamed of themselves for failing to protect our mitochondrial DNA.  Topoisomerase interrupters should never have been approved for use as antibiotics.  It’s simply absurd.

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Your Mighty Mitochondria

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Fun facts – Nalidixic acid, the chemical compound that is the base of all fluoroquinolones, was discovered in 1962. Mitochondrial DNA was discovered in 1967 (by Lynn Margulis who happened to be married to Carl Sagan). So, if you are under the impression that naladixic acid was tested for its affects on mitochondrial DNA, you would be wrong. Information regarding how mitochondria affect gene expression is being uncovered… um… now-ish. So, in the 30+ years that fluoroquinolones have been pushed, they have been used by the human population with zero knowledge of how they affect gene expression (both mitochondrial and nuclear). Gene expression, as you might imagine, is important.

More information can be found in this post, “Your Mighty Mitochondria” published on Hormones Matter:

http://www.hormonesmatter.com/mighty-mitochondria/

 

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Is FQ Induced Insomnia an Autoimmune Problem?

In the December 9, 2013 issue of The New Yorker, there was an article by Ian Parker entitled “The Big Sleep” about Merck’s new sleeping pill called Suvorexant.  The article is interesting and I recommend that you check it out – http://www.newyorker.com/reporting/2013/12/09/131209fa_fact_parker

There were a couple of things that I found to be of interest in the article, from a Floxie perspective.

First, Parker noted that, “In narcoleptic humans, the cells that produce orexin have been destroyed, probably because of an autoimmune response.”  This is a really interesting assertion/finding.  Narcolepsy may be an autoimmune response/dysfunction/disease.  I wonder if insomnia is also an autoimmune response/dysfunction/disease.  I wonder if the cells that produce orexin (“Orexin neurotransmitters, first identified fifteen years ago, promote wakefulness.”) are over-stimulated in some Floxies, hence the horrible insomnia that some people suffer from.  Or, another possibility is that an autoimmune response in Floxies destroyed the cells that produce melatonin, or other hormones/neurotransmitters that are necessary to induce sleep.

My thinking at this time (subject to change with the introduction of more information), is that much of floxing is an autoimmune response/dysfunction/disease that results from a loss of mitochondrial DNA (mtDNA) from lymphocytes (immune system cells).  Here are some articles on the effects of fluoroquinolones on lymphocytes:

Perhaps, if the insomnia that Floxies suffer from is an autoimmune response of some sort, a pill that is an orexin antagonist, like Suvorexant, can help relieve, or even cure their insomnia.

The experience of getting floxed has made me VERY averse to pharmaceuticals (I intend to never take a drug again).  I empathize with anyone who is wary of trying a new drug.  But insomnia is horrible and when these orexin antagonist drugs are released into the market, if any Floxies are willing to try it, please let me know how it works for you.

Insomnia is one of those disorders that is easy to blame on the victim.  It is thought that everyone should be able to simply turn their mind off and sleep.  If it turns out that insomnia is an autoimmune response/dysfunction/disease, perhaps it will be recognized that, a) sleeping is not a simple condition to treat, and, b) a lot of people have autoimmune dysfunction and disease.  If even 10% of insomniacs are suffering from insomnia because of autoimmune dysfunction, the number of people with autoimmune problems is significantly larger than it is thought.  What could cause so many people (those with official autoimmune diseases, narcoleptics, insomniacs and those with chronic mysterious diseases like fibromyalgia) to have malfunctioning lymphocytes?  FLUOROQUINOLONES!  The articles above go into more detail and actually build a case, and there are more to be found on the internet and in the library (search for “fluoroquinolone or ciprofloxacin and lymphocytes”).  There are probably other factors at work too, but the role that fluoroquinolones play in inducing dysfunctional lymphocytes is large and it has been systematically overlooked.

The other interesting point in the article was this:

“In a recent paper in the online edition of the British Medical Journal, Daniel Kripke, a professor emeritus at the University of California San Diego School of Medicine, examined five years of electronic medical records collected by a health system in Pennsylvania. He compared more than ten thousand patients who had been prescribed a sleep medicine—most commonly Ambien—and more than twenty thousand patients who had not. After adjusting for age, gender, smoking habits, obesity, ethnicity, alcohol use, and a history of cancer, and after controlling, as much as possible, for other diseases and disorders, Kripke found that people who had taken sleeping pills were more than three times as likely to have died during the study period as those who had not. Those on higher doses of the drugs were more than five times as likely to have died.”

I wonder if Dr. Kripke could do an analysis of health outcomes among people who have taken fluoroquinolones versus those who have taken other kinds of antibiotics (or no antibiotics).  I would bet quite a bit of money that those who have taken a fluoroquinolone are significantly more likely to be diagnosed with an autoimmune disease, fibromyalgia, chronic fatigue syndrome, insomnia, leaky gut syndrome, lymphoma, etc. and that they are more likely to have children with autism, ADD, ADHD, allergies, etc.  I’m going to write him a letter requesting that he look into doing a study of health outcomes for people who take fluoroquinolones.  It can’t hurt to ask.  Besides, he’s a colleague of Dr. Beatrice Golomb, who is conducting the UCSD Fluoroquinolone Effects Study.  Dr. Golomb will almost certainly have enough evidence to conclusively show that Gulf War Syndrome was caused by Cipro soon.  When that news is released to the public, people will want to know what the consequences of 20+ million prescriptions for fluoroquinolones being given to American civilians each year for the past two decades has done to human health.  If Dr. Kripke is prepared with the answer, maybe this ridiculousness of prescribing fluoroquinolones for any situation other than a life-threatening emergency will stop.

 

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Conflicting Study Results: Do DNA Breaks Hold Answers?

There is a lot of conflicting information about fluoroquinolone antibiotics (Cipro, Levaquin, Avelox, Floxin and a few others) noted in scientific journals.  One study will conclude one thing about how fluoroquinolones effect human cells and another study will reach the opposite conclusion.  It’s frustrating for everyone involved and it leads to the conclusion, that is also noted in most journal articles about fluoroquinolones, that, “Despite their widespread application, the exact mechanism of action of the quinolones is not fully understood.” (1)  Despite the fact that the exact mechanism of action of fluoroquinolones is unknown, shouldn’t some of the details of their effects on human cells be known?  Shouldn’t there be some clarity in how these drugs affect cells, if not how they work or sometimes don’t work?  Basic, verifiable, answers are sought, but they remain elusive.  Some interesting, and possibly useful, information may be found in examining why clear answers are so difficult to obtain.

Shouldn’t it be testable whether fluoroquinolones increase or decrease levels of Reactive Oxygen Species (ROS)?  Shouldn’t the question of whether fluoroquinolones increase or decrease cellular inflammation be verifiable?  Shouldn’t Scientists know whether fluoroquinolones activate or inhibit t-cell gene expression?  These things can be studied in laboratories.  Answering these questions doesn’t require long-term studies, surveys that are subject to interpretation or vague definitions.  They should be answerable questions and the answers should be clear.  It’s science, not philosophy.  The answers should be black or white, yes or no, not shades of grey.

Yet with each of these questions there are multiple conflicting reports.  No one seems to be able to consistently verify what happens to human cells when they are exposed to fluoroquinolones.  Some studies done by well-run institutions and published in reputable journals say that fluoroquinolones decrease ROS, reduce inflammation and inhibit t-cell gene expression (2).  Other articles in equally well-respected journals say the opposite (3, 4, 5, 6).  So which is true?  Does the arrow go up or down?  I’m sure that answering these questions isn’t easy, but they should be answerable and the answers should be the same each time an experiment is done, right?

So why are there differing answers?  Why can’t Scientists, many of whom are undoubtedly brilliant and capable, figure this out?  A couple of possible answers are that one group of Scientists’ methods are wrong, or that cells react differently to fluoroquinolones with each exposure.  Both possibilities are fascinating on some level.  If the methodologies of one group of Scientists produce an anti-inflammatory response within cells, but the methodologies of another group of Scientists produce an inflammatory response within cells, perhaps the difference in methodologies holds the key to limiting an inflammatory response in living humans.  A cure, or an antidote to the inflammation that is definitely experienced by some people having an adverse reaction to fluoroquinolones, may be revealed from the study methodologies in which an anti-inflammatory response was induced/observed.

An even more interesting possibility is that how cells react to fluoroquinolones depends on which strand of DNA the quinolone molecules attach to.  Studies have found that fluoroquinolones form a poisonous adduct to DNA (7, 8).  Perhaps the reaction of the cell in response to exposure to fluoroquinolones depends on which DNA strands are broken, where they’re broken and where the quinolone molecule attaches to the DNA.  It is plausible that there are some places where DNA could be broken and adducted to that would create an inflammatory response and there are other places where DNA could be broken and adducted to that would create an anti-inflammatory response.  I have neither the tools nor the expertise to test this hypothesis, but from the perspective of someone who has been studying adverse reactions to fluoroquinolones for the past 2 years, the notion that fluoroquinolones break and attach to DNA makes sense of many perplexing aspects about fluoroquinolone toxicity.  If we assume that DNA breaks and quinolone adduction to DNA is behind adverse reactions to fluoroquinolones, the following questions may have the following answers:

Why are some people adversely affected by fluoroquinolones while others aren’t?  Potential answer – some people have important strands of DNA affected while other people have unimportant strands of DNA affected.  And/Or, some people have DNA affected that triggers and inflammatory response and the over-production of ROS, while others don’t because their DNA is broken in less consequential spots.

Why could I handle Cipro for 3 prescriptions but the 4th prescription hurt me?  Potential answer – the Cipro affected inconsequential strands of DNA the first 3 times it was administered, but it damaged an important strand of DNA the 4th time it was administered.

Why did I experience a delayed adverse reaction to Levaquin?  Potential answer – it takes time for damaged DNA to replicate.

Why can’t anyone seem to figure out how these drugs work?  Potential answer – because the human genome is not fully mapped out and most Researchers aren’t looking at how fluoroquinolones affect DNA.

I’m not a Scientist.  I certainly could be wrong about the above hypothesis.  But I do find it both frustrating and interesting that Scientists, who are undoubtedly smarter than I am, can’t seem to figure out some basic facts about how fluoroquinolones work.  I think that there are some answers in their inability to find clear answers.  I suspect that the answers lie in quinolone adducts to DNA.  Perhaps someone with the tools to determine whether I’m right or wrong will design an experiment (that is consistently verifiable) to determine the effects of fluoroquinolones on DNA, and to determine whether or not DNA damage results in differing effects of the drugs.

Sources:

  1. Inorganic Chemistry, “New uses for old drugs: attempts to convert quinolone antibacterials into potential anticancer agents containing ruthenium.
  2. The Journal of Immunology, “Mitochondrial Reactive Oxygen Species Control T Cell Activation by Regulating IL-2 and IL-4 Expression:  Mechanism of Ciprofloxacin Mediated Immunosuppression
  3. The Tohoku Journal of Experimental Medicine, “Fluoroquinolone Induced Tendinopathy: Etiology and Preventative Measures
  4. Nepal Medical College Journal, “Genotoxic and cytotoxic effects of antibacterial drug, ciprofloxacin, on human lymphocytes in vitro”
  5. Journal of Young Pharmacists, “Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients
  6. Science Translational Medicine, “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells
  7. The Journal of Biological Chemistry, “The Mechanism of Inhibition of Topoisomerase IV by Quinolone Antibacterials.”
  8. Proceedings of the National Academy of Sciences of the United States, Biochemistry, “Quinolone Binding to DNA Mediated by Magnesium Ions”

 

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