Tag Archives: DNA

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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New Study Finds that Ciprofloxacin Depletes Mitochondrial DNA

An excellent article about the effects of ciprofloxacin (a fluoroquinolone antibiotic) on mitochondrial DNA was recently published in the journal, Nucleic Acids Research. The article, Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2, by Anu Hangas, Koit Aasumets, Nina J Kekäläinen, Mika Paloheinä, Jaakko L Pohjoismäki, Joachim M Gerhold, and Steffi Goffart, gives a great amount of insight into the damage that ciprofloxacin does to mitochondria, and I recommend that you read it (linked through the article title). I’m going to go over the article in this post, and point out some of the more interesting findings.

First, a bit of background information to help readers to understand the article.

Mitochondria are the energy centers of our cells. There are over ten million billion mitochondria in the human body (Lane p. 1). Each cell (with a few exceptions) contains an average of 300-400 mitochondria that are responsible for generating cellular energy through a process called ATP (Adenosine Triphosphate). Mitochondria regulate energy production, aging, epigenetic signaling between and within cells and many other important functions. Proper functioning of mitochondria is vital, and when mitochondria are not operating properly, a wide range of disease states can ensue (2).

Mitochondria have their own DNA (mtDNA) that is separate from (though it interacts with) nuclear DNA. The structure of mtDNA is similar to that of bacterial DNA, and it is widely thought that mitochondria descended from ancient bacteria. The similarities between bacteria and mitochondria should make everyone take pause to think about how antibiotics of all kinds are affecting mitochondrial health. This post, and the article that it is based on, only focuses on the effects of ciprofloxacin, a fluoroquinolone antibiotic, on mitochondrial health, but if you want to read about the effects of other antibiotics on mitochondria, the article “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells” is a great place to start.

There are enzymes in our cells called topoisomerases. According to the wikipedia article for topoisomerase:

Topoisomerases are enzymes that participate in the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double-helical structure. During DNA replication and transcription, DNA becomes overwound ahead of a replication fork. If left unabated, this torsion would eventually stop the ability of DNA or RNA polymerases involved in these processes to continue down the DNA strand.

In order to prevent and correct these types of topological problems caused by the double helix, topoisomerases bind to DNA and cut the phosphate backbone of either one or both the DNA strands. This intermediate break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed again. Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their global topology, resulting in the name for these enzymes. Topoisomerases are isomerase enzymes that act on the topology of DNA.[1]

Bacterial topoisomerases and human topoisomerases proceed via similar mechanisms for managing DNA supercoils.

The mechanism of action for all fuoroquinolones is that they are topoisomerase interruptors. The FDA warning label for ciprofloxacin states that 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.”

Here is a video that describes how fluoroquinolones work, and how they interrupt topoisomerase and thus interrupt the process of bacterial (and mitochondrial, as we shall discuss below) DNA replication.

I have argued, and I believe, that EVERY drug that is a topoisomerase interruptor, should be thought of as a chemotherapy drug. All other topoisomerase interrupting drugs ARE chemo drugs. But fluoroquinolones are thought of as antibiotics, and handed out as if they are inconsequential. They are extremely consequential though, and they are hurting too many people. More information on fluoroquinolones being chemo drugs can be found in the post, “Cipro, Levaquin and Avelox are Chemo Drugs.”

Now to highlight some of the important parts of Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2.

The abstract of the article, Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2, notes that:

“Loss of Top2β or its inhibition by ciprofloxacin results in accumulation of positively supercoiled mtDNA, followed by cessation of mitochondrial transcription and replication initiation, causing depletion of mtDNA copy number. These mitochondrial effects block both cell proliferation and differentiation, possibly explaining some of the side effects associated with fluoroquinolone antibiotics.”

When you look into the multiple roles of mitochondria–from controlling cellular energy production to aging, and the links between mitochondrial damage and various multi-symptom chronic illnesses (from ME/CFS to autism to autoimmune diseases), yes, most definitely, the damaging effects of fluoroquinolones on mitochondria can certainly explain many, if not all, of the side effects associated with fluoroquinolone antibiotics.

The study found that, “In agreement with the in vitro assay, also HeLa cells treated with ciprofloxacin or doxorubicin rapidly accumulated supercoiled mtDNA (Figure 3A).”

This accumulation of supercoiled mtDNA led to a “change in topology” of the mitochondria, and a depletion of the mitochondrial DNA. Per the article:

“The change in topology caused by the inhibition of mitochondrial Top2 was connected with an impairment of mtDNA replication. 7S DNA, the 650bp ssDNA strand incorporated at the D-loop region of mtDNA, was rapidly depleted upon ciprofloxacin, ethidium bromide and doxorubicin treatment.”

Ciprofloxacin treatment not only depleted mtDNA, it also inhibited mtDNA synthesis:

“ciprofloxacin treatment reduced mtDNA copy number by 18% within 3 days (Figure 3C). As at the same time the growth rate of ciprofloxacin-treated cells was strongly reduced doubling time 170.2 h versus 22.7 h in untreated controls (Supplementary Figure S4), the observed depletion reflects a nearly complete inhibition of mtDNA synthesis.”

Ciprofloxacin treatment, and the resulting supercoiled mtDNA, also stalled mtDNA replication.

“Ciprofloxacin caused a strong reduction in these intermediates already after 2 h treatment (Figure 3E). After 20 h, this effect was clearly enhanced, with the strand-asynchronous intermediates being replaced by strand-coupled replication intermediates, a hallmark of mtDNA replication stalling (25,31–33).”

It was also found that ciprofloxacin inhibited the increase of mtDNA that typically comes with building muscle. It was found that:

“The impairment of mtDNA maintenance by ciprofloxacin not only disturbed cellular proliferation and the physiological increase of mtDNA copy number during muscle maturation, it also effectively impaired the fusion of confluent myoblasts to multinuclear myotubes (Figure 4E) and cell differentiation as indicated by the reduced expression of the heavy chain of Myosin II, a marker of differentiated skeletal muscle (Figure 4F).”

In the paragraph that the above quote was taken from, it was stated that “This increase (of mtDNA when muscle matures) was completely abolished by ciprofloxacin.” I’ve said it multiple times before, but, again, fluoroquinolones should NEVER be given to athletes (or anyone who values their ability to move, or have their heart beat).

In the article’s discussion section, this summary of the demonstrated damage done by ciprofloxacin was given:

“Ciprofloxacin caused a dramatic effect on mtDNA topology, blocking replication initiation, reducing copy number and inhibiting mitochondrial transcription (Figures 2B3AE and 4A). Ciprofloxacin, the third most commonly used antibacterial antibiotic, stops the cleavage/re-ligation reaction of type II topoisomerases midway, generating double-strand breaks, persistent protein–DNA adducts and reduces also the overall enzyme activity (30). Its toxicity to mitochondria has been reported in various studies, suggesting a broad range of mechanisms including topoisomerase inhibition, oxidative stress, altered calcium handling and photosensitization (38–40). In our study, we observed ciprofloxacin to clearly reduce Top2 topoisomerase activity both in vitro and in vivo, but did not find any indication of increased mtDNA double-strand breaks (Figure 3AC). However, ciprofloxacin did impair the overall mtDNA integrity in post-mitotic cells (Figure 4D). As our detection method (long-range PCR) does not distinguish between strand-breaks, abasic sites or base alterations inhibiting Taq polymerase, the observed effect might be caused by oxidative damage, which fluoroquinolones have been reported to induce in a variety of cell types (41,42).”

And the study’s authors also surmise that many of the severe adverse effects of fluoroquinolones are due to the depletion of mtDNA caused by the drugs:

“The severe side effects of ciprofloxacin and other fluoroquinolones include tendinopathies such as tendon rupture, joint inflammation, muscle weakness, central and peripheral neuropathies, epilepsy and psychological symptoms such as depression. These symptoms have been proposed to be connected to enhanced oxidative stress (42,54,55), but the molecular mechanism remained unclear. The reduction of mtDNA copy number and mitochondrial transcription caused by the altered topology of mtDNA might result in severe dysregulation of the electron transport chain complexes, as known to occur under ciprofloxacin treatment (56), lead to respiratory chain dysfunction and cause the observed enhanced oxidative stress.

Ciprofloxacin has also been reported to interfere with physiologically significant cell differentiation processes, such as spermatogenesis (57), brain development (41), bone mineralization (58), as well as to induce renal toxicity and heart arrhythmia (59). While the molecular mechanisms of these adverse effects are yet unclear, mitochondria play a central role in all of these physiological processes, making mitochondrial impairment a likely culprit for the disturbed cellular physiology.”

Throughout the article, the effects of ciprofloxacin are compared to the effects of another topoisomerase interrupting drug, doxorubicin. Per its wikipedia post, Doxorubicin “is a chemotherapy medication used to treat cancer.[3] This includes breast cancer, bladder cancer, Kaposi’s sarcoma, lymphoma, and acute lymphocytic leukemia.” The authors of Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2 noted that, “Interestingly, doxorubicin had a similar, but milder inhibitory effect on mtDNA replication than ciprofloxacin.” Why, yes, it is interesting that a drug that is marketed and dispensed as an antibiotic is more damaging than a similar drug that is marketed and dispensed as a chemotherapy drug. It’s very interesting indeed. It is also interesting that another topoisomerase interrupting chemotherapeutic drug, topotecan, was found to increase the expression of genes related to autism (“Topoisomerases facilitate transcription of long genes linked to autism“).

The Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2, authors conclude their article with two points. First, that very little is known about the consequences of mtDNA supercoiling. “Although central in bacterial genome maintenance, the whole phenomena of DNA supercoiling and its functional implications are virtually unstudied in mitochondria and calls for future research.” Yes, future research is needed, and better late than never. But nalidixic acid, the backbone of all fluoroquinolone antibiotics, was first used clinically in 1967. Shame on the medical and scientific communities for not studying the effects of fluoroquinolones on mtDNA earlier. We should have known more about the consequences of these drugs long before millions of prescriptions had been doled out, and millions of people affected.

Second, the authors of Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2 conclude by stating, “As fluoroquinolone antibiotics are widely used and effective drugs against a number of important bacterial pathogens, their dosage, systemic enrichment and side-effects should be reviewed in the mitochondrial context, and their clinical use should be considered with great care.” Yes, indeed, the effects of fluoroquinolones on mitochondria should be given long, hard, thoughtful consideration by every doctor, pharmacist, scientist, and every relevant person in the FDA and other regulatory agencies.

Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2 is an eye-opening article with groundbreaking research. Yes, more research needs to be done. But the research that has been done, that is described in the article, is greatly appreciated. Thank you to all the authors – Anu Hangas, Koit Aasumets, Nina J Kekäläinen, Mika Paloheinä, Jaakko L Pohjoismäki, Joachim M Gerhold, and Steffi Goffart.

 

Fluoroquinolone Antibiotics Increase Risk of Birth Defects

A few years ago, a friend from high school who was in her second trimester of pregnancy with her second child, reached out to me to ask me what antibiotics she should avoid. She had pneumonia, and was on her way to the doctor’s office. I told her that she should steer clear fluoroquinolones (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, and Floxin/ofloxacin).

Being an empowered and skeptical person, my friend didn’t just take my word for it that fluoroquinolones were dangerous, she did her own research and noted that the warning label for Cipro/ciprofloxacin stated:

Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. CIPRO should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.2

With that information in-hand, she was empowered to adamantly refuse the prescription for Cipro that her doctor wanted to give her, and instead insisted that she get a prescription for a safer antibiotic (a pregnancy category B antibiotic).

I was relieved beyond words when she told me that she had refused the Cipro prescription. She wasn’t going to get floxed, and whatever effects the Cipro may have had on her baby were avoided.

Study Indicates that Fluoroquinolones May Increase Risk of Birth Defects

A recent study in the British Journal of Pharmacology, “Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study” has shown that, “antibiotics in the class called quinolones — ciprofloxacin, levofloxacin and others — are particularly dangerous and should be avoided in pregnancy.”

The study, which “followed 139,938 mothers of babies born in Quebec from 1998 to 2008, tracking their antibiotic use in the first trimester, and their babies’ birth defects through the first year of life” found that:

Moxifloxacin exposure was associated with a 5-fold increased risk of respiratory system malformations and ofloxacin use with an 8-fold increased risk of MCMs. However, these results should be interpreted with caution given the small number of exposed cases.

Teratogenicity of quinolone has been reported in the literature in animal and experimental studies [50, 51]. Indeed, quinolones can act as DNA gyrase inhibitors and also as mitotic inhibitors [52]. This may partially damage DNA and induce fetal malformation, which supports our findings [52].

The other antibiotics examined were also more dangerous during pregnancy than I think any pregnant woman should feel comfortable with, but fluoroquinolones were found to be particularly dangerous.

Too Many Pregnant Women are Prescribed Fluoroquinolone Antibiotics

My friend had a healthy son, and he is now a happy and healthy toddler. She took antibiotics (but not fluoroquinolone antibiotics) during pregnancy, but her son was not negatively affected.

My friend was fortunate. However, most pregnant women don’t have a high school friend who incessantly posts about the dangers of fluoroquinolones, and many of them take fluoroquinolones during pregnancy without being aware of the risks these drugs pose to them or their babies. Doctors who prescribe fluoroquinolones to pregnant women, when there are safer alternative antibiotics, are endangering women and children, and there is nothing okay about that.

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New York Times, “Certain Antibiotics May Increase Risk of Birth Defects

British Journal of Clinical Pharmacology, “Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study

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Studies Link Topoisomerase Interrupting Drugs to Autism

It has recently been discovered 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.”  (1)

Topoisomerases are enzymes that are essential for DNA and RNA replication and reproduction.  Without topoisomerase enzymes, DNA and RNA supercoiling fail to resolve correctly during cell division and gene transcription.  Topoisomerases are like oil to the DNA and RNA replication engine—making the process go smoothly.  Without topoisomerases, DNA and RNA supercoiling jams up and “over-heats,” causing transcription errors.  Topoisomerases are also “integral for gene expression, as they resolve DNA supercoiling that is generated during transcription.” (1)

DNA_replication_en.svg

Many pharmaceutical drugs inhibit topoisomerases.  Most of these drugs are chemotherapeutic agents such as topotecan, a drug used to treat various forms of cancer.  The most widely used topoisomerase inhibitors are fluoroquinolone antibiotics—Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and Floxin/ofloxacin—drugs used to treat simple urinary tract, prostate, sinus and other infections.  The fluoroquinolone antibiotics that are in wide use were first patented in the late 1980s and their use increased steadily from then until now, with 26.9 million prescriptions for orally and IV administered fluoroquinolones written in 2011. (2)  A similar number of topically administered fluoroquinolone prescriptions have been written, and though orally and IV administered fluoroquinolones are not recommended for use in children because they cause cartilage lesions in juvenile animals (3), topically administered fluoroquinolones are approved for use in children as young as 6 months of age (4), and are regularly given to young children in the form of ear and eye drops.

Autism rates have been skyrocketing since the 1980s, with the most recent numbers out of the CDC stating that one in 68 American children is on the autism spectrum. (5)

prevalence-graph1

It is likely that a variety of environmental and genetic components has led to the staggering figure of 1 in 68 American children on the autism spectrum.  Studies have focused on vaccines (and there are vaccine injured children), but epidemiological studies have suggested that factors other than vaccines are likely at play.  Birth control pills, acetaminophen, antidepressants and other categories of drugs have been pointed to for their deleterious effects on the human brain, and their possible contributions to the increasing number of people on the autism spectrum.

STUDY SUMMARY AND IMPLICATIONS

In this article, I will go over some studies that point to topoisomerase interrupting drugs as a potential cause of autism.  The studies are out of the University of North Carolina at Chapel Hill—“Topoisomerases facilitate transcription of long genes linked to autism,” published in Nature (as well as the corresponding author manuscript), and “Topoisomerase 1 inhibition reversibly impairs synaptic function,” published in PNAS.  I will link these studies to the fact that fluoroquinolones are also topoisomerase interrupters.

The mechanism of action for Cipro/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.”(6)

The mechanism of action for other fluoroquinolones—Levaquin/levofloxacin, Avelox/moxifloxacin, Floxin/ofloxacin, and their generic equivalents—are the same.

Why anyone thought that it was a good idea to give DNA disrupting chemotherapeutic drugs to children with ear infections is beyond my comprehension, but it happens every day.

Fluoroquinolone use has gone up hand in hand with autism rates.  As critics of all possible causes of autism are quick to point out, correlation does not mean causation.  While that criticism is true, the causes of autism are undoubtedly correlated with autism rates, and thus correlations should be examined.

The articles that I will be reviewing note that topoisomerase interrupting drugs profoundly affect the expression of genes related to autism.  A large number of the genes that have been found to be related to autism are particularly long and complex, and are related to neurotransmitter synaptic function and neurodevelopment.  The expression of these long genes is affected by topoisomerase interrupting drugs, as one may expect when noting that topoisomerases are necessary for gene transcription, and longer genes can more easily get mis-transcribed when exposed to topoisomerase interrupting drugs.

fluoroquinolone-lawsuit-banner-trulaw

Topoisomerase enzymes are expressed throughout the adult brain, and thus the connections between topoisomerase inhibiting drugs and neurodegenerative diseases should be explored along with connections between those drugs and autism.  It is noted in “Topoisomerases facilitate transcription of long genes linked to autism” that, “Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.”

Both “Topoisomerases facilitate transcription of long genes linked to autism” and “Topoisomerase 1 inhibition reversibly impairs synaptic function” examine the effects of topotecan, a topoisomerase 1 (TOP1) inhibitor, on autism related genes and synapses.  Studies of the effects of fluoroquinolones, topoisomerase 2 and 4 interrupters, have not yet been published.

It should be noted that the existing studies have looked at nuclear gene expression, and that the effects of topoisomerase interrupting drugs on the expression of mitochondrial and microbiome genes have not yet been explored.

The implications of “Topoisomerases facilitate transcription of long genes linked to autism” and “Topoisomerase 1 inhibition reversibly impairs synaptic function” are potentially huge given the wide-spread use of topoisomerase interrupting fluoroquinolones, both directly in humans and in agriculture.  If fluoroquinolones are conclusively linked to autism, their use in children and people of child-bearing age (exactly how gene expression is affected by topoisomerase interrupting drugs, and what the intergenerational effects may be, are not yet known) should be prohibited—effective immediately—regardless of what the average physician who knows little about the effects of topoisomerase inhibitors on gene expression thinks about the “excellent safety record” of fluoroquinolones as a class of drugs.

As a person who has been hurt by ciprofloxacin, a fluoroquinolone antibiotic, I am not without bias—but I do not think that it’s unreasonable to assert that all topoisomerase interrupting drugs should be strictly limited—especially if they’re connected in any way to autism or neurodegenerative diseases.

STUDIES LINKING TOPOISOMERASE INTERRUPTING DRUGS TO AUTISM

Topoisomerases facilitate transcription of long genes linked to autism” concludes 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 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.”

This conclusion has multiple levels of significance.  It involves a shift in thinking about ASD as either a genetic disorder or an environmentally caused disorder, to noting the interplay between genes and the environment (epigenetics).

The study is also significant in that it notes that genes that encode synaptic function and neurodevelopment, that are also related to autism, are particularly long and complex.  Those long and complex genes aren’t transcribed properly when topoisomerase enzymes are inhibited via pharmaceuticals.  When topoisomerase interrupting drugs impair gene transcription, expressions of long genes become impaired.

Whether or not the silencing of expression of particularly long genes through topoisomerase interrupting drugs is a possible unifying cause of autism spectrum disorders depends on the prevalence of topoisomerase interrupting drugs in our environment.  Topotecan, the topoisomerase 1 interrupter that was studied, is a chemotherapeutic drug that is only used in cancer patients, and is rarely used in pediatric patients.  Fluoroquinolone antibiotics, on the other hand, are topoisomerase interrupting drugs that are used commonly in the general population, including the pediatric population, and are even used in agriculture and thus are present in the food we eat, the soil our food is grown in and even the water we drink.

More than 20 million prescriptions for fluoroquinolones—topoisomerase interrupting drugs—have been written each year for more than two decades.  One is hard pressed to find an adult American who has not had at least one fluoroquinolone prescription in his or her lifetime.  Fluoroquinolone use has gone up hand in hand with incidence rates of autism.  As noted earlier, that correlation does not mean causation, but if topoisomerase interrupting drugs in our pharmacies and environment are a unifying cause of ASD (and other neurodegenerative diseases of modernity), fluoroquinolones would need to be the causal factor, not prudently used chemo drugs like topotecan.  Studies looking into this line of thinking are pending, and the similarities between fluorquinolones and chemotherapeutic topoisomerase interrupters have not escaped the attention of the researchers looking into the relationships between topoisomerases and autism.

The UNC researchers found that, “topotecan reduced expression of nearly all extremely long genes in mouse cortical neurons,” (1) and were able to reproduce the same results in human neurons.  Interestingly, not only was the expression of long genes suppressed, “topotecan increased expression of a majority of genes that were <67 kb in length, although the magnitude of this increase was very small for most genes.” (1)  The expression of long genes, those genes that are involved in encoding neural synapses, was downgraded, whereas the expression of shorter genes was up-regulated.

An example of a particularly long gene that is related to ASD whose expression is altered by topotecan is “Ubiquitin-protein ligase E3A (Ube3a), a gene that affects synaptic activity and that is deleted or duplicated in distinct neurodevelopmental disorders (Angelman syndrome and autism, respectively)” (7)  Ube3a is “normally expressed only from the maternal allele in neurons and regulates synaptic function.” (1)  However, in cells that have been exposed to topoisomerase interrupting drugs, the paternal allele of Ube3a is transcriptionally upregulated.  “Duplication of the chromosomal region containing maternal Ube3a is frequently detected in individuals with autism.”

Other particularly long genes are affected by topoisomerase interrupting drugs include:

“many genes down-regulated by topotecan are associated with synapses, cell adhesion, and neurotransmission.  Moreover, a number of those down-regulated long genes are associated with autism, including Neurexin-1 (Nrxn1; 1059 kb), Neuroligin-1 (Nlgn1; 900 kb) and Contactin-associated protein 2 (Cntnap2; 2,241 kb), genes that are well known to regulate inhibitory and excitatory synaptic function.” (7)

I wasn’t able to find any scholarly articles about the effects of fluoroquinolones on Nrxn1, Nlgn1 or Cntnap2.  However, it is hypothesized in “Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology,” that all adverse reactions to fluoroquinolones are due to epigenetic mechanisms:

“The quinolones are a family of broad-spectrum antibiotics. They inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV, so it has been assumed that quinolones and fluoroquinolones have no effect on human cells, but they have been shown to inhibit eukaryotic DNA polymerase alpha and beta, and terminal deoxynucleotidyl transferase, affect cell cycle progression and function of lymphocytes in vitro, and cause other genotoxic effects. These agents have been associated with a diverse array of side-effects including hypoglycemia, hyperglycemia, dysglycemia, QTc prolongation, torsades des pointes, seizures, phototoxicity, tendon rupture, and pseudomembranous colitis. Cases of persistent neuropathy resulting in paresthesias, hypoaesthesias, dysesthesias, and weakness are quite common. Even more common are ruptures of the shoulder, hand, Achilles, or other tendons that require surgical repair or result in prolonged disability. Interestingly, extensive changes in gene expression were found in articular cartilage of rats receiving the quinolone antibacterial agent ofloxacin, suggesting a potential epigenetic mechanism for the arthropathy caused by these agents. It has also been documented that the incidence of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolones is increased compared to controls, suggesting the possibility of persistent gene expression changes in the liver and heart.”(8)

Also, it has been known since 1996, when “Delayed Cytotoxicity and Cleavage of Mitochondrial DNA in Ciprofloxacin-Treated Mammalian Cells” was published in Molecular Pharmacology, that fluoroquinolones deplete mitochondrial DNA.  The article states, “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.” (9)  Nuclear gene expression is linked to mitochondrial functioning and, “Mitochondria generate signals that regulate nuclear gene expression via retrograde signaling,” (10).  Fluoroquinolone induced mitochondrial DNA damage may lead to changes in nuclear DNA expression.

Fluoroquinolones are also known to affect neurotransmitters, particularly GABA neurotransmitters.  (11)  GABA neurotransmitters are responsible for regulation of inhibitory and excitatory synaptic function.  It is noted in “Topoisomerase 1 inhibition reversibly impairs synaptic function” that, “GABA-A receptor subunits are encoded by long genes.” And that, “multiple synaptic proteins encoded by long genes including cell adhesion molecules linked to autism and GABA receptor subunits, are depleted in topotecan-treated neurons.”

GABA receptors

Given that GABA receptors are critical for inhibitory and excitatory synaptic functioning, examining the role between GABA receptors, topoisomerases, topoisomerase inhibiting drugs, and attention deficit hyperactivity disorder (ADHD) is certainly warranted.  Many individuals with ASD also display symptoms of ADHD, and the interactions between GABA and glutamate receptors may be why many individuals with ASD find symptom relief through a gluten and casein free diet that is low in glutamate.

As the title of “Topoisomerase 1 inhibition reversibly impairs synaptic function” indicates, it was found that “the synaptic effects of topotecan are reversible” upon washout of the drug.  However, the complexity of neurotransmission is acknowledged in the discussion section of the article, where it is noted that, “adding back one synaptic cell-adhesion molecule would not likely restore the protein levels of all affected synaptic cell-adhesion molecules as well as multiple GABA-A receptor subunits.” It is also noted that, “transient TOP1 (topoisomerase 1) inhibition has the potential to impair brain function reversibly, whereas a persistent change in TOP1 activity has the potential to disrupt neurodevelopment and promote neurodegeneration.”  With limited exposure to a topoisomerase interrupting drug, the neurological effects appear to be reversible.  However, persistent exposure can cause more persistent harm.

Adult patients with fluoroquinolone toxicity syndrome often note that they were able to tolerate fluoroquinolones without experiencing adverse effects prior to getting “floxed.”  This tolerance threshold may indicate that fluoroquinolones somehow accumulate in cells and that the adverse effects of fluoroquinolones are amplified with each exposure.  It is also possible that mitochondrial DNA needs to cross over a damage threshold before resulting in adverse effects.  More about this can be found in the post, “The Fluoroquinolone Time Bomb – Answers in the Mitochondria.”

IS IT POSSIBLE THAT FLUOROQUINOLONE ANTIBIOTICS ARE RESPONSIBLE FOR MANY CASES OF AUTISM? 

The possibility hasn’t been explored, despite the documented effects of fluoroquinolones that line up with many of the symptoms and effects of autism.  In addition to the correlation between fluoroquinolone prescription rates and autism rates, and the points noted above about topoisomerase interrupting drugs changing the expression of autism related genes, fluoroquinolones also damage mitochondria (12)—and mitochondrial damage has been linked to autism (13) .  Fluoroquinolones also cause cellular leakage (14) and depletion of minerals (15) that are necessary for synthesis of minerals and vitamins that (deficiencies of) have been linked to autism (16).  Fluoroquinolones, as powerful antibiotics, are extremely destructive to the gut microbiome and gut microbiome health has also been linked to autism (17).

Even though a pretty good argument can be made for fluoroquinolones causing autism, if there is a relationship, it is not entirely clear-cut.  There are children who have been hurt by fluoroquinolones, but there are also children who have been administered fluoroquinolones without any apparent harm.  Like adults, children almost certainly have a tolerance threshold for fluoroquinolone use before they are injured.  Delayed adverse reactions (18) make recognition of symptoms of fluoroquinolone toxicity difficult to recognize, and recognition in the pediatric population is even more difficult because children have incompletely developed communication skills.  Studies that take into account delayed reactions and tolerance thresholds for fluoroquinolones have not been conducted on the adult population, much less the pediatric population, and thus it is unknown what the true effects of fluoroquinolones are.

It is possible that parental genes are altered by fluoroquinolone use and the damaged genes are passed on to children.  This possibility has not yet been explored, but, anecdotally, it does not appear to be a clear-cut relationship either.  Many mothers and fathers who have suffered from fluoroquinolone toxicity have had neurodevelopmentally normal children.  Some have had neurodevelopmentally challenged children though too, and it would be nice to see an actual study of the children of parents exposed to fluoroquinolones, as opposed to the anecdotes that are currently available.

Autism is a complicated disorder (or set of disorders) that likely has multiple environmental, genetic and epigenetic causes.  I strongly suspect that fluoroquinolones are part of the autism-cause-puzzle, but I also suspect that other cellular poisons compound the deleterious effects of fluoroquinolones on neural synapses, and can trigger autism.

Autism_Spectrum_Disorder-1

I noted above that adverse reactions to fluoroquinolones are often delayed.  Delayed adverse reactions to fluoroquinolones have been reportedly triggered by other stressors, including other pharmaceuticals (especially NSAIDs and steroids), benzodiazepine withdrawal, vigorous exercise, emotional stress, alcohol, hormonal changes and other things that can alter neurotransmitters and the autonomic nervous system.  The combined effects of fluoroquinolones and subsequent stressors have not yet been studied, despite (some) recognition of delayed adverse reactions to fluoroquinolones.

Given the indications of “Topoisomerases facilitate transcription of long genes linked to autism,” and “Topoisomerase 1 inhibition reversibly impairs synaptic function,” it is certainly prudent to explore whether or not fluoroquinolones affect gene expression similarly to topotecan.  Other drugs that inhibit topoisomerase activity, such as irinotecan and camptothecin, demonstrated similar effects to those of topotecan and thus the UNC researchers “speculate that other drugs that inhibit TOP1 or TOP2 enzymes could have similar effects on synaptic function.”  We shall see if their results show that fluoroquinolones affect the expression of long genes.  I’m betting that they will find that fluoroquinolones dramatically alter gene expression, especially after multiple uses and also especially when combined with NSAIDs.  Given the prevalence of both fluoroquinolone antibiotics and NSAIDs in our environment though, I hope that I am wrong.

It was never prudent for fluoroquinolones to be used as first-line antibiotics.  They are dangerous, DNA and RNA disrupting chemo drugs that should only be used in life-or-death situations, not as treatment for travelers’ diarrhea or sinus infections.  They’re topoisomerase interrupters.  They’re topoisomerase interrupters.  They’re topoisomerase interrupters.  They’re topoisomerase interrupters.  I’m not sure how many times I need to say that for people who know what topoisomerases are (those who went to medical school) to recognize that it is NOT APPROPRIATE TO GIVE TOPOISOMERASE INTERRUPTING DRUGS TO CHILDREN (or anyone else who isn’t dying).

A former biochemist friend noted, “I was stunned that people thought quinolones were perfectly safe. Coming through the ranks, I always thought, as was taught, that they were a last-ditch drug. There was absolutely no long-term research done with them, and apparently still isn’t.  But there sure was money involved.”

Long-term and intergenerational research need to be done on drugs that affect DNA before they are released into the public.  Neither long-term nor intergenerational studies were done on fluoroquinolones before flooding the market with them.  The odd intricacies of how fluoroquinolones affect people were not taken into consideration either—things like delayed effects, tolerance thresholds, drug and hormonal interactions, etc.

I’m hopeful that the UNC scientists that are looking at the interactions between topoisomerases and autism will start screaming about the deleterious effects of fluoroquinolones on our genes.  I hope that they have the resources to do the study with delayed adverse reactions and tolerance effects taken into consideration too.

We shall see.

I’m hopeful that the study will be well-done and, if not conclusive, interesting–and that it opens the door for more research.

I can’t say that I hope that fluoroquinolones are a unifying cause of autism spectrum disorders, because that would be too sad.

One thing that I’ve found through researching how fluoroquinolones damage human health, is an appreciation for how complex and multifaceted humans are.  Nothing happens in isolation.  There are feedback and feedforward loops within the body that compound the effects of a stimulus on one bodily system on another, there are interactions between drugs that can occur long after a drug “should” have cleared the body, the interactions between mitochondria and neurotransmitters and cellular signaling exist but little is known about them, and more.  It is difficult, if not impossible, for scientists to adequately take into account the incredible complexity of the human body.  What is not known cannot be taken into consideration, and don’t for a second think that we know “enough” about the human body to be throwing pharmaceuticals that are topoisomerase interrupters into the mix.

Fluoroquinolones never should have been approved for human use until long-term, intergenerational safety studies were performed.  They should be taken off of the market until those studies are done.  That won’t happen though.  Drugs aren’t taken off of the market unless they immediately kill a lot of people.  The damage that fluoroquinolones do is more nuanced than that.  If pharmaceutical makers can create a drug that is complex enough, and that can affect people in multiple different ways—through affecting gene expression—they can get away with just about anything.  Bayer and Johnson & Johnson have figured this out.  The FDA isn’t smart enough to protect the public.  Individuals need to be smart enough to protect themselves and their families—a difficult thing to do considering that some knowledge of biochemistry and genetics is necessary for protection against dangerous pharmaceuticals.

Fluoroquinolones are topoisomerase interrupters.  They’re topoisomerase interrupters.  They’re topoisomerase interrupters.  They’re topoisomerase interrupters.  They’re topoisomerase interrupters.  Repeat until someone who should know better shouts – “STOP.”

REMAINING QUESTIONS

The existing research into connections between topoisomerase interrupting drugs and autism spectrum disorders raises multiple questions.  It would be nice if some money, time, effort and other resources were devoted to answering these questions.

  1. What are the effects of fluoroquinolone antibiotics on nuclear, mitochondrial and microbiome gene expression?  What are the implications of these effects?
  2. Do topoisomerase interrupting drugs change gene expression of the person who takes them, the offspring of the person who takes them, or both?
  3. Do topoisomerase interrupting drugs increase a person’s chances of having a child with Autism? How?
  4. If a person takes a topoisomerase interrupting drug, is their DNA altered? If so, are the changes temporary or permanent?
  5. Are some people’s genes affected by these drugs more than others? What factors determine whether or not an individual’s genes are affected?
  6. Are DNA/gene alterations triggered by pharmaceuticals reversible? If so, how?
  7. What, if anything, can people who have taken these drugs do to discourage the expression of the ASD related genes?
  8. When would the administration of the drug happen to influence genes in a way that could trigger the genes associated with Autism – when a mother is pregnant or at any point before the child is conceived – or does the drug need to be directly administered to the person whose genes are altered?
  9. Do these drugs change gene expression in the ways that diet and music change gene expression or do they change DNA like Agent Orange? What level and scale are we talking about?

SOURCES:

  1. Ian F. King, et al. “Topoisomerases facilitate transcription of long genes linked to autismNature – author manuscript. 2013 Sep 5; 501(7465): 58–62.
  2. FDA Safety Announcement, “FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection” 08/15/2013
  3. Adam D. “Use of quinolones in pediatric patients.” Reviews of Infectious Diseases. 1989 Jul-Aug;11 Suppl 5:S1113-6.
  4. Ciprodex Warning Label
  5. CDC Newsroom Press Release, “CDC estimates 1 in 68 children has been identified with autism spectrum disorder” March 27, 2014
  6. FDA Warning Label for Cipro/Ciprofloxacin
  7. Mabb AM, et al. “Topoisomerase 1 inhibition reversibly impairs synaptic function.” Proceedings of the National Academy of Sciences of the United States of America, 2014 Dec 2;111(48):17290-5. doi: 10.1073/pnas.1413204111. Epub 2014 Nov 17.
  8. Antonei B. Csoka and Moshe Szyf. “Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology.” Medical Hypotheses 73 (2009) 770–780
  9. JW Lawrence, et al. “Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells.” Molecular Pharmacology November 1996 vol. 50 no. 5 1178-1188
  10. Martin Pickard, et al. “Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogrammingProceedings of the National Academy of Sciences of the United States of America, 2014 Sep 23; 111(38): E4033–E4042.
  11. Pharmacology Weekly Newsletter, “What is the mechanism by which the fluoroquinolone antibiotics (e.g., ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin) can increase a patient’s risk for developing a seizure or worsen epilepsy?” August 31, 2009.
  12. Sameer Kalghatgi et al. “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells.” Science Translational Medicine, 5, 192ra85 (2013)
  13. Suzanne Goh, et al. “Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder – Evidence From Brain ImagingJAMA Psychiatry. 2014;71(6):665-671
  14. Marta Kicia, et al. “Comparison of the effects of subinhibitory concentrations of ciprofloxacin and colistin on the morphology of cardiolipin domains in Escherichia coli membranes.” Journal of Medicinal Microbiology, April 2012 vol. 61 no. Pt 4 520-524
  15. G Palu, et al. “Quinolone binding to DNA is mediated by magnesium ionsProceedings of the National Academy of Sciences of the United States of America, Vol. 89, pp. 9671-9675, October 1992
  16. Richard E. Frye, MD, PhD, and Daniel A. Rossignol, MD, FAAFP, “Cerebral Folate Deficiency in Autism Spectrum Disorders” Autism Science Digest: The Journal of Autism One. Issue 02.
  17. Jennifer G. Mulle, et al. “The Gut Microbiome: A New Frontier in Autism Research.” Current Psychiatry Rep. 2013 Feb; 15(2): 337.
  18. Jacquelyn K. Francis, BA and Elizabeth Higgins, MD, “Permanent Peripheral Neuropathy: A Case Report on a Rare but Serious Debilitating Side-Effect of Fluoroquinolone AdministrationJournal of Investigative Medicine High Impact Case Reports 1–4 © 2014 American Federation for Medical Research
  19. Thomas D. Gootz, et al. “Inhibitory Effects of Quinolone Antibacterial Agents on Eucaryotic Topoisomerases and Related Test SystemsAntimicrobial Agents and Chemotherapy. Jan. 1990, P. 8-12.
  20. Mukherjee, S. Sen, K. Agarwal, “Ciprofloxacin: mammalian DNA topoisomerase type II poison in vivo.” Mutation Research Letters. Volume 301, Issue 2, February 1993, Pages 87–92

 

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Truth Seeker or Conspiracy Theorist? You Decide.

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The disbelief that we face when telling people about our reaction to FQs is frustrating beyond belief. People assume that we’re wrong, or lying, or crazy conspiracy theorists when we tell them that an antibiotic caused our body to go completely hay-wire. We’re not wrong, crazy, lying, etc. The human body is just exceedingly complex and, unfortunately, poorly understood, and the effects of fluoroquinolones on our body are devastating. Here is an essay that I wrote about the topic of being thought of as a conspiracy theorist for shouting about the dangers of FQs. As always, shares are greatly appreciated. Thanks so much for reading it!

Truth Seeker or Conspiracy Theorist, You Decide

 

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