Tag Archives: fluoroquinolone

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.

 

A Delicate Balance: Fluoroquinolones Disrupt Cellular Homeostasis

This post was inspired by, “My Father’s Body, at Rest and in Motion: His systems were failing. The challenge was to understand what had sustained them for so long.” by Siddhartha Mukherjee, published in the January 8, 2018 issue of The New Yorker. (When not noted otherwise, all quotes are from “My Father’s Body, at Rest and in Motion.”) It’s a poignant personal account of Dr. Mukherjee’s father’s decline and death. It is also about the beautiful and delicate balance that is life. I cannot do the article justice in taking excerpts from it, and I suggest that you read it yourself. It is only related to fluoroquinolone toxicity peripherally (if at all), but I think there are lessons to be learned about fluoroquinolone toxicity within it. There are certainly lessons about life, and death, within it, and I recommend it to anyone who likes thoughtful, New-Yorker-esque articles.

I never thought about cellular homeostasis before I got floxed. Who, other than biochemists and med students, thinks about cellular homeostasis?

“There’s a glassy transparency to things around us that work, made visible only when the glass is cracked and fissured. Look, it’s nothing. To dwell inside a well-functioning machine is to be largely unaware of its functioning. That’s its gift, and we accept it thoughtlessly, ungratefully, unknowingly.”

Homeostasis, the ability to maintain internal consistency, is crucial for life. Indeed, “Homeostasis, the capacity to maintain a functional equilibrium, would turn out to be one of the cardinal principles of all organisms; it’s often described as one of the defining principles of life.” The dance within our cells that maintains homeostasis, that keeps us functioning properly, that keeps each feedback and feed-forward loop operating optimally, is necessary for health, and for maintaining life.

Fluoroquinolones disrupt cellular mineral levels, the balance of antioxidants and ROS within cells, hormonal balance, gut biome balance, and more. They cause mitochondrial apoptosis, and nervous system dysfunction. Fluoroquinolones disrupt homeostasis—the delicate balance and intricate dance of keeping minerals, hormones, vitamins, etc. in-balance within our cells. Fluoroquinolones disrupt crucial functions, and in doing so, throw a wrench in health, and in life.

What happens when homeostasis is disrupted by fluoroquinolones?

The answer seems to depend on multiple factors. How many physiological processes were disrupted? To what extent? Where? What feedback and feed-forward loops were triggered? What is the downstream damage? What are the genetic (and other) predispositions of the individual who has been hurt? What is the ROS/MMP burden on the body/cell at the time that a person takes ciprofloxacin or levofloxacin? What are the hormone levels at the time that a person takes the pill(s)? What are the compensating factors that make a person stronger or more resilient? What makes someone vulnerable? Who? What? How?

In theory, we can know the answers to these questions. In practice though, we can’t, and a certain amount of luck, or lack thereof, enters the equation. We cannot know the answers to those questions before we take any pharmaceutical, and thus, we are playing Russian Roulette with our bodies when we take drugs like fluoroquinolones that disrupt multiple systems, and cause disrupted cellular homeostasis.

“Indeed, once self-regulation fails, complex systems of all kinds can be claimed by a version of this process, sometimes called a failure cascade. A storm-battered tree takes down a transmission line; the increased load causes another network component to fail, further increasing the load, turning a local outage into a regional blackout. The failure of one division in one bank can trigger a global cataclysm. That’s a failure cascade.”

Perhaps the difference between a person who takes multiple fluoroquinolone prescriptions without notable effect and a person who experiences severe toxicity and even death, is whether or not the fluoroquinolones throw a person into a “failure cascade.” Homeostasis can be disturbed a bit with no notable effect (our healing and stability mechanisms kick in), but if it is disturbed enough to throw a person into a “failure cascade” everything goes wrong in his or her body, and it feels as if a bomb has exploded.

“Yet maintenance defies measurement; it’s the glass pane that’s visible only when it cracks. In the several months of my father’s decline, hospitalization, and death, we recorded the values of hundreds of things in his body: potassium, temperature, breathing rate, creatinine, bicarbonate, chloride, the oxygen saturation of his blood, the output of his urine. What we didn’t measure—couldn’t measure—was how hard his body was working to bestill these values, how much “unnatural vigilance” was required to keep things steady, and how deeply his physiology must have collapsed when the numbers finally dipped into abnormalcy. We had, in short, no real measure of homeostatic resilience, of physiological reserve.”

In “My Father’s Body, at Rest and in Motion” Dr. Mukherjee is writing about his elderly father, whose body is failing because of old-age and a bad fall. As difficult as it is for the elderly people (and their loved ones) who enter a “failure cascade” due to old-age and/or trauma, it is expected that old-age brings bodily failures, and that some of those failures will lead to other failures. We expect that time will disrupt homeostasis and that our cellular functions will eventually fail. But we don’t expect that a drug—a popular antibiotic no less—will trigger a “failure cascade.” They do though. Ciprofloxacin, levofloxacin, moxifloxacin, and other fluoroquinolones trigger multi-symptom, chronic, disabling illness—often in young people.

How do people who have been hurt by fluoroquinolones get back to a healthy state of cellular homeostasis? How do you stop the feedback loops that are leading to the “failure cascade?” I don’t know the answer for any individual, and nothing on this site should be interpreted as medical advice (I’m not a doctor), but some basic advice, that seems to have helped other people, can be found in the post, I’m Floxed, Now What? 

It struck me as I read “My Father’s Body, at Rest and in Motion” just how little we (collectively–including doctors and scientists) know about health, or even life (not how to live life, but the actual process of life, and our cellular processes that are at the center of life). Health, healing, and even life, are things that are easy to take for granted, and to fail to study or even notice, until they go away or are threatened. I barely thought about my health, much less my cellular homeostasis, until it was threatened by ciprofloxacin. After I got “floxed” I had a reason to notice how delicate and precarious my health was. Health and its basis of homeostasis are both robust and delicate. Our feedback and feed-forward loops work as they should–until they don’t. Without homeostasis, without the processes that compose life working the way they should, life ceases. Fluoroquinolones disrupt homeostasis, and cause many physiological systems to go hay-wire. The damage that fluoroquinolones do can be severe–particularly if a “failure cascade” is triggered. With every fluoroquinolone pill taken, damage is done, and the risk of a “failure cascade” occurs. Nothing is worth risking a “failure cascade” if that cascade results in death, and very few “floxies” would say that treatment of their infection was worth the pain and disability caused by fluoroquinolones. We may not fully understand the delicate balance of life, or the processes occurring in our cells, but they are important none-the-less, and throwing a wrench in them with fluoroquinolones is both damaging and foolish. 

 

 

A Fluoroquinolone Toxicity Post Goes Viral

A post about fluoroquinolone toxicity, i.e. getting “floxed,” i.e. getting “ruined” by Cipro, has gone viral.

Check it out!

This antibiotic will ruin you.

It has been shared more than 10,000 times on Facebook (probably closer to 20,000 – the web site stops updating each share after 10,000 shares) – including more than 6,000 shares from The Fluoroquinolone Wall of Pain Facebook page.

It is resonating with thousands of people, who are not only reading it, they are sharing it. It has been viewed by MILLIONS of people. The author, Amy, posted on her facebook page that, in just a couple days, the post has been viewed more than 4 million times. That’s amazing!

Please shareThis antibiotic will ruin you with your friends and family. It’s getting through to people. It’s informing people. It’s connecting people.

Thank you, Amy, for sharing your journey and your story, and for doing it in a way that has resonated with so many people!

This post has done more to get the word out about the dangers of fluoroquinolone antibiotics (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, Floxin/ofloxacin, and a few others) than 90% of the other posts, media stories, etc. that have been produced. It has gone viral. It has gone so viral that people are writing about it going viral, including WOMAN SAYS FLOUROQUINOLONES ANTIBIOTICS ‘WILL RUIN YOU,’ GETS 40K FACEBOOK LIKES on Inquistr.com (which, I believe is part of Buzzfeed), and, obviously, this post.

Viral posts aren’t something that happens every day, so, CONGRATULATIONS, Amy! Most importantly, her viral post, This antibiotic will ruin you, is increasing awareness about fluoroquinolone toxicity.

This antibiotic will ruin you has more than 1,000 comments on it – many of which are from fellow “floxies.” Amy has stated (on facebook) that she wants to respond to all of them, but that she’s drowning in the volume of comments. Can you, my friends in the “floxie” community, who are experts in fluoroquinolone toxicity, please help her? Please take some time to respond to some of the people who have commented on This antibiotic will ruin you. Your help will be appreciated!

The viral nature of the post has given us a window of opportunity to inform people about fluoroquinolone toxicity, and to support those who are going through it who didn’t realize that there is a support network available. Any help that you can provide in further spreading the post, and helping to answer comments on the post, will help. Thank you!

 

 

EMA to review persistence of side effects known to occur with quinolone and fluoroquinolone antibiotics

I hope I’m not too late in posting this. The following notice was published by the European Medicines Agency (EMA) in February, 2017 (and I’m posting it in March). I want to encourage all of my European “floxie” friends to contact the EMA to report your reaction, and to inquire about testifying. Even if testifying isn’t a possibility, we should all pay attention to what the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) decides.

The contact person listed on the EMA notice is:

Monika Benstetter
Tel. +44 (0)20 3660 8427
E-mail: press@ema.europa.eu

HOWEVER, the EMA has given us the contact information for the UK representatives of PRAC (the EMA’s Pharmacovigilance Risk Assessment Committee). Please contact them instead. They are:

julie.williams@mhra.gsi.gov.uk
and
patrick.batty@mhra.gsi.gov.uk

European floxie friends, please reach out to Ms. Benstetter to share your story, or to find out who you should share your story with. The patient testimony at the FDA hearing was moving, powerful, and I believe that it made a difference. Hopefully patient testimony will be allowed by the EMA, and it will make a difference too.

Here is the EMA announcement:

EMA to review persistence of side effects known to occur with quinolone and fluoroquinolone antibiotics: Review to focus on long-lasting effects mainly affecting musculoskeletal and nervous systems

The European Medicines Agency (EMA) is reviewing systemic and inhaled quinolone and fluoroquinolone antibiotics to evaluate the persistence of serious side effects mainly affecting muscles, joints and the nervous system. These side effects are of particular importance when the medicines are used for less severe infections.

The review is at the request of the German medicines authority (BfArM) following reports of longlasting side effects in the national safety database and the published literature. There has been no previous EU-wide review specifically focusing on the persistence of the side effects, but the side effects themselves are known and covered in the EU prescribing information for these medicines.

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) will now evaluate all available data and determine whether there is a need to introduce new measures to minimise these risks or modify how the medicines are used.

Quinolones and fluoroquinolones are widely prescribed in the EU and are important options for treating serious, life-threatening bacterial infections. Healthcare professionals using these medicines should continue to follow the official prescribing information.

Patients who have any questions about their treatment should speak to their doctor.

More about the medicines

Quinolones and fluoroquinolones are a class of broad spectrum antibiotics that are active against so-called Gram-negative and Gram-positive bacteria.

The review covers the following medicines: cinoxacin, ciprofloxacin, enoxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin.

More about the procedure

The review of quinolone and fluoroquinolone antibiotics was initiated on 9 February 2017 at the request of German medicines authority (BfArM), under Article 31 of Directive 2001/83/EC.

The review will be carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which will issue recommendations. The PRAC recommendations will then be sent to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which will adopt the Agency’s opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all EU Member States.

I hope that the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) decides to acknowledge the serious adverse reactions caused by fluoroquinolones, and that they restrict the use of fluoroquinolones in Europe.

European friends, if you hear of anything that you can do to push the EMA’s PRAC to to decide to restrict fluoroquinolone use in Europe, please let me know. I’ll update this post if I hear anything new. Thank you!

March 2018 Update

The following is from the EMA Press Release, “Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 5-8 March 2018

Public hearing to be organised for quinolone and fluoroquinolone antibiotics

The PRAC decided to organise a public hearing as part of its review of quinolone and fluoroquinolone antibiotics, to listen directly to the experience of interested parties with these medicines, so this can be taken into account in the Committee’s recommendation.

In February 2017 the PRAC started a review of oral, injectable and inhaled quinolone and fluoroquinolone antibiotics to evaluate the persistence of rare serious side effects mainly affecting muscles, joints and the nervous system, some of which may be of long duration. As the review progressed, EMA observed an increased public interest in the safety of these medicines. The PRAC, taking into account this increased interest, considered it would be useful to hold a hearing to better understand the public’s views on the risks associated with these antibiotics and the feasibility of certain measures to optimise their safe use.

This public hearing will take place during the Committee’s meeting of June 2018. Further information, including a summary of the safety concerns, a list of specific questions on which information from the public is sought, as well as practical information on how to participate and an application form will be published soon on the Agency’s website.

It is the second time that the PRAC will hold a public hearing during a safety review of a medicine, following the first public hearing held in September 2017 to inform the review of valproate – a medicine that treats epilepsy, bipolar disorder and migraine.

If you would like to attend the public hearing, please see THIS DOCUMENT for instructions. Thank you!

April 2018 Update

The following email was received from the EMA:

Dear All,

The European Medicines Agency (EMA) would like to let you know it is going to hold a Public Hearing on 13 June 2018 at its offices in London.

The hearing is part of an ongoing review of Quinolone and fluoroquinolone medicines being carried out by the Agency’s safety committee – the Pharmacovigilance Risk Assessment Committee (PRAC).

The EMA is reviewing these antibiotics due to reports of serious persistent side effects mainly affecting muscles, joints and the nervous system.

The PRAC would like to hear the public’s view on acceptability of risks associated with quinolones and fluoroquinolones in both mild and severe infections, and to explore what further measures could be taken to ensure that these antibiotics are used as safely as possible.

The public hearing will focus on several questions on which the PRAC is seeking the views of different stakeholders who have experience in the use of these medicines within Europe (e.g. patients, consumers, carers, general practitioners/family physicians, urologists, respiratory specialists, pharmacists, nurses).

The questions, together with an overview of the safety issues are published on the EMA website together with a link to the electronic application form, guidance documents and a video.

Those wishing to participate at the hearing need to register in advance and may request to speak in front of the Committee or simply observe the proceedings. The hearing will also be broadcast live via our website.

The deadline for applications is 30 April 2018.

Please share this email with anyone else who might be interested to participate, and if you have any questions please do not hesitate to contact us at:PublicHearings@ema.europa.eu

If you are available, please participate. Thank you!


 

 

 

Fluoroquinolone Warning Labels to be Updated in Canada

Health Canada, the department of the government of Canada with responsibility for national public health (like the U.S. Food and Drug Administration) has “carried out a review of the potential risk of persistent and disabling side effects linked to the use of fluoroquinolones. The review was triggered by a benefit and safety review done by the United States Food and Drug Administration (FDA) on systemic (taken by mouth or by injection) fluoroquinolone drugs.”

The Canadian Review of fluoroquinolones concluded that (SOURCE):

  • Health Canada’s review concluded that some of the known side effects, specifically tendonitis/tendinopathy, peripheral neuropathy and central nervous system disorders, already linked to the use of fluoroquinolones, may be persistent and/or disabling. Given the high use of fluoroquinolones in Canada and the information reviewed, these side effects are considered rare.
  • Health Canada recommended that the safety information for all fluoroquinolone products be updated to include information about this rare but serious risk. Health Canada is working with manufacturers to update the safety information of all systemic (taken by mouth or by injection) fluoroquinolone products marketed in Canada. In addition, an Information Update and a Health Care Professional Letter will be published and distributed to further inform Canadians and healthcare professionals about this risk.
  • Health Canada is working with the Drug Safety and Effectiveness Network (DSEN) and the Canadian Agency for Drugs and Technologies in Health (CADTH) to conduct additional studies to better understand the use of fluoroquinolones in Canada.
  • On October 6, 2016, Health Canada brought together a Scientific Advisory Panel on Anti-Infective Therapies to discuss the risks associated with the use of fluoroquinolones. The panel recommended that the safety information for fluoroquinolones be updated, and risk communications be published and distributed to further inform Canadians and healthcare professionals about the potential risk that some of the known side effects, specifically tendonitis/tendinopathy, peripheral neuropathy and central nervous system disorders may be persistent and/or disabling.
  • Health Canada will continue to monitor safety information involving fluoroquinolones, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

As a result of its safety review, Health Canada is working on updating fluoroquinolone warning labels.

Additionally, above and beyond what the U.S. F.D.A. has done, Health Canada has agreed to publish and distribute a Healthcare Professional Letter regarding fluoroquinolone risks. The Healthcare Professional Letter includes the following points:

  • It is recommended that the potential for disabling and persistent serious adverse events be considered when choosing to prescribe a fluoroquinolone.
  • Fluoroquinolones should not be prescribed to patients who have experienced serious adverse reactions during or after prior treatments.
  • Healthcare professionals are advised to stop systemic fluoroquinolone treatment if a patient reports a serious adverse reaction. The patient’s treatment should be switched to an alternative treatment with a non-fluoroquinolone antibacterial drug if needed to complete the treatment course.
  • Healthcare professionals should be aware that some adverse reactions associated with the use of fluoroquinolones can occur within hours to weeks after exposure to the treatment.

This acknowledgement from Health Canada that fluoroquinolones may have permanent and/or disabling effects is a huge step in the right direction for Canadian “floxies.”

All Canadians who have experienced adverse reactions to fluoroquinolones are encouraged to report their reactions to Health Canada through the Canada Vigilance Adverse Reaction Online Database.

This acknowledgement from Health Canada is a huge step in the direction of safety and informed consent for all Canadians. It is appreciated!

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Fluoroquinolones and Lead Toxicity

Several people have asked me to write a post about how fluoroquinolones may mobilize, or otherwise affect, lead in our bodies. I haven’t gotten around to doing the research that would be involved in writing a post like that, BUT, my friend and fellow “floxie” JMR did. I encourage you to read the post, “Love May Be Fleeting, but Lead Is Forever: Testing for Lead Toxicity” published on Hormones Matter.

The entire post is enlightening and informative, and I encourage you to read the whole thing. Here are some excerpts that are particularly enlightening and useful for “floxies.”

“A particularly interesting, and in my opinion, potentially significant “Lead Re-exposure” incident may have occurred when I took a fluoroquinolone antibiotic over six years ago. I experienced a severe, acute, and ultimately permanent adverse reaction to just a few pills, described in articles I previously wrote for this website, here and here.   Symptoms of “Fluoroquinolone Toxicity” appear to mimic many other conditions, and lead toxicity is one of them. I describe how these FQ antibiotics may have contributed to yet another bout of “Acute Lead Toxicity” within myself after taking these antibiotics here (Scroll down about 60% of the page to “V-ATPase:  Target for Osteoporosis /Adverse Effects”).  How do I know if that did or did not happen to me?  I don’t – because I didn’t know to test blood lead levels during the acute stage (first 6 months) of my reaction or beyond. But now that I do, I would recommend all severely affected fluoroquinolone victims monitor blood lead levels over time during the course of their reaction, especially during the acute phase and relapses, to see if this might be something occurring in this population. A nice summary in table form shows the biological fate of Lead and its clinical significance here.”

And:

“After that, it’s well accepted that overall mineral status is a factor. Lead competes with essential minerals such as calcium, iron, phosphorus, and zinc for the same receptors in enzymes, transporters, and in cell signaling processes.  Adequate concentrations of minerals can offset the small concentrations of lead found in background levels of foods and soils, and can only help if Lead exposure increases. Keeping a healthy balanced mineral status is probably one of the best defenses against lead toxicity, forcing lead excretion rather than binding to enzymes or storing in bone.  High concentrations of healthy essential minerals combined with low concentrations of lead levels is the best scenario, as essential minerals we need to function would be able to out-compete lead for enzymes, receptors, and transporters. On the other hand, low concentrations of healthy essential minerals combined with high lead levels would be a worst case scenario for potential toxicity. Children and adults eating healthy diets with adequate minerals will probably experience less toxicity to the same exposures of lead than someone who is deficient in calcium, iron, phosphorus, zinc or other minerals. Unlike when I was a young child, there is so much more knowledge and awareness about minerals and their importance today, and the internet makes this type of information easily accessible. A vast array of mineral supplements are available as well, making this an easy approach to help with prevention.  A nice lead-related summary of nutrients can be found here:  Fact Sheet: Nutrients That Reduce Lead Poisoning.”

The whole post is filled with great information, and I encourage each of you to read it. It also contains a list of links and resources that is immensely valuable to anyone interested in learning more about lead as it relates to illness.

Thank you for checking it out, and a huge THANK YOU to JMR for the post!

More information about the connections between fluoroquinolone toxicity and lead poisoning can be found on JMR’s web site, www.fluoroquinolonethyroid.com, on the post “Lead Toxicity: Secondary to Hyperthyroidism, Hyperparathyroidism . . . and Fluoroquinolone Toxicity?

This article, “Osteoporosis, lead, and baby boomers: When time gets the lead out.” is also full of excellent information.

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Fluoroquinolone Toxicity and Acetylcholine (ACh) Damage

I suspect that fluoroquinolone antibiotics deplete, inhibit, or otherwise adversely affect acetylcholine (ACh). ACh is a neurotransmitter that has the following functions:

  1. It is a neuromodulator of the central nervous system, the autonomic nervous system, and the peripheral nervous system.
    1. In the autonomic nervous system, ACh has key roles in both the sympathetic and parasympathetic nervous systems, and affects motility through the digestive tract, sweating, tear production, balance, heart-rate, breathing, etc.
    2. In the central nervous system, ACh plays a role in regulating arousal, attention, sleep, and motivation.
    3.  In the peripheral nervous system, ACh controls muscle activation (both skeletal muscles and smooth muscles–the muscles that involuntarily contract and release).
  2. It affects vascular tone.
  3. A lack of ACh is linked to Alzheimer’s Disease, Parkinson’s Disease, autism, schizophrenia, bipolar disorder, and other chronic CNS illnesses.
  4. It suppresses inflammation.
  5. It affects the release of hormones.

Fluoroquinolones damage connective tissues (tendons, ligaments, cartilage, fascia, etc.) throughout the body, as well as the nervous systems (central, peripheral, and autonomic). After getting “floxed” people often suffer from autonomic nervous system dysfunction (including dysautonomia, loss of digestive motility, problems sweating, balancing, etc.), central nervous system dysfunction (including psychosis, insomnia, changes in personality, etc.), and peripheral nervous system dysfunction (including peripheral neuropathy). Fluoroquinolone toxicity often resembles autoimmune diseases in its symptoms, and, like many people with autoimmune diseases, inflammation is often rampant in those who are floxed. Many “floxies” have reported hormonal problems, including thyroid hormone abnormalities, as well as undesirable levels of estrogen, progesterone, and testosterone.

There is significant match-up between the list of documented effects of ACh depletion/damage (summaries of ACH effects can be found HERE and HERE) and the documented effects of fluoroquinolones (the warning labels go over most of the symptoms of fluoroquinolone toxicity, but the personal stories on this site, as well as the stories on www.fqwallofpain.com, facebook, and other places on the internet better exemplify the actual effects of these drugs).

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In addition to the obvious links and overlaps noted above, the links between fluoroquinolones/fluoroquinolone toxicity and ACh damage are more thoroughly explored in the post, “Acetylcholine (ACh) – Related Damage” on www.fluoroquinolonethyroid.com. In it, JMR describes the connections between fluoroquinolones (and fluoroquinolone toxicity) and acetylcholine:

“Still, there were many reasons I felt that many of my problems could be ACh related, and here are some of them.  As I’ve already stated, I felt that many of my symptoms and acute flox reaction could be described as “cholinergic/anti-cholinergic” in nature, and/or MG (myasthenia gravis) related.   Drug label warnings specifically state the Fluoroquinolones have neuromuscular blocking activity, so pharma is giving us a big clue here.  ACh modulates a host of physiological processes in the central and peripheral nervous systems.  Centrally, ACh regulates motor function, sensory perception, cognitive processing, arousal, sleep/wake cycles, and nociception, while in the periphery it controls heart rate, gastrointestinal tract motility, and smooth muscle activity.   Non-neuronal ACh and AChE are distributed throughout the body, making ACh transmission and metabolism important for all cells in the body, not simply neurogenic cells.  Additionally, Non-neuronal ACh and AChE are found in tendons, and increased expression of both occurs in pathological tendinosis, and is thought to contribute to tendon pathology. (Forsgren/Danielson lab studying role of non-neuronal ACh in chronic tendinosis and tendon pathology  – search “non-neuronal ACh Tendons”).  In relationship to the thyroid, cholinergic interaction with the thyoid gland is extensive, and common epitopes may exist relating thyroid autoimmunity and ACh/muscarinic receptor autoimmunity.  ACh appears to be necessary for iodine organification (so this might be one underlying mechanism of action to explore for Hashi’s).  MuSK form of MG (myasthenia gravis) may be a separate condition from MG and there is a known association between “MuSK MG” and Graves disease.  Magnesium prevents or controls convulsions by blocking neuromuscular transmission and decreasing the release of acetylcholine at the nicotinic ACh motor nerve terminals (the analgesic properties of Mg are due to NMDA receptor blocking action). In (my) Year 5 post, as my symptoms progressed, it became apparent that Magnesium was actually exacerbating my muscle weakness, presumably by blocking neuromuscular transmission, and magnesium is something that is known to exacerbate MG symptoms (so for any flox victims for whom magnesium makes your symptoms worse, especially muscle weakness, this is something to consider).   ACh is an underlying common denominator anytime we eat; distention in the stomach or innervation by the vagus nerve activates the Enteric Nervous System, in turn leading to the release of ACh.  Once present, ACh activates G cells (produces gastrin) and parietal cells necessary for digestion.   From an FQ-Induced collagen/connective tissue damage point of view, appropriate collagen formation is also very necessary for AChE function and ACh transmission, and lack of it can result in Myasthenia Gravis like symptoms, as these COL Q studies confirm: 1, 2, 3, 4,  (and suppression of collagen prolylhydroxylation as in this FQ study here can affect COL Q; also scroll to “collagenous domains as substrates”, AChE, in this “Prolyl 4-hydroxylase” paper here).    Because of the necessary symbiotic relationship of mitochondria with their host cells (as I described here), anything that affects the host cell will often affect mitochondria as well, and this most certainly will include ACh-related problems.   However, never to be left out of an opportunity for direct damage, it turns out mitochondria also express a number of nicotinic acetylcholine receptors too (1,2).  I won’t be surprised if muscarinic receptors will also be found in mitochondria some day as well.”

I highly recommend reading the entire post to understand the arguments as to why and how fluoroquinolones may be connected to ACh disorders.

Can fluoroquinolones trigger anti-ACh antibodies? Can fluoroquinolones trigger a form of myasthenia gravis? How are autoimmune diseases connected to ACh depletion? We know that inflammation is a feature of autoimmune diseases, and that ACh modulates inflammation. We also know that lack of vagal nerve tone is related to both inflammation and autoimmune diseases, and that ACh is produced by a healthy and toned vagal nerve. We know that many of the symptoms of fluoroquinolone toxicity resemble symptoms of various autoimmune diseases, including rheumatoid arthritis, Sjogren’s Syndrome, Lupus, M.S., etc. How are autoimmune diseases, vagal nerve tone, ACh production and/or depletion, and fluoroquinolones related?

I’m not sure of the answers to those questions (I’m not sure that anyone knows the correct answers to them), but I do think that both vagal nerve tone and ACh production and/or depletion is related to fluoroquinolone toxicity (more on that assertion can be found in this post – https://floxiehope.com/2015/06/13/hacking-fluoroquinolone-toxicity-via-the-nervous-system/).

How can floxies increase their ACh? One way to increase ACh is to eat foods that are rich in choline, a precursor to acetylcholine. Choline-rich foods include:

  • Eggs
  • Chicken
  • Fish
  • Liver
  • Nuts

Some herbs and supplements that can increase ACh are listed HERE and HERE. Interestingly, caffeine, which many floxies respond negatively to, is on the list of things that increase ACh, and the supplements noted that decrease ACh have reportedly helped some floxies. As with everything, caution is warranted, and it’s best to consult with a trusted medical professional before starting any supplement protocol.

Exercises and practices that stimulate the vagus nerve can also stimulate the production and movement of ACh. Some things that stimulate the vagus nerve include:

  • Meditation
  • Breathing deeply and slowly
  • Singing
  • Playing a wind instrument
  • Submerging your face in cold water
  • Gargling
  • Chanting “OM”
  • Laughter
  • Exercise
  • Massage
  • Acupuncture
  • Chiropractic adjustments
  • Positive social interactions

More information about the benefits of stimulating the vagus nerve can be found HERE and HERE.

Many of the vagal nerve stimulating exercises and practices listed above helped me in my recovery from fluoroquinolone toxicity. Meditation and mindfulness were key elements to my recovery. Acupuncture, massage, breathing exercises, and support from loved ones (positive social interaction), were key as well. Even though none of these exercises are “quick fixes” or “big guns,” they are healing practices, and the ACh and vagus nerve connection may be how they help to repair the body and mind.

I hope that some research is done into the connections between fluoroquinolones/fluoroquinolone toxicity and ACh. It’s reasonable to think that there are connections–they just need to be proven.

Until then…. meditate, breathe, laugh, and eat liver. They really do help.

 

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