Tag Archives: mitochondria

Mitochondria Summit

I just had surgery (just a couple hours ago as I write this), so this post is going to be short and sparse. BUT, I wanted to let you all know that there is a summit about Mitochondria that is happening THIS WEEK (December 9-15). You can access it through clicking on the image above, or through THIS LINK.

Fluoroquinolones damage mitochondria, and have been shown to deplete mitochondrial DNA. More information about the damage done to mitochondria (the energy-producing organelles of our cells) can be found in these posts:

Study Finds that Ciprofloxacin Depletes Mitochondrial DNA

New Study Finds that Ciprofloxacin Depletes Mitochondrial DNA

More posts about how fluoroquinolones damage mitochondria can be found through doing a search for mitochondria on floxiehope.com, and through searching for “mitochondria” on the links & resources page where you can find media and journal articles about the effects of fluoroquinolones on mitochondria.

In their April 27, 2013 Pharmacovigilance Review, “Disabling Peripheral Neuropathy Associated with Systemic Fluoroquinolone Exposure,” the FDA describes the damage done to mitochondria by fluoroquinolones:

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

The FDA Pharmacovigilance Report also notes that mitochondrial damage (and the ensuing oxidative stress that occurs when mitochondria are damaged) is related to multi-symptom, chronic diseases like optic neuropathy, neuropathic pain, hearing loss, muscle weakness, cardiomyopathy, lactic acidosis, Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS).

I am excited to hear what the mitochondria experts featured in the Summit have to say about healing mitochondria, possibly un-doing the damage done by fluoroquinolones, and maybe even how to prevent the diseases associated with damaged and depleted mitochondria.

One of the featured speakers is Dr. Terry Wahls, author of The Wahls Protocol, that has helped many floxies including Renee and Jamieson. You can read Renee’s story HERE and you can listen to her podcast HERE and you can read Jamieson’s story HERE. Dr. Wahls was also featured on The Floxie Hope Podcast and you can listen to her interview HERE.

I’m also excited to hear Bridgit Danner, LAc, FDNP discuss the effects of toxic mold on mitochondria, and to hear Michelle Sands, ND discuss the hormone-mitochondria connection, and to hear Jason Prall discuss microbiota-mitochondria communication, and to hear what many more wonderful speakers have to say about mitochondria.

I look forward to spending the next couple days relaxing, recuperating, and recovering from my surgery while learning lots about mitochondria.

I think it will be helpful for floxies, and give insight into healing our mitochondria. It’s THIS WEEK – please let me know your thoughts in the comments below. We can all learn together. 🙂

Fluoroquinolone Toxicity Featured in NATURE

Fluoroquinolone toxicity is highlighted and featured in NATURE – one of the oldest, most reputable, journals in the world. This is so exciting!!

You can read the article, When antibiotics turn toxic, that was published in Nature on March 21, 2018 HERE.

Here are some highlights from the Nature article:

First, thank you to Dr. Miriam van Staveren whose story was told in the Nature article. She is a physician and a fellow “floxie.” Even as a physician, she had trouble getting her experience of being poisoned by Levofloxacin acknowledged:

“Since then, she has seen a variety of medical specialists. Some dismissed her symptoms as psychosomatic. Others suggested diagnoses of fibromyalgia or chronic fatigue syndrome. Van Staveren is in no doubt, however. She’s convinced that the antibiotic poisoned her.”

Second, the article mentions Fluoroquinolone Toxicity and Fluoroquinolone Associated Disability (FQAD) by name. This is huge! Rather than calling what we are experiencing something like, “a rare adverse reaction,” it is referred to as fluoroquinolone toxicity or FQAD. This is subtle acknowledgement that what we are going through is a syndrome–a thing in itself–not just a “side-effect” to be dismissed.

Third, even though the word “rare” is used throughout the article, and I know that this is annoying and off-putting for all of us who see that fluoroquinolone toxicity is NOT RARE, the article also notes that the frequency of fluoroquinolone toxicity is higher than many assume:

“From the 1980s to the end of 2015, the FDA received reports from more than 60,000 patients detailing hundreds of thousands of ‘serious adverse events’ associated with the 5 fluoroquinolones still on the market (most commonly tendon rupture, as well as neurological and psychiatric symptoms), including 6,575 reports of deaths. The FDA says that the reports of adverse events it receives — sent in by drug manufacturers, by doctors and directly by consumers — cannot be used to reach conclusions about the severity of problems associated with drugs. Still, the fluoroquinolones have attracted more complaints than other more widely used antibiotics. And only 1–10% of adverse events are estimated to be reported to the FDA, suggesting that fluoroquinolones might have harmed hundreds of thousands of people in the United States alone, says Charles Bennett, a haematologist at the University of South Carolina’s College of Pharmacy in Columbia. Bennett is also director of the Southern Network on Adverse Reactions, a state-funded pharmaceutical-safety watchdog, which has been working with people affected by fluoroquinolones since 2010.”

Fourth, mitochondrial damage is noted as a cause of fluoroquinolone toxicity:

“Accumulating evidence, Golomb says, suggests that fluoroquinolones are damaging mitochondria, the power packs inside human cells that evolved from symbiotic, bacteria-like cells billions of years ago. This kind of harm can affect every cell in the body, explaining why a wide range of symptoms can appear and get worse over time.”

Fifth, the article noted that Dr. Charles Bennett, may have found some genes shared by people who are hurt by fluoroquinolones:

“At a conference last September, Bennett reported preliminary data that might hint at why only some people develop serious side effects from fluoroquinolones. He took saliva samples from 24 people who reported neuropsychiatric side effects — such as memory loss, panic attacks and depression — and found that 13 of them (57%) shared a gene variant usually seen in only 9% of the population.”

If there are genes that make people more succeptible to disabling fluoroquinolone toxicity, perhaps those can be tested for before fluoroquinolone prescriptions are written.

Sixth, the article notes the obstacles that scientists, researchers, and doctors face when they question and investigate adverse drug reactions. It is noted that little support or funding for adverse drug reaction research is available, and that many scientists face push-back from pharmaceutical companies when they attempt to research fluoroquinolone toxicity.

Last, Floxie Hope was mentioned in the article. Squeee! What an honor and a privilege to be mentioned in an article in Nature!

“On websites and Facebook groups with names such as Floxie Hope and My Quin Story, thousands of people who have fallen ill after fluoroquinolone treatment gather to share experiences. Many of them describe a devastating and progressive condition, encompassing symptoms ranging from psychiatric and sensory disturbances to problems with muscles, tendons and nerves that continue after people have stopped taking the drugs. They call it being ‘floxed’.”

Those seven points are the highlights of the article, in my opinion, but I suggest that each of you read the article yourself. It’s currently (03/25/18) on the home-page of nature.com. Squee!

*****

 

Persistent Fluoroquinolones in the Body and Delayed Adverse Reactions

This is a guest post written by Gary. You can read Gary’s story HERE. It contains a wonderful wealth of knowledge, insight, and advice. 

Fluoroquinolone side effects are often multisymptom affecting a wide range of bodily functions, ie: CNS, Muscles, Tendons, Brain, etc (Halkin, 1988l Mattappalil and Mergenhagen, 2014; Menzies et al., 1999; Moorthy et al., 2008; Thomas and Reagan, 1996; etc)

The chronic, often multisymptom, effects are not well documented and are normally assigned (often multiple) different diagnosis by doctors, such as clinical depression, fibromyalgia, etc/ (Strauchman and Morningstar, 2012)

I argue the reason for the chronic effects is because the Fluoroquinolones are not metabolized correctly, or the are metabolized and the normal biological enzymes that are responsible for detoxification of xenobiotic substrates is impared. A xenobiotic is a synthetic chemical such as Levaquin, Cipro, pestacides, etc. It’s also likely that FQ exposure changes gene expressions relating to various cytochrome P-450s (which is responsible for metabolizing and detoxification) causing your body to accumulate toxic chemicals, being unable to remove them.

For example, According to Liang et al., (2015), Fish that were exposed to a specific FQ had changes to cytochrome P450 1A (CYP1A), cytochrome P-450 3A (CYP3A), glutathione S-transferase (GST), P-glycoprotein (P-gp), which are all responsible for metabolizing and/or removal of xenobiotics. Other animals exposed to FQs were shown to have changes in cytochrome P-450 sites – For example, Dogs exposed to FQs showed inhibiting only cytochrome P-450 3A (Regmi et al., 2005; 2007), Chickens (Shlosberg et al., 1997; Granfors et al., 2004). To be fair, this might not affect humans completely, but this would likely explain the delayed toxicity to the CNS and other parts of the body – Delayed toxicity for FQ patients are likely a result of impared detoxification pathways due to FQ exposure overall which means the body has a high level of xenobiotics that cannot be removed.

There are even a few case studies on /people/ to support this article. In a paper (Strauchman and Morningstar, 2012), a patient was prescribed Moxifloxacin in 2005 and developed a worsening set of symptoms (after inclusion of medication), such as episodic tachycardia, episodic dizziness, episodic shortness of breath, and chronically swollen glands. Additional symptoms included daily episodes of nausea, sweating, tremors, brain fog, blurred vision, panic attacks, and phonophobia. Over the course of 3 years, after Moxifloxacin treatment, her condition improved, modestly.

In 2011, the PCP diagnosed the patient with diverticulitis and prescribed her ciprofloxacin 500 mg – Over the course of the treatment, she started to experience all the previous symptoms from 2005 – including panic attacks, insomnia, blurred vision, tachycardia, and nausea. This episode additionally included diffuse musculoskeletal joint pain. The patient also reported that her elbows, wrists, and knees seemed to crack too easily and too often. (p.3). Full workup was ordered, including genetic testing which showed the following:

– Genetic polymorphism in the cytochrome P-450 pathway

– Genetic variations in the catechol-o-methyl transferase enzyme, the Nacetyl transferase enzyme, and the glutathione-s-transferase enzyme necessary for glutathione conjugation and phase II detoxification.

The patient was also tested for polychlorinated biphenyls and other volatile solvents. They found the patient to have elevated levels of ethylbenzene, xylene, and the pesticide dichlorodiphenyldichloroethylene. Although these levels could indicate environmental accumulation, impaired detoxification pathways may make this accumulation more of a contributing factor.

Fluoroquinolone treatment seems to affect enzymes possesses, causing reduced activity due to chelation of ions, such as Se2 [Selenium], Mg2 [Magnesium], Fe2/3+ [Iron] (Badal et al., 2015; Uivarosi, 2013; Seedher and Agarwal, 2010) which explains the chronic issues, as well as delayed toxicity (due in part to impaired detoxification)

Even more evidence that either FQs remain in the body, impairing detoxification of xenobiotics (or they contribute to impairment) is from a journal (Cohen, 2008) where a patient was on a 14 day course of Moxifloxacin and became disabled, for many years; His symptoms were Brain Fog, Cognitive Defects/memory loss, tingling and numbness in his legs, joint pains, Achilles pain, Chronic Fatigue, Weakness, to a degree that he could barely stand or walk; The patient began IV Based Antioxidant therapy, and his condition improved considerably (95%+ recovery within a month). It’s highly likely that the IV Antioxidant therapy activated/modulated cytochrome P-450 to allow the patients body to excrete the excessive, normal environmental xenobiotics (and including Moxifloxican) and the patient recovered.

Fluoroquinolones have a very high melting point, over 200C, which means the crystals they form are very stable in neutral pH. (Andriole et al., 2000). If FQs are stuck within the cells, then that means they are responsible with mitochondrial ETC leakage, causing depressed health effects (ie: Brain Fog from FQ exposure is likely caused by FQs interfering with ATP energy output, which affects the Brain’s homeostasis).

What causes the delayed toxicity? There are only 3 possible explanations.

– You have pre-existing genetic polymorphisms in cytochrome P450s (and others) that prevent you from metabolizing and/or excreting FQs – Which leads to various normal systems in the body to suffer for a long period of time. (FQ crystals are ‘stuck’ in your body)

– FQs /cause/ the polymorphisms because they chelate heavy metals that enzymes require for proper biological function, such as phase II detoxification. Once this happens, your body begins to accumulate xenobiotics and you develop delayed toxicity.

– FQs cause mitochrondia dysfunction with organs responsible for generting glutathione, causing your body to have extremely low levels of glutathione, leading to increased amounts of xenobiotics that you cannot remove.

If this behavior takes place, how do we prove it?

– Genetic testing is the only way to be sure you have these Genetic polymorphisms/Genetic Variations – Some sites out there do provide this.

– Liquid Chromatography-tandem mass spectrometry will need to be performed on blood samples from people currently damaged by FQs to see if any concentrations of it exist in plasma.

– Total GSH testing would likely show lower-than-expected glutathione levels in the body with someone that is disabled, because if FQs are embedded in the cells, they are likly decreasing ATP output of various organs.

How would we remove the FQs that are ‘stuck’ in the body?

– Ozone is able to remove FQs from water (Feng et al., 2016). Therefor, Ozone therapy might be an idea If this behavior of FQs takes place.

– Fluoroquinolones have a Michael acceptor in them, making them very electrophilic. The non-aromatic double bond could potentially be subject to nucleophilic attack via a Michael addition, so one removal strategy could be allowing ligating the fluoroquinolone/associated polymorphs to something that is readily transported across cell membranes and excreted. However, this would need to be drawn up on a computer simulation to see if this could be done, cost effectively.

– Prolonged IV Antioxidant therapy, as shown above, seems to reverse FQ toxicity in some patients but further testing will need to be done (A heavy metal toxscreen via blood to be tested for chemical insult will likely need to be ordered)

Pharmacogenomics is going to likely show who is compatible with FQs and who isn’t, down the road–once we identify specific SNP’s that are broken with us floxies, the /good/ news is, with CRISPR technology, those of us with pre-existing polymorphisms (pre/post-FQ) will likely be able to have them corrected with little to no side effects.

Data from the following:

Strauchman M, Morningstar MW. Fluoroquinolone toxicity symptoms in a patient presenting with low back pain. Clinics and Practice. 2012;2(4):e87. doi:10.4081/cp.2012.e87.

N. L. Regmi, A. M. Abd El-Aty, R. Kubota, S. S. Shah, and M. Shimoda, “Lack of inhibitory effects of several fluoroquinolones on cytochrome P-450 3A activities at clinical dosage in dogs,” Journal of Veterinary Pharmacology and Therapeutics, vol. 30, no. 1, pp. 37–42, 2007.  ·  ·

N. L. Regmi, A. M. Abd El-Aty, M. Kuroha, M. Nakamura, and M. Shimoda, “Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs,” Journal of Veterinary Pharmacology and Therapeutics, vol. 28, no. 6, pp. 553–557, 2005.  ·  ·

M. D. Brand, R. L. Goncalves, A. L. Orr et al., “Suppressors of superoxide-H2O2 production at site IQ of mitochondrial complex I protect against stem cell hyperplasia and ischemia-reperfusion injury,” Cell Metabolism, vol. 24, no. 4, pp. 582–592, 2016.  ·  ·

M. A. Simonin, P. Gegout-Pottie, A. Minn, P. Gillet, P. Netter, and B. Terlain, “Pefloxacin-induced Achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 4, pp. 867–872, 2000.  ·  ·

Krzysztof Michalak, Aleksandra Sobolewska-Włodarczyk, Marcin Włodarczyk, Justyna Sobolewska, Piotr Woźniak, and Bogusław Sobolewski, “Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 8023935, 15 pages, 2017. doi:10.1155/2017/8023935

J. M. Radandt, C. R. Marchbanks, and M. N. Dudley, “Interactions of fluoroquinolones with other drugs: mechanisms, variability, clinical significance, and management,” Clinical Infectious Diseases, vol. 14, no. 1, pp. 272–284, 1992.

H. H. M. Ma, F. C. K. Chiu, and R. C. Li, “Mechanistic investigation of the reduction in antimicrobial activity of ciprofloxacin by metal cations,” Pharmaceutical Research, vol. 14, no. 3, pp. 366–370, 1997.

N. Seedher and P. Agarwal, “Effect of metal ions on some pharmacologically relevant interactions involving fluoroquinolone antibiotics,” Drug Metabolism and Drug Interactions, vol. 25, no. 1–4, pp. 17–24, 2010.

H. Koga, “High-performance liquid chromatography measurement of antimicrobial concentrations in polymorphonuclear leukocytes,” Antimicrobial Agents and Chemotherapy, vol. 31, no. 12, pp. 1904–1908, 1987.

A. Pascual, I. García, S. Ballesta, and E. J. Perea, “Uptake and intracellular activity of trovafloxacin in human phagocytes and tissue-cultured epithelial cells,” Antimicrobial Agents and Chemotherapy, vol. 41, no. 2, pp. 274–277, 1997.

V. T. Andriole, The Quinolones – Third Edition, Acedemic Press, San Diego California, 2000.

S. Badal, Y. F. Her, and L. J. Maher 3rd, “Nonantibiotic effects of fluoroquinolones in mammalian cells,” The Journal of Biological Chemistry, vol. 290, no. 36, pp. 22287–22297, 2015.

J. Y. Lee, S. H. Lee, J. W. Chang, J. J. Song, H. H. Jung, and G. J. Im, “Protective effect of metformin on gentamicin-induced vestibulotoxicity in rat primary cell culture,” Clinical and Experimental Otorhinolaryngology, vol. 7, no. 4, pp. 286–294, 2014.  ·  ·

Z. K. Salman, R. Refaat, E. Selima, A. El Sarha, and M. A. Ismail, “The combined effect of metformin and L-cysteine on inflammation, oxidative stress and insulin resistance in streptozotocin-induced type 2 diabetes in rats,” European Journal of Pharmacology, vol. 714, no. 1–3, pp. 448–455, 2013.  ·  ·

A. I. Morales, D. Detaille, M. Prieto et al., “Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway,” Kidney International, vol. 77, no. 10, pp. 861–869, 2010.  ·  ·

W. Chowanadisai, K. A. Bauerly, E. Tchaparian, A. Wong, G. A. Cortopassi, and R. B. Rucker, “Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression,” The Journal of Biological Chemistry, vol. 285, no. 1, pp. 142–152, 2010.  ·  ·

T. Stites, D. Storms, K. Bauerly et al., “Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice,” The Journal of Nutrition, vol. 136, no. 2, pp. 390–396, 2006.

Y. Huang, N. Chen, and D. Miao, “Biological effects of pyrroloquinoline quinone on liver damage in Bmi-1 knockout mice,” Experimental and Therapeutic Medicine, vol. 10, no. 2, pp. 451–458, 2015.  ·  ·

M. Feng, L. Yan, X. Zhang et al., “Fast removal of the antibiotic flumequine from aqueous solution by ozonation: influencing factors, reaction pathways, and toxicity evaluation,” Science of The Total Environment, vol. 541, pp. 167–175, 2016

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Fluoroquinolone Toxicity Article – Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications

I’m so excited to share this article, “Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications” by Krzysztof Michalak, Aleksandra Sobolewska-Wlodarczyk, Marcin Włodarczyk, Justyna Sobolewska, Piotr Woźniak, and Bogusław Sobolewski, with you! It is the first article of its kind that I’ve seen. While there are thousands of articles about fluoroquinolones, many of which focus on the damaging effects of fluoroquinolones, and many case-studies that note the adverse-effects of fluoroquinolones (hundreds of articles about fluoroquinolones are linked HERE), this is the first article that acknowledges that fluoroquinolone toxicity (referred to as both Fluoroquinolone Associated Disability (FQAD) and fluoroquinolone toxicity throughout the article) is a disabling syndrome, that also goes over the mechanisms by which fluoroquinolones can cause fluoroquinolone toxicity/FQAD, and even gives recommendations on how to treat fluoroquinolone toxicity/FQAD (while also acknowledging that there are no cures or verified treatments). The article even calls for more extensive research to be done into fluoroquinolone toxicity, and the various mechanisms through which fluoroquinolones hurt people.

It is an enlightening article, and I encourage you to print it out and give it to your doctors, family members, and anyone else who is interested in what fluoroquinolones do and how they hurt people. In this post, I’m going to go over some highlights from the article, but I recommend that you read it yourself (you can access it through THIS LINK, after clicking on the “provisional pdf” link).

The first paragraph of the abstract to the article states:

“Long term Fluoroquinolone Associated Disability (FQAD) after fluoroquinolone (FQ) antibiotic therapy appears in recent years a significant medical and social problem, because patients suffer for many years after prescribed antimicrobial FQ-treatment from tiredness, concentration problems, neuropathies, tendinopathies and other symptoms. The knowledge about the molecular activity of FQs in the cells remains unclear in many details. The effective treatment of this chronic state remains difficult and not effective. The current paper reviews the pathobiochemical properties of FQs, hints the directions for further research and reviews the research concerning the proposed treatment of patients.”

To see that in writing, in an academic article, is incredibly validating.

Adverse Effects of Fluoroquinolones

Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications, goes over the documented effects of fluoroquinolones. For tendinopathies and tendon ruptures, researchers have found that:

“FQs are associated with an increased risk of tendinitis and tendon rupture. This risk is further increased in those over age 60, in kidney, heart, and lung transplant recipients, and with use of concomitant steroid therapy.”

Fluoroquinolones cause neurotoxicity, as well as central and peripheral nervous system ailments:

“Taking FQs is associated with their neurotoxicity, as well [5-8]. The main symptoms being correlated to FQ treatment include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis [9-11]. Many reports point to chronic persistent peripheral neuropathy to be generated by FQs [12-18]. Cohen et al. [19] showed that a possible association between FQ and severe, long-term adverse effects involving the peripheral nervous system as well as other organ systems are observed.

Fluoroquinolones also cause cardiotoxicity and an elongation of the QT interval, as well as hepatotoxicity and nephrotoxicity. Fluoroquinolone use has even been linked to type-2 diabetes onset.

Fluoroquinolone toxicity / FQAD is a multi-symptom, chronic illness that affects all body systems. Fluoroquinolones deleteriously affect every muscle, tendon, ligament, nerve, and even bone, in the body. They damage every cell in the body.

Fluoroquinolone Damage Mechanisms

Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications, notes the various mechanisms by which fluoroquinolones cause cellular (mitochondrial) damage, including oxidative stress, and the downstream effects of oxidative stress, including disruptions in the mitochondrial Permeability Transition Pore (PTP) (and the article authors state, “The influence of FQs on the detailed regulation of PTP is the urgent topic for further research.”), Calcium and magnesium homeostasis, lowered ATP production, and more.

Here is a diagram of the mechanisms of fluoroquinolone toxicity (published in the article):

Figure 2. The main ways of FQ toxicity. The positive regulatory loops magnifying the toxicity of FQs are marked with ‘+’. The ‘?’ signs denote the possible but not confirmed effects of FQ toxicity.

The article also notes the epigenetic effects of fluoroquinolones and oxidative stress:

“Beside OS (oxidative stress), epigenetic effects of FQs are of high importance, as well. The epigenetic effects may depend on the methylation of DNA and/or histones, however, ROS contribute also to epigenetic changes [42]. Some authors point also to the similarity of bacterial and mitochondrial DNA, both existing in circular super-twisted helices and gyrase-like enzymes being postulated to be responsible for the organization of mitochondrial DNA, suggesting the possible direct effect of FQs to mitochondrial DNA leading to the disturbed mitochondria regeneration and division [43, 44]. The changes in the cytoskeleton were observed also after FQ treatment [45] and cytoskeleton has been demonstrated to be strictly connected with energy dissipation and organization in mitochondria [46-49].”

Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications, also notes that fluoroquinolones chelate various minerals and metals. The article notes that, “Seedher’s results indicate that chelation formation with bivalent metals can cause significant alterations in the human serum-FQ binding affinity.” The article also describes how fluoroquinolones chelate iron, zinc, magnesium, and other minerals, and how this chelation can have enzymatic and even epigenetic adverse effects.

Fluoroquinolones are GABA antagonists, and the effects of fluoroquinolones are similar to those of benzodiazepine withdrawal. The authors of Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications, describe a potential mechanism through which GABA is depleted by fluoroquinolones:

“One of the proteins which can support PTP opening is Translator Protein (TSPO), called also peripheral-type benzodiazepine receptor or isoquinoline binding protein. TSPO is predominantly located on the surface of the mitochondria where it is postulated to physically associate with VDAC-ANT. It has been suggested that TSPO may activate PTP opening, causing ∆Ψm reduction and leading to apoptosis [80, 81]. Some authors suggest that epileptogenic activity of FQs possibly relates to GABA-like structure of some FQs which may allow them to act as GABA antagonists [82, 83]. Since TSPO is also a benzodiazepine receptor, similar interaction may maybe also take place between FQs and TSPO leading to opening PTP.”

I have always wondered how GABA inhibition is connected to mitochondrial destruction. The article excerpt above answers that question for me.

Fluoroquinolones can lead to chronic illness and permanent disability, which has led many people to question whether or not they remain in the body for an extended period of time (or, if they do damage while they’re in the body that continues long after the drug has left the body). The authors of Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications note that:

“The other important feature of FQs has been presented by V.T. Andrioleet al. [55]. Namely, they estimated the minimum solubility of FQs in neutral pH. They pointed that this class of molecules is characterized by very high melting point, generally >200°C, which indicates that the crystal forms are very stable. All these FQ features strongly support the thesis that FQs can survive in the cell for a long time contributing to chronic, long-term adverse reaction in patients treated with FQs. The question, to what extent takes this phenomenon place and if it contributes to chronic symptoms of FQAD, remains unclear.”

It is acknowledged throughout the article that it is unknown whether or not fluoroquinolones stay in the body for an extended period of time. It is possible, through the mechanism noted above, but no hypotheses about fluoroquinolones remaining in the body after they “should” have been metabolized and fully excreted, have been explored. It’s both possible that they remain in cells, and that they don’t – no one really knows.

The article authors repeatedly call for additional research into the various mechanisms by which fluoroquinolones lead to pain, disability, and chronic illness:

“Summing up, the number of enzymes possessing reduced activity due to their ion-cofactor chelation is probably long and it is the important topic for further research. The separate problem consists the chronicity of ion-chelation by FQs. The presented research does not describe the chronic state of FQAD but the phenomena taking place during FQ application. It must be analyzed, to which degree persistent ion chelation takes place at FQAD patients.”

Fluoroquinolone Toxicity Treatment

Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications is the first article I’ve seen that discusses the treatment of fluoroquinolone toxicity as a multi-symptom, chronic illness. The authors note that the first step in approaching a treatment is to discover why fluoroquinolones are causing chronic illness in the first place. Effective treatment, of course, depends on effective identification of the problem. With that noted, the article authors have enough knowledge to make a few suggestions:

“Until detailed knowledge concerning FQ toxicity would be recognized, the following directions in supporting FQAD patients are proposed according to the known and probable mechanisms of FQ toxicity: A. reduction of the oxidative stress; B. restoring reduced mitochondrial potential ∆Ψm; C. supplementation of uni- and bivalent cations that are chelated by FQs;D. supporting the mitochondrial replication in the cell – pulling the more destroyed to apoptosis and proliferation of the more healthy ones; E. removing FQs permanently accumulated in the cells (if this phenomenon takes place); F. regulating the disturbed epigenetics and enzyme activities”

The article authors note that antioxidant supplementation is a broad topic and that fixing the damage done by fluoroquinolones and oxidative stress is not as simple as just ingesting an antioxidant pill. However, antioxidant supplements that specifically target the mitochondria have shown some promising results:

“The antioxidants which enter easily the mitochondria are the most interesting ones. Lowes et al. [79] shows that the mitochondria targeted antioxidant MitoQ protects against fluoroquinolone-induced oxidative stress and mitochondrial membrane damage in human Achilles tendon cells. In cells treated with MitoQ the oxidative stress was lower and mitochondrial membrane potential was maintained.”

Other antioxidants have also had promising results in repairing fluoroquinolone treated cells. Some of the antioxidants with promising results include N-acetylcysteine, resveratrol, as well as Vitamins C and E. Supplementation of the trace minerals that are important cofactors for antioxidants is also important.

Conclusion

I greatly appreciate the authors of Treatment of the Fluoroquinolone Associated Disability – the pathobiochemical implications. They approach fluoroquinolone toxicity/FQAD as a complex and multifaceted illness. It IS a complex and multifaceted illness, and it is refreshing to read an article that doesn’t over-simplify or downplay the illness. I also appreciate the exploration of what is currently known about fluoroquinolone toxicity/FQAD, and the assertions that more research into fluoroquinolone toxicity is needed (it is!). I think that everyone who is going through fluoroquinolone toxicity/FQAD should read it, and share it as widely as possible.

 

 

 

NSAIDs and FQs Damage Mitochondria, Increase Oxidative Stress, and Cause Cell Death

As I noted in the post, Why NSAIDs Suck for Floxies (and Probably Everyone Else Too), NSAIDs often exacerbate fluoroquinolone toxicity symptoms, and there are several mechanisms through which NSAIDs can interact with fluoroquinolones. The results of a recent article published in the Journal of Molecular and Cellular Cardiology by researchers at UC Davis, Different effects of the nonsteroidal anti-inflammatory drugs meclofenamate sodium and naproxen sodium on proteasome activity in cardiac cells, help to further explain why NSAIDs trigger fluoroquinolone toxicity symptoms, and why they are a horrible combination.

NSAIDs and Fluoroquinolones Damage Mitochondria

The study showed that NSAIDs “Attack mitochondria, reducing the cardiac cell’s ability to produce energy” (source).

Likewise, fluoroquinolones have been shown to attack mitochondria. The studies, Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells and Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells show that fluoroquinolones damage mitochondria, deplete mitochondrial DNA, and cause oxidative stress.  Also, the FDA admits that mitochondrial damage is the likely mechanism through which fluoroquinolones cause peripheral neuropathy.

Healthy mitochondria are vital for cellular energy and health. Unhealthy mitochondria have been linked to many diseases, including M.S., fibromyalgia, M.E./C.F.S., P.O.T.S., diabetes, cancer, aging, and more. Do NSAIDs and fluoroquinolones increase one’s chances of getting those diseases that are related to mitochondrial dysfunction? It’s certainly reasonable to think so – via the mitochondrial damage link – but studies have not shown a direct connection (mainly because neither have been researched).

NSAIDs and Fluoroquinolones Increase Reactive Oxygen Species (ROS)

NSAIDs also “Cause the production of reactive oxygen species, which stresses heart cells and is associated with many diseases, including heart disease” (source).

Fluoroquinolones have also been shown to increase production of reactive oxygen species (ROS – aka oxidative stress). The article, Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients notes that, “Several in vitro and in vivo study using animals revealed that fluoroquinolones induced oxidative stress by producing reactive oxygen species (ROS)” and that in vivo human studies show that, “ciprofloxacin and levofloxacin induce more reactive oxygen species that lead to cell damage than gatifloxacin.

ROS are described as follows:

Without oxygen, we could not exist. However, in the process of generating energy by “burning” nutrients with oxygen, certain “rogue” oxygen molecules are created as inevitable byproducts. Known as free radicals and reactive oxygen species, these unstable, highly reactive molecules play a role in cell signaling and other beneficial processes when they exist in benign concentrations.  But when their numbers climb, as may occur as a result of aging and other conditions, they may wreak havoc with other molecules with which they come into contact, such as DNA, proteins, and lipids. As such, these “pro-oxidant” molecules become especially toxic.

In fact, a prevailing theory of disease and aging states that the gradual accumulation of pro-oxidant molecules, and the harm they incur, is responsible for many of the adverse changes that eventually cause various diseases. These include cancer (possibly triggered by free radical-induced damage to cellular DNA) and inflammatory and degenerative diseases such as Alzheimer’s, arthritis, atherosclerosis, and diabetes. While scientists have not yet reached consensus on the topic, accumulated evidence overwhelmingly identifies increased oxidative stress with age as a source of damage to cellular structure and function. (source)

To drastically over-simplify things, ROS are the opposite of antioxidants. If you’ve ever read about the benefits of antioxidants like vitamin C or glutathione, ROS have the opposite effects. In excess, ROS are harmful and damaging to cells.

NSAIDs and Fluoroquinolones Cause Cell Death

NSAIDs were found to “Impair the cardiac cell’s proteasome, the mechanism for degrading harmful proteins. This leads to toxic buildup and eventually to the death of cardiac cells” (source).

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Fluoroquinolones have also been found to cause cell death (apoptosis). This has been shown in many articles that note that fluoroquinolones are useful as chemotherapeutic agents specifically because they kill cells. Unfortunately, they don’t just kill cancer cells, they also kill healthy cells. The following articles note that fluoroquinolones are chemotherapeutic drugs that damage and kill cells:

  1. In an article published in the journal Urology, it was noted that, “Ciprofloxacin and ofloxacin exhibit significant time and dose-dependent cytotoxicity against transitional carcinoma cells.” That’s great – excellent, actually – if you happen to have carcinoma cells in your bladder. But if you just happen to have a bladder infection, chemo drugs that exhibit toxicity toward human cells – cancer or otherwise – are inappropriate for use (1).
  2. The mechanism for action for fluoroquinolones is that they are topoisomerase interrupters (2).Topoisomerases are enzymes that are necessary for DNA replication and reproduction. All of the other drugs that are topoisomerase interrupters are approved only for use as chemotherapeutic agents. It is only appropriate to use drugs that disrupt the process of DNA replication and reproduction when someone’s cells are already so messed up that they have cancer.
  3. Fluoroquinolones have been found to interfere with the DNA replication process for human mitochondria (3, 4, 5). Mitochondria are vital parts of our cells, (cellular energy is produced in our mitochondria), and disrupting the process through which mitochondrial DNA replicates causes cellular destruction, oxidative stress and disease.
  4. Fluoroquinolones have been shown to be genotoxic and to lead to chromosomal abnormalities in immune system cells (6).
  5. Fluoroquinolones disrupt cellular tubulin assembly (7). All of the other drugs that disrupt tubulin assembly are chemotherapeutic drugs.
  6. Fluoroquinolones disrupt enzymes, including CYP1A2 enzymes, which are necessary for detoxification.

Avoid NSAIDs and Fluoroquinolones

Dr. Aldrin V. Gomes, one of the authors of Different effects of the nonsteroidal anti-inflammatory drugs meclofenamate sodium and naproxen sodium on proteasome activity in cardiac cells, “advised caution when using NSAIDs either topically or orally” (source). Likewise, caution is warranted when using fluoroquinolones, as one can gather from reading any of the stories of pain and suffering caused by fluoroquinolones. Personally, I will do everything in my power to avoid both NSAIDs and fluoroquinolones for the rest of my life. Mitochondrial destruction, oxidative stress, and cell death aren’t things I want.

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Loss of Faith in the Healthcare System

After getting “floxed,” I lost a lot of faith in the medical system.

I used to think that the medical system, as a whole, was trustworthy. I knew that the system was imperfect, but I thought that most of the problems had to do with cost and insurance, and that drugs generally were well understood and regulated, and that they did more good than harm.

Getting hurt by a prescription drug, an antibiotic no less, shook my faith in the medical system. Researching fluoroquinolones and other drugs made me realize how little anyone knows about how drugs work, and why they sometimes don’t work, and I further lost faith in the system.

As I witnessed a prescription drug causing people to be chronically ill, I started to wonder if many of the chronic illnesses (autoimmune diseases, neurodegenerative diseases, mysterious diseases like ME/CFS and fibromyalgia, diabetes, etc.) were due to the cellular destruction inflicted by prescription drugs. Many prescription drugs, not just fluoroquinolones, wreak havoc on the microbiome, mitochondria, neurotransmitters, and more–and problems with those systems have been linked to many of the chronic diseases of modernity.

I saw that the only thing that the FDA is inclined to do about adverse drug reactions is to increase the size of the warning labels–as if anyone reads the warning labels and as if this is actually a solution. I noted that thousands of people are killed by prescription drugs each year, and I lost faith in the FDA’s ability to regulate the pharmaceutical industry.

The 21st Century Cures Act, a piece of legislation that is going through Congress right now, is a thinly-veiled give-away to the pharmaceutical industry that decreases drug regulation at a time when it needs to be increased. Congress is not only failing to recognize the problem of prescription drugs hurting and killing people, it is actively encouraging the pharmaceutical industry to do more of the same. I didn’t have a lot of faith in the U.S. Congress before I got “floxed,” but I have even less faith in them now. (If you want to read my take on the 21st Century Cures Act, I wrote about it in the post, “The 21st Century Cures Act” Is On Its Way – Here’s Why You Haven’t Heard About It that was published on Collective Evolution on 7/7/15.)

I wonder how many other people there are like me–who no longer trust the medical system after being hurt by it. I suspect that most (but certainly not all) people who get hurt by prescription drugs no longer view the system as a whole as trustworthy or credible.

Once a system loses credibility, many people opt out of it and seek alternatives. If the healthcare system loses credibility in the minds of most people, and most people opt out of it, it will, eventually, collapse. I have no idea when this will happen, or even if there are enough people who think like me that it will happen. We shall see.

Unfortunately, a lot of people are currently being hurt by adverse drug reactions, and more people will have to get hurt for a crash to happen. I don’t hope for a crash. I hope that the regulators (the FDA) start doing their jobs and that the pharmaceutical companies start upholding their credos and start having morals. I wish I saw that happening, but I don’t. Maybe we will reach a tipping point where it will happen–to be determined.

The healthcare industry is immense, and it is much more complicated than the sub-prime housing market that crashed in 2007-2008. However, I see some similarities between the sub-prime housing market crash and my assertion that the healthcare industry is going to crash (at some point–maybe). Those similarities are described in the post, The Healthcare System Collapse: Lessons from the Housing Market Crash and “The Big Short” that was published on Hormones Matter yesterday – 2/4/16. (This post started as an intro to the Hormones Matter post, and it just morphed into its own post. Please read and share The Healthcare System Collapse: Lessons from the Housing Market Crash and “The Big Short” – Thanks!)

I foresee a crash in the medical system because I’ve lost faith in it. Maybe I’m wrong and other people will respond differently from how I have after getting hurt by the medical system. Maybe I really am “rare” and other people won’t get hurt by the medical system. Or, maybe drugs will get more and more dangerous because of lack of regulation, and more and more people will get hurt by pharmaceuticals and they will lose faith in the system just like I did, and the demise of the system as we know it will arrive. To be determined, and we shall see. Hopefully I’m just being too pessimistic and the FDA will start doing a better job at protecting people from dangerous drugs. I really do hope that occurs.

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Bulletproof Radio Interview

I had the honor of being interviewed by Dave Asprey for Bulletproof Radio, one of the best, and most popular, health podcasts in the world.

Check it out!

Bulletproof fluoroquinolone antibiotics

https://www.bulletproofexec.com/lisa-bloomquist-know-antibiotics-restore-mitochondria-263/

https://itunes.apple.com/us/podcast/bulletproof-executive-radio/id451295014?mt=2&ign-mpt=uo%3D4

Please subscribe to Bulletproof Radio, download episode #263, “Know Your Antibiotics & Restore Your Mitochondria” and tell all your friends to do the same. Thank you!

Bulletproof Radio has more than 1,000,000 subscribers, and to be able to reach that many people with information about fluoroquinolone toxicity is, potentially, a very, very, very big opportunity, and a very big deal for the “floxie” community.

Where do I even begin describing what an honor it is to have the opportunity to be featured on Bulletproof Radio, Dave Asprey’s popular and influential podcast?

Dave Asprey is the ultimate Bio-Hacker. (You can read about his biohacking endeavors in this article – http://www.mensfitness.com/life/entertainment/inside-personal-health-laboratory-bulletproof-coffees-dave-asprey-worlds-most.) He has sought to optimize his health and performance in all areas, and he has shared his optimal diet, as well as supplement tips, on his web site, https://www.bulletproofexec.com/, and in his excellent book, The Bulletproof Diet: Lose up to a Pound a Day, Reclaim Energy and Focus, Upgrade Your Life.

According to his bio on facebook, “Dave Asprey is a, biohacker, Silicon Valley investor, entrepreneur and the man behind Bulletproof® Coffee. He is the founder of Bulletproof Nutrition, which reaches more than 1.5 million visitors monthly. His top-ranked podcast, Bulletproof Radio, has 9+ million downloads. He has also been featured on the Today show, Nightline, CNN, and in Financial Times, Rolling Stone, Men’s Health, Vogue, Marie Claire, Slate, Forbes, and more. He lives with his family in Victoria, British Columbia.”

And, according to the iTunes summary of Bulletproof Radio, “Bulletproof Executive Radio was born out of a fifteen-year single-minded crusade to upgrade the human being using every available technology. It distills the knowledge of world-class MDs, biochemists, Olympic nutritionists, meditation experts, and more than $250,000 spent on personal self-experiments. From private brain EEG facilities hidden in a Canadian forest to remote monasteries in Tibet, from Silicon Valley to the Andes, high tech entrepreneur Dave Asprey used hacking techniques and tried everything himself, obsessively focused on discovering: What are the simplest things you can do to be better at everything? Welcome to being Bulletproof, the State of High Performance where you take control and improve your biochemistry, your body, and your mind so they work in unison, helping you execute at levels far beyond what you’d expect, without burning out, getting sick, or just acting like a stressed-out a*****e. It used to take a lifetime to radically rewire the human body and mind this way. Technology has changed the rules. Follow along as Dave Asprey and guests provide you with everything you need to upgrade your mind, body, and life.”

It is truly an honor to have the opportunity to share information about fluoroquinolone toxicity on Bulletproof Radio. Thank you for listening!

 

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Floxie Hope Podcast Episode 14 – Dr. Terry Wahls

It was an absolute HONOR to interview Dr. Terry Wahls for episode 14 of The Floxie Hope Podcast. Dr. Wahls has inspired millions of people with her personal story of putting progressive multiple sclerosis (M.S) into remission through diet and lifestyle changes. She is the author of The Wahls Protocol: A Radical New Way to Treat all Chronic Autoimmune Conditions Using Paleo Principles. In addition to reversing the course of various autoimmune diseases, the Wahls Protocol has helped thousands of people to recover from mysterious chronic illnesses like Lyme Disease, fibromyalgia, chronic fatigue syndrome / M.E, and fluoroquinolone toxicity.

In this interview, Dr. Wahls and I discuss how mitochondria can be repaired through diet and lifestyle changes. We go over the basics of The Wahls Protocol diet, and we discuss how everyone who has been hurt by a mitochondrial poison can nourish their cells. Information about Dr. Wahls can be found on http://terrywahls.com/.

You can listen to the podcast through these links:

https://itunes.apple.com/us/podcast/floxie-hope-podcast/id945226010

http://www.floxiehopepodcast.com/episode-014-dr-terry-wahls/

Please accept my sincere apologies for the horrible sound quality in the first 5 minutes of the podcast. It is better after the 5 minute mark, so please hang in there and listen past the fuzziness at the beginning.

Renee’s story illustrates how helpful The Wahls Protocol is for those suffering from fluoroquinolone toxicity – https://floxiehope.com/renees-story-cipro-reaction/.

Dr. Wahls’ TED talk has been viewed more than 2.2 million times and has inspired and touched every person who has viewed it. I encourage you to listen to the podcast, buy the book, and watch Dr. Wahls’ inspirational TED talk

 

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The Mitochondrial Link – Fearless Parent Podcast #81

In my first episode as a host of the Fearless Parent Podcast, I interviewed Dr. Chris Meletis about mitochondria, and how mitochondrial damage relates to health and chronic illness.  Dr. Meletis is brilliant and insightful and it was an honor to have him on the show!

You can learn more about the show, and download it, from this link:

http://fearlessparent.org/radio-blog-the-mitochondrial-link/

Or, you can get it through iTunes:

https://itunes.apple.com/us/podcast/fearless-parent-radio/id761449886?mt=2

Information about Dr. Meletis and his practice in Beaverton, Oregon, can be found on http://www.drmeletis.com/.  Dr. Meletis is changing the world’s health, one person at a time, through books, lectures, podcasts and his practice of naturopathic medicine.

A couple of Dr. Meletis’s wonderful articles on mitochondria are:

Mitochondria Resuscitation: The Key to Healing Every Disease

Mitochondria: The Missing Link in Hormone Therapy

They are highly recommended.

What does this have to do with fluoroquinolone toxicity?  Fluoroquinolones have been shown to damage mitochondria, the energy centers of our cells, so mitochondrial health and fluoroquinolone toxicity are tightly linked.

Thank you for listening and for sharing this podcast!

 

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Fluoroquinolones Damage Mitochondrial Lipids

Fluoroquinolones are Mito-Toxic

Many articles about how fluoroquinolones damage mitochondria and lead to mitochondrial dysfunction have been published.  In Science Translational Medicine, “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells,” it is noted that bactericidal antibiotics, including ciprofloxacin, a fluoroquinolone, “damage mammalian tissues by triggering mitochondrial release of reactive oxygen species (ROS).”  Additionally, in Molecular Pharmacology, “Delayed Cytotocicity and Cleavage of Mitochondrial DNA in Ciprofloxacin Treated Mammalian Cells” it is noted that fluoroquinolones “cause a selective loss of mitochondrial DNA (mtDNA)” and “The loss in mtDNA was associated with a delayed loss in mitochondrial function.”  Even the FDA acknowledges that fluoroquinolones cause mitochondrial damage.  In their April 27, 2013 Pharmacovigilance Review, “Disabling Peripheral Neuropathy Associated with Systemic Fluoroquinolone Exposure,” the FDA notes that the mechanism for action through which fluoroquinolones induce peripheral neuropathy is mitochondrial toxicity. The report says:

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

Fluoroquinolones are very, very bad for mitochondria.  And, as the engines of our cells, healthy mitochondria are very necessary for healthy cells.  Mitochondrial dysfunction is connected with many chronic diseases, including autism, CFS/ME, fibromyalgia, Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis, etc.

Even though there is quite a bit of evidence that fluoroquinolones damage mitochondria, it is not generally acknowledged that fluoroquinolones are mito-toxic.  A petition has been filed with the FDA asking them to add a warning about mitochondrial toxicity to the label of fluoroquinolones.  If the FDA adds the information that is in their internal documents to the public warning label, it will become accepted and acknowledged that fluoroquinolones damage mitochondria, and that fact will be further reflected in research articles.  The ball has to start rolling somewhere.  I thank the researchers who have uncovered the mitochondrial toxicity of fluoroquinolones very much for their research that got the realization of the mito-toxicity of fluoroquinolones started.

Similarities between Fluoroquinolones and other Mito-Toxic Drugs

A drug that is acknowledged to be mito-toxic is adriamycin (doxorubicin).  In Toxicological Sciences, “Review: Mitochondria as a Target of Environmental Toxicants” it is noted that:

“One well-studied example is adriamycin (doxorubicin), a chemotherapeutic whose clinical use is limited by the fact that it also causes irreversible and cumulative cardiomyopathy (Wallace, 2007). It appears to act largely by poisoning mitochondria, both via redox cycling to generate ROS and by inhibiting ATP production via uncoupling of oxidative phosphorylation. Although its antineoplastic function is largely a result of DNA intercalation and topoisomerase II inhibition in the nucleus, a substantial amount reaches mitochondria, where it has a high binding affinity for cardiolipin, a lipid found only in the mitochondrial inner membrane (Mustonen and Kinnunen, 1993).”

It should be noted that, like adriamycin (doxorubicin), fluoroquinolones also cause topoisomerase inhibition and DNA intercalation.  In fact, the mechanism of action for fluoroquinolones is the disruption of topoisomerases, enzymes that are necessary for DNA and RNA replication.  (The “Mechanism of Action” for cipro/ciprofloxacin, as listed on the warning label, 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.”)

Also like adriamycin (doxorubicin), fluoroquinolones bind with and damage cardiolipin, a mitochondrial (and bacterial) membrane lipid.  I suspect that the damage done to mitochondrial cardiolipin by fluoroquinolones is key to understanding fluoroquinolone toxicity.

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Cardiolipin and Fluoroquinlones

In order to explain the relationship between fluoroquinolone induced damage of mitochondrial cardiolipin and FQ toxicity, I’m going to attempt to summarize and synthesize information from The Journal of Cell Biology, “Making Heads or Tails of Phospholipids in Mitochondria” and the Journal of Medicinal Microbiology, “Comparison of the effects of subinhibitory concentrations of ciprofloxacin and colistin on the morphology of cardiolipin domains in Escherichia coli membranes.”  I highly recommend that you read the articles yourself though, because there is a lot of information in them that I won’t be able to get to, and, frankly, I may be wrong in my interpretations of some of the information in the articles.

It should be noted that very little is known about mitochondrial phospholipids.  We know how to mess them up through pharmaceuticals and environmental toxins, but we don’t know how to fix them or even detect the damage done to them very well.  It is noted in “Making Heads or Tails of Phospholipids in Mitochondria,” which was published in 2011, that, “Although an increasingly detailed structural and mechanistic picture is emerging for the biogenesis, sorting, and compartmentation of mitochondrial proteins (Schmidt et al., 2010), much less is known about mechanisms regulating the supply of phospholipids and the maintenance of mitochondrial membrane integrity.” (Emphasis added)  It is also stated that, “The biosynthesis of PE (phosphatidylethanolamine) and CL (cardiolipin) occurs, at least in part, within mitochondria and relies on an intricate exchange of precursor forms between the membrane of the ER (endoplasmic reticulum) and the mitochondrial outer membrane at distinct contact sites, whose structural basis we are just beginning to understand.” And, “Specific mechanisms must exist to ensure the transport of phospholipids from the ER to mitochondria and between outer and inner mitochondrial membranes. However, we are only beginning to understand how these transport processes occur and how they are regulated.”  So don’t feel confident at all that even scientists who publish in the Journal of Cell Biology really have any solid answers about how fluoroquinolones, or any other pharmaceutical, mess up mitochondrial membranes.

What is known about cardiolipin (CL) is that it creates “tension in membranes that is likely of functional importance to various mitochondrial processes like membrane fusion or the movement of proteins or solutes across membranes,” and “CL regulates multiple steps of the apoptotic program” (apoptosis is programmed cell death) and CL also plays an important role in protein import into mitochondria.  Additionally, these pictures (taken directly from “Making Heads or Tails of Phospholipids in Mitochondria,” and all credit should go to the authors and publisher) further explain the important role of cardiolipin:

Cardiolipin

The role of CL in mitochondrial processes. (A) CL (depicted in red) affects mitochondrial energy production and is required for dimerization and optimal activity of the AAC and the formation of respiratory chain supercomplexes. (B) Assembly and activity of protein translocases in the outer (TOM) and inner membrane (TIM22 and TIM23 complexes), the SAM complex in the outer membrane, and the assembly of TIM23 complex with the mitochondrial import motor (PAM complex) is supported by CL. (C) Various roles of CL during apoptosis. (1) Cytochrome c (Cyt c) binds to CL in the inner membrane. (2) Release of cytochrome c upon oxidation of CL. (3) Pro–caspase-8 (pro-8) binds to the surface of mitochondria, oligomerizes, and undergoes autocatalytic processing in a CL-dependent manner. (4 and 5) Bid cleavage to truncated Bid (t-Bid) by pro–caspase-8 (4) and activation and oligomerization of Bax/Bak is stimulated by CL (5). (6) PLS3 allows export of CL from the inner to the outer mitochondrial membrane. (D) CL affects fusion of mitochondrial outer and inner membranes. The phospholipase MitoPLD converts in trans CL into PA (depicted in red), triggering the fusion of outer membranes. CL in the inner membrane stimulates oligomerization and GTP hydrolysis of short Mgm1/OPA1 isoforms. IM, mitochondrial inner membrane; OM, mitochondrial outer membrane.”

Got it?  Yeah, this stuff is hard.  Cardiolipin and the other mitochondrial membranes are important for cellular functioning, and messing up mitochondrial DNA messes up mitochondrial membranes – that’s the gist of it.

Shape Shifting Mitochondria

In “Comparison of the effects of subinhibitory concentrations of ciprofloxacin and colistin on the morphology of cardiolipin domains in Escherichia coli membranes” it was found that “exposure of bacteria to ciprofloxacin significantly increased the percentage of filamentous cells with altered morphology of the cardiolipin domains.”  This finding was surprising to the researchers who authored the study because fluoroquinolones are not supposed to work by disturbing the cell wall of bacteria, they disrupt bacterial DNA reproduction, “but surprisingly, changes were found exclusively in CIP-treated cells.”  (CIP stands for ciprofloxacin.)  They noted that:

“We are not the first to report that DNA topoisomerase inhibition can be followed by the alterations at the level of the bacterial membrane. Dougherty & Saukkonen (1985) showed that inhibition of DNA synthesis by nalidixic acid, a DNA gyrase inhibitor, results in morphological changes consistent with a loss of membrane integrity and leakage of intracellular components. Similar results were presented by Wickens et al. (2000), who noticed a decrease of both membrane integrity and membrane potential after exposure of E. coli to CIP. One of the proposed explanations of this finding is that, as a result of processes induced by inhibition of DNA replication, cells lose their capacity to synthesize necessary components and to maintain the proper membrane structure (Dougherty & Saukkonen, 1985).”

It has been known, SINCE 1985, that fluoroquinolones (the backbone of all fluoroquinolones is naladixic acid) cause “a loss of membrane integrity and leakage of intracellular components.”  Intracellular components, especially minerals, especially magnesium, are pretty important.  Thanks, FDA, and all the other powers that be within the medical/pharmaceutical complex for completely ignoring that valuable piece of information when making use guidelines for fluoroquinolones.  Sigh.

It is also noted in “Comparison of the effects of subinhibitory concentrations of ciprofloxacin and colistin on the morphology of cardiolipin domains in Escherichia coli membranes” that:

“It has also been reported that the unique chemical structure of CL (cardiolipin) allows for trapping of protons and lateral shuttling of them from oxidative phosphorylation complexes to ATP synthase (Haines & Dencher, 2002). This ability determines a unique role of CL as a proton trap within membranes that conduct oxidative phosphorylation and thus ATP synthesis, which suggests why CL is found in membranes which pump protons, e.g. mitochondrial inner membrane and cell membrane of eubacteria (Haines & Dencher, 2002). This specific CL function allows us to speculate that presumably after the fluoroquinolone treatment bacterial membranes maintain CL domains, but (due to membrane perturbation) in altered shapes. Such an effect was observed in our experiments, as CIP treatment induced a significant increase in the number of filamentous cells with FT2 morphology.”

The changing of the shape of mitochondria that is induced by ciprofloxacin induced damage of cardiolipin (and other mitochondrial lipids) is important as well.  In the post on Hormones Matter entitled “Hormones, Hysterectomy and the Aging Brain” it is noted that:

“I just finished writing an extensive paper on acquired mitochondrial illness. Over the course of the research, I stumbled upon a short essay linking mitochondrial structure and function to estradiol. More specifically, the rapid estradiol decline common post oophorectomy (ovary removal), fundamentally alters the shape, and ultimately, the function of mitochondria. (emphasis added)  Researchers found that a rapid decline in estradiol evokes significant damage in the brains (and presumably other body parts) of female monkeys. Additional studies using estradiol starved mitochondria from female rodents showed similar shape alterations and consequent declines in brain bioenergetics. Interestingly though, with natural menopause, where estradiol declines more gradually, no such structural changes were observed. In fact, with the more gradual decline in estradiol the mitochondria appear to increase their production of the lifesaving ATP as a compensatory reaction.”

Mitochondrial shape, which is determined by phospholipid integrity, is connected to hormones and brain health as well.  It’s all connected.  Fluoroquinolones throw a wrench in the whole thing.

Molecular Shape of Mitochondrial Lipids and Possible Solution

It is noted in “Making Heads or Tails of Phospholipids in Mitochondria” that “The non–bilayer-forming lipids PE and CL are more conical shaped with a smaller hydrophilic head group diameter and a relatively larger hydrophobic domain diameter. This shape allows the formation of hexagonal phases that can be observed for isolated lipids depending on the pH and ionic strength” and that, “Early studies with model membranes demonstrated that the formation of hexagonal structures induce membrane fusion and suggested a crucial role of non-bilayer lipids such as CL or PE for membrane fusion in vivo.”

This may be a reach and I could be wrong to connect these things, but the mention of a hexagonal structure made me think of a treatment that has helped several long-time floxies.  The treatment is called Buckminsterfullerene/c60.  In the few articles that I’ve read about Buckminsterfullerene/c60 it appears that the molecular shape is important.  Per the article, “Liposome Formulation of Fullerene-Based Molecular Diagnostic and Therapeutic Agents,” published in Pharmaceutics, “Fullerenes are hollow cage molecules with sp2 carbon atoms arranged in hexagons and pentagons.”   They’re also powerful antioxidants and the results that the floxed friends are getting from supplementing with Buckminsterfullerene/c60 are impressive.

I think that a lot more research needs to be done on Buckminsterfullerene/c60 before it is determined to be an effective or safe treatment for FQ toxicity.  As with everything, do your own research, be careful, know that I’m not a doctor, etc.

Here are a couple of articles about Buckminsterfullerene/c60:

Huffington Post, “Do Buckyballs Extend Lifespan?

Vaughter Wellness, “Aerobic- & strength gains, longevity, brain rejuvenation and tumor prevention with lipofullerene C60 olive oil

It is also noted in “Fullerenes are hollow cage molecules with sp2 carbon atoms arranged in hexagons and pentagons” that, “Fullerene medicine is a new but rapidly growing research subject. Fullerene has a number of desired structural, physical and chemical properties to be adapted for biological use including antioxidants, anti-aging, anti-inflammation, photodynamic therapy, drug delivery, and magnetic resonance imaging contrast agents.”

I don’t currently have enough information to say whether or not Buckminsterfullerene/c60 will help to put your mitochondrial lipids (especially cardiolipin) back together.

But I do think that there is enough information about the severe damage done by fluoroquinolones to mitochondrial lipids that another black box warning for mitochondrial toxicity is warranted.

 

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The Importance of the Microbiome

The bacterial cells in our body outnumber the human cells ten to one.  Additionally, within each eukaryotic (human) cell in our body, there are many (hundreds in many cells) mitochondria – ancient bacteria that got absorbed into non-bacterial cells and formed eukaryotic cells.  Bacteria are an important, vital part of us.  Bacteria affect every aspect of human health, including immune system regulation, digestion, personality, etc.  Additionally, disturbances in the make-up of the microbiome has been connected with multiple chronic diseases, including Parkinson’s Disease, Alzheimer’s Disease, diabetes, autism, autoimmune diseases, etc.

Given the importance of the bacteria that work symbiotically with us, and that ARE US, it drives me a little nuts when people minimize the harm in damaging the microbiome with pharmaceuticals.  If a drug “just” damages bacteria, but doesn’t damage eukaryotic cells directly, it hurts the person who takes the drug, because the bacteria within that person are a vital part of him/her and an integral part of his/her health.

Dismantling the DNA of bacteria (and mitochondria), and inducing massive amounts of oxidative stress (the Fenton Reaction) with fluoroquinolones is particularly stupid.

The above is elaborated upon in the following post on Hormones Matter:

THE HARMFUL EFFECTS OF ANTIBIOTICS ON THE HUMAN MICROBIOME

Thank you for reading it and for sharing it!

 

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Lyme Disease and Fluoroquinolone Antibiotics

To my dear friends with chronic Lyme Disease,

I am so sorry for all that you are going through!  The pain, the exhaustion, the fear, the frustration – all of it.  My heart goes out to all of you!

I know that treatment options are a touchy topic, and that antibiotics are often a necessary part of dealing with Lyme Disease.  However, I’m going to jump right into a volatile sea and say, PLEASE, please, please be careful with antibiotics, and know that they are not all created equally.  Fluoroquinolone antibiotics – Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and Floxin/ofloxacin – are chemo drugs that can do absurd amounts of harm.  I would hate for you to have to deal with two chronic illnesses at once – chronic Lyme and Fluoroquinolone Toxicity Syndrome.  Both are horrible.

Words of Wisdom from a Floxie with Lyme

A few comments on this site, from people who are dealing with both chronic Lyme Disease and Fluoroquinolone Toxicity, are more illustrative than anything I can say.  Here is a comment from my dear friend Catherine, who has been dealing with Lyme Disease for 18 years and Fluoroquinolone Toxicity for 2 years:

My situation is complicated, because I have been wheelchair bound with lyme and co infections for 18 years. I have had about 400 doses of Cipro and 12 days of avelox. I actually got quite a lot better on the cipro for about 4 years, before deteriorating again. Unfortunately, I didn’t realize it was the cipro – because I had done well on it before, it never occurred to me that it was now harming me – and carried on taking it for a year or two after I was first floxed. I then took nearly two weeks of avelox which finished me off, and I have now been bedbound for the last 18 months. I only made the connection between FQs and my health 12 months ago, when I took my last avelox.

I have had massive CNS and PN symptoms.  Over 100 symptoms in all. Some digestive issues too. By Christmas last year I felt that I had stabilized, but have recently developed new symptoms of dry eyes and receding gums.

Other aspects have improved – anxiety and panic attacks have lessened somewhat, and most nights I get 6 or 7 hours solid sleep.

Obviously, I’ve got a lot of damage to repair, and a long road ahead. This summer I have managed a few trips out in the car, which is more than I could do last summer. I have two young children, so I have to keep going for them!

She added, in a different comment on another conversation:

I had chronic borrelia and rickettsia for years before I began antibiotics. I then took FQs for years, and did well for a while. But at some point (I can’t be sure exactly when) I stopped doing so well and felt I was no longer responding – not just to FQs but to all the other antibiotics I was taking. And so the doctor gave me different and stronger FQs until eventually I became totally incapacitated and finally made the connection between FQs and floxing etc. I still don’t understand why the rickettsia/lyme now seems untouchable by any antibiotic. I would have thought after nearly 10 years of FQs I would have no infection left, but it’s worse and more virulent than ever. I can only guess that the FQs have effected a change in the rickettsia bugs themselves.

Tolerance Thresholds for Fluoroquinolones

Many people have suggested that fluoroquinolones bring out latent Lyme Disease.  I don’t know if this theory is true or not, as there haven’t been any studies (that I know of) trying to prove that hypothesis.

What has been shown to be true, however, is that fluoroquinolone antibiotics severely damage cells.  The parts of cells that are most damaged by fluoroquinolones are the mitochondria.  Mitochondrial damage is tricky in that both delayed adverse reactions, and tolerance thresholds are features of drug induced mitochondrial damage.  Thus, as Catherine’s comments illustrate, a drug that was once well tolerated can harm you the next time you have it.  (More info about tolerance thresholds for mitochondria damaging drugs can be found here – http://www.hormonesmatter.com/fluoroquinolone-time-bomb-mitochondria-damage/.)

Everyone’s tolerance threshold for fluoroquinolones is different.  Some people develop Fluoroquinolone Toxicity Syndrome after taking one pill.  Other people can handle hundreds of pills before their lifetime threshold is reached.  After an individual’s threshold is crossed though – the multi-symptom, chronic illness of Fluoroquinolone Toxicity results.

Delayed adverse reactions make it so that, often, people don’t even realize that they’ve crossed their tolerance threshold for fluoroquinolones until they have taken too many pills and the bomb in their body has gone off.  It’s Russian Roulette – but you can pull the trigger and release more and more bullets after the one that starts the reaction goes off – and each additional bullet does additional damage.

The symptoms of Fluoroquinolone Toxicity Syndrome are very similar to the symptoms of chronic Lyme Disease – pain, fatigue (um… bedridden exhaustion is more apt), insomnia, aching joints and muscles, decreased cognitive abilities, anxiety, depression and other psychiatric problems, etc.  The similarities between the two make it difficult to distinguish one from another.  They’re both real and they’re not mutually exclusive.  Some people even surmise that they’re related (but, like I mentioned above, I’m not sure about that).

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We’re in This Together

Humans like to break things into categories.  It helps us to understand them.  But, rather than attempting to convince you that your symptoms are from FQ toxicity, or listening to arguments that I might have latent Lyme, may I suggest that we all listen to Rene’s words of wisdom (also from a comment on www.floxiehope.com – Rene has also dealt with both Lyme and fluoroquinolone toxicity) :

Be careful about getting married to the disease label: “Look at the systems involved.” The massive amounts of data that I have combed through, during the years of illness, (before I was retested & given the diagnosis of Lyme), unveiled the commonality of all these illness or chronic conditions. If you have Lyme, MS, Fibromyalgia, Chemical Sensitives, Flouroquinolone injuries, Cancer it is a cellular issue of detoxification and efficiently utilizing the bio nutrients, the raw material we are made up of that send those signals & then receive the messages. The terrain is everything, which is why everything we eat and absorb is signally the terrain. The beliefs we have, what we covet and worship. How to improve the terrain and the function of these systems. Send the right signals and receive the right signals.

She also wrote:

the most beneficial & healing things you can do for Lyme are tantamount to doing much of what Fluoroquinolone injured do.

I know that for FQ toxicity, there is no one single “magic bullet” cure, but that many different things help people.  Some people are helped by a clean and healthy diet full of vitamins and minerals (Douglas recovered with the help of a healthy diet), some are helped by glutathione injections and liver cleanses (Richard was), Some are helped by antioxidant and mineral supplements (Ruth has some excellent antioxidant supplement advice), some are helped by alternative medicine (my acupuncturist helped me a lot) and most are helped by a combination of approaches.  All of the approaches are holistic and affect multiple systems.  Multiple systems with multiple negative feedback loops are broken by fluoroquinolones, and by Lyme spirochetes.  Systems break down with both diseases – and those broken systems break other systems.  The negative feedback loops are complex and difficult to fix.  But I thoroughly believe that the innate positive feedback loops are stronger than the negative feedback loops.  I hope that this belief is true.

All of us “spoonies” with under-recognized, systemic, often chronic illnesses have more in common than we don’t.  I hope that the stories of hope and healing on this page resonate with anyone with Lyme or any other chronic disease who reads this.

Back to Lyme and Fluoroquinolones

Perhaps I’m biased because fluoroquinolones hurt me, but I can’t believe that a drug that depletes mitochondrial DNA, leads to a massive amount of oxidative stress, depletes intracellular magnesium and decimates the microbiome is helpful to people who are already suffering from a chronic illness.  I understand that the Lyme bacteria need to be fought, but destroying your cells seems like a lousy way to do it.  (Interestingly, it has been suggested that tetracyclines, including doxycycline, are supportive of mitochondria whereas FQs are destructive.)  You need healthy cells in order to fight.  How to improve the health of your cells is a really difficult question and I don’t know the right answer.  I’m pretty sure that fluoroquinolones aren’t the answer to much though – certainly not for chronic Lyme Disease.

The main thing that I can ask of my friends with Lyme is this – please be careful.  Don’t think that the side-effects of drugs are “rare” or that they won’t happen to you.  Know the potential for chronic multi-symptom illness that comes with each fluoroquinolone pill, and if you choose to take Cipro, Levaquin or Avelox, do so with your eyes wide open.  Informed consent is, after all, quite important.

May you all find healing.

Best regards,

Lisa

 

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Mitochondria, Neuropathy, HIV and Fluoroquinolones

mitochondria structure

I wrote the following post and put it on one of my other sites, Mito Madness.

Mitochondria, Neuropathy, HIV and Fluoroquinolones

Though the damage done by fluoroquinolones to mitochondria is well documented, as is the connection between mitochondrial damage and many illnesses and maladies, the knowledge of the connections is not widespread.  Hopefully, some emerging research will change that.

Thank you for reading it!

Regards,

Lisa

 

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Dr. Robert Rountree’s Presentation about Mitochondria

I highly recommend that you watch this –

http://www.viddler.com/v/703896d9?secret=27514482

It’s a video of Dr. Robert Rountree giving a presentation about mitochondria. It’s fascinating!

Fluoroquinolones damage mitochondria. Here are my posts about fluoroquinolones damaging mitochondria –

There are more interesting posts about mitochondria on Hormones Matter, and probably some other sites too.

I try to make this complex information a bit more comprehensible than it is in journal article format, but if you want to read through some source articles on how fluoroquinolones damage mitochondria, here are some good ones:

Also, at roughly minute 26 of Dr. Rountree’s presentation, he mentions the link between cardiolipin damage and autoimmune diseases. Here is an article about how fluoroquinolones affect cardiolipin –

Journal of Medical Microbiology, “Comparison of the Effects of Subinhibitory Concentrations of Ciprofloxacin and Colistin on the Morphology of Cardiolipin Domains in Escherichia Coli Membranes

Dr. Rountree is brilliant and I don’t mean to be critical, but I think that some of the graphs toward the end of the presentation need to be re-drawn. From what I understand from reading the above articles, and others on mitochondria, the effects of ROS (reactive oxygen species – also known as oxidative stress), are not linear. When mitochondria experience a healthy amount of stress – through exercise, for example – there is an adaptive response. It is actually likely that the initial response of mitochondria to fluoroquinolones is an adaptive and healthy one – that could explain some of the experimental results that show a healthy or adaptive response of cells to fluoroquinolones. It is only after the threshold for damage is crossed that a maladaptive/unhealthy response begins. And once that maladaptive/unhealthy response begins, well, it’s bad news because the cell perpetuates damage on itself in the “vicious cycle” of mitochondrial damage. This article explains the phenomenon of a threshold for mitochondrial damage well –

Molecular Interventions, “Mechanisms of Pathogenesis in Drug Hepatoxicity Putting the Stress on Mitochondria

Can the cycle of cellular damage be stopped? I think so. If feeling good is an indicator of health, I know so. As always, I hope the same for all of you!

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Antibiotics After Fluoroquinolone Toxicity

People often ask about what they should do to treat infections post-flox.  Here are my tips.

First, please INSIST on getting your infection cultured and confirmed before you take any antibiotics.  As anyone who has had an adverse reaction to an antibiotic can tell you, antibiotics are not benign drugs.  They have side-effects (HERE is the 43 PAGE warning label for Cipro/Ciprofloxacin).  Some of those side-effects are life-altering and/or life-threatening.  You don’t want to put any drugs into your body unless you absolutely need them.  A culture should be done to confirm that an infection is present before you take an antibiotic – no matter what.

Because antibiotics have been shown to wreak havoc on the microbiome and bactericidal antibiotics damage mitochondria – and because both microbiome disruptions and mitochondrial dysfunctions are linked with every chronic disease there is – I highly recommend looking into some non-pharmaceutical options first.  Garlic has been shown to have antibiotic qualities and to be more effective against biofilms than many antibiotics.  For urinary tract infections, D-mannose has effectively helped thousands of people get rid of their infection.  Some other non-pharmaceutical remedies for urinary tract infections can be found HERECoconut oil has been shown to have anti-bacterial qualities and it may be good for treating skin and GI infections.  Colloidal silver not only has anti-bacterial qualities on its own, it also has been shown to increase the effectiveness of pharmaceutical antibiotics when used in conjunction with them.  Andrographis is an herb that has antibiotic qualities.

If non-pharmaceutical options aren’t working and you need an antibiotic to get rid of your confirmed infection, here are the antibiotics that I recommend along with reasons as to why I recommend them (or not).

  1. Most Floxies seem to do well with doxycycline and other tetracyclines. Tetracyclines are bacteriostatic antibiotics that, “stops bacteria from multiplying but does not kill them.” (source)
  2. Several Floxies have taken Z-pack’s without incident
  3. Amoxicillin seems to be about as benign as antibiotics get. So, it’s not harmless, but it’s well tolerated generally.
  4. Penicillin seems to be well tolerated – unless you’re allergic to it.
  5. Cephalosporins seem to be well tolerated

There are probably some other antibiotics that are fine for Floxies, I just haven’t heard about them.  Please feel free to leave a comment below if there is an effective and relatively safe one that I’m missing.

Here are the antibiotics that I recommend avoiding because they have side-effects that are similar to those of fluoroquinolones, and because many Floxies react badly to them –

  1. Macrobid / Nitrofurantoin
  2. Flagyl / Metronidazole
  3. Bactrim / Trimethoprim / Sulfamethoxazole
  4. Augmentin

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Fluoroquinolones – Cipro/Ciprofloxacin, Levaquin/Levofloxacin, Avelox/Moxifloxacin, Floxin/Ofloxacin and a few others – should be avoided entirely unless you are dying and make the decision that getting “floxed” is preferred to death.  Every warning label for every fluoroquinolone says that people who have an existing hypersensitivity to a fluoroquinolone should not take them again.  “Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components.” (Warning Label)

Before you take an antibiotic, or any pharmaceutical for that matter, I highly recommend that you look up the review for that drug on http://www.askapatient.com/ and look it up on http://www.peoplespharmacy.com/.  Also, look up the drug’s warning label.  Be informed.  Make an informed decision.

Here is a list of antibiotics – http://en.wikipedia.org/wiki/List_of_antibiotics  I didn’t get close to going through all of them.  But I hope that this post gives you some guidance when/if you are faced with an infection.

I’m not a doctor, so please take this advice for what it’s worth.  Doctors should be consulted when you have an infection.  The internet should be consulted too though, because doctors aren’t capable of knowing everything and informed consent is really important.

 

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Cellular Oxidative Damage from Fluoroquinolones

Here are some thoughts about what is/was going on in our floxed bodies.

First, here’s my typical disclaimer.  I’m not a doctor or scientist.  I’m doing my best to put together this information, but I could be wrong.  I do my best to be right and I back up my assertions with peer-reviewed journal articles.

As I mentioned in Article Breakdown – “Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria,” I believe that this paragraph describes much of what occurs in floxed cells:

“Increased steady-state levels of mitochondrial superoxide, arising from reduction of Sod2 activity in the Sod+/−mice (i.e., approximately half the wild-type activity), may be exacerbated by drugs that directly target the ETC [e.g., the complex I inhibitors flutamide and troglitazone (122)]. The increased amount of superoxide raises two considerations. First, superoxide that escapes dismutation to hydrogen peroxide cannot cross the inner mitochondrial membrane and can oxidize [Fe-S]-containing enzymes (e.g., aconitase and complex I/III subunits). Alternatively, superoxide can rapidly react with mitochondrial nitric oxide (NO) to form peroxynitrite (ONOO−). For example, the fluoroquinolone antibiotic trovafloxacin (TVX), a typical DILI (drug induced liver injury) associated drug, raises steady-state levels of NO in hepatocellular mitochondria (unpublished data). The mechanisms are not known, but TVX also increases cytosolic (non-ferritin-bound) Ca2+, likely activating the Ca2+-dependent mitochondrial NO synthase (123) to produce ONOO−. Peroxynitrite is dangerous for a number of reasons: i) under acidic conditions, it can be degraded to form the extremely reactive hydroxyl radical; ii) it may directly cause the nitration of aconitase, Sod2, and the [Fe-S]-containing subunits of ETC complexes; and iii) it can induce mitochondrial permeabilization (Figure 4B) (124). This superimposed oxidative/nitrative stress could ultimately push the cell across the threshold to observable injury.”

SUPEROXIDE DAMAGE OF MITOCHONDRIAL DNA

Superoxide is a powerful oxidant that is quite toxic.  Per “Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling,” “ROS are produced continuously as a by-product of aerobic metabolism.  Superoxide can be produced as a result of the one-electron reduction system within the mitochondrial electron transport chain.  Superoxide can then be converted into hydrogen peroxide (H2O2) by superoxide dismutase (the Mn isoform in the matrix and cu, Zn-superoxide dismutase in the cytosol).  H2O2 can be converted into highly reactive hydroxyl radicals (OH-) by the Fenton reaction, and can cause lipid peroxidation.” More info about superoxide can be found here – http://en.wikipedia.org/wiki/Superoxide

In properly functioning cells, superoxide dismutase (SOD) converts superoxide into hydrogen peroxide (H2O2) and water.  Unfortunately, fluoroquinolones deplete cellular SOD.  In “Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients” it was found that, for human patients with urinary tract infections and treated with various fluoroquinolones, “There was substantial depletion in both SOD and glutathione levels particularly with ciprofloxacin.”

Without sufficient SOD, as noted above, superoxide “cannot cross the inner mitochondrial membrane and can oxidize.”  Oxidization within the mitochondrial membrane is harmful because it damages mitochondrial DNA (mtDNA) and starts the vicious cycle of oxidative damage to mitochondria.  (This “vicious cycle” theory is described in “Oxidative stress induces degradation of mitochondrial DNA” – “According to this theory, the production of ROS by mitochondria leads to mtDNA damage and mutations which in turn lead to progressive respiratory chain dysfunction and to a further increase in ROS production as a consequence of this dysfunction. The exponential escalation of these processes is commonly referred to as a ‘vicious cycle’, and the theory predicts that the rise in mtDNA mutations and ROS eventually reach levels that are incompatible with life.”  It should be noted that whether or not this theory is true for how aging works is contentious.  The vicious cycle of damage done by ROS does occur in mitochondria though.)

THE NITRIC OXIDE / PEROXYNITRITE (NO/ONOO-) CYCLE

Additionally, “superoxide can rapidly react with mitochondrial nitric oxide (NO) to form peroxynitrite (ONOO−).”  The ways in which peroxynitrite are dangerous are noted in the paragraph from “Mechanisms of Pathogenesis” at the beginning of this post.

Dr. Martin L. Pall, Professor Emeritus of Biochemistry and Basic Medical Sciences at Washington State University describes the NO/ONOO- (nitric oxide / peroxynitrite) cycle in his web site, http://www.thetenthparadigm.org/index.html.  Here is a diagram from The Tenth Paradigm describing the NO/ONOO- cycle –

ONOO cycle

Here is Dr. Pall’s description of the above diagram:

“Fig. 1 legend.  Vicious (NO/ONOO-) cycle diagram.  Each arrow represents one or more mechanisms by which the variable at the foot of the arrow can stimulate the level of the variable at the head of the arrow.  It can be seen that these arrows form a series of loops that can potentially continue to stimulate each other.  An example of this would be that nitric oxide can increase peroxynitrite which can stimulate oxidative stress which can stimulate NF-kappaB which can increase the production of iNOS which can, in turn increase nitric oxide.  This loop alone constitutes a potential vicious cycle and there are a number of other loops, diagrammed in the figure that can collectively make up a much larger vicious cycle.  The challenge, according to this view, in these illnesses is to lower this whole pattern of elevations to get back into a normal range.  You will note that the cycle not only includes the compounds nitric oxide, superoxide and peroxynitrite but a series of other elements, including the transcription factor NF-kappaB,  oxidative stress, inflammatory cytokines (in box, upper right), the three different forms of the enzymes that make nitric oxide (the nitric oxide synthases iNOS, nNOS and eNOS), and two neurological receptors the vanilloid (TRPV1) receptor and the NMDA receptor.”

The NO/ONOO- cycle provides a reasonable explanation for why it feels as if a bomb has gone off in the body of the floxie.  It also is an explanation as to why the adverse effects of drugs that damage mitochondria and cause oxidative stress are not transient.  There are feedback loops within the cells that perpetuate the damage.

Here is Dr. Pall’s table of signs of the NO/ONOO- cycle –

Explanations for Symptoms and Signs

Symptom/Sign Explanation based on elevated nitric oxide/peroxynitrite theory
energy metabolism /mitochondrial dysfunction Inactivation of several proteins in the mitochondrion by peroxynitrite; inhibition of some mitochondrial enzymes by nitric oxide and superoxide
oxidative stress Peroxynitrite, superoxide and other oxidants
PET scan changes Energy metabolism dysfunction leading to change transport of probe; changes in perfusion by nitric oxide, peroxynitrite and isoprostanes
SPECT scan changes Depletion of reduced glutathione by oxidative stress; perfusion changes as under PET scan changes
Low NK cell function Superoxide and other oxidants acting to lower NK cell function
Elevated cytokines NF-kappaB stimulating of the activity of inflammatory cytokine genes
Anxiety Excessive NMDA activity in the amygdala
Depression Elevated nitric oxide leading to depression; cytokines and NMDA increases acting in part or in whole via nitric oxide.
Rage Excessive NMDA activity in the periaqueductal gray region of the midbrain
Cognitive/learning and memory dysfunction Lowered energy metabolism in the brain, which is very susceptible to such changes; excessive NMDA activity and nitric oxide levels and their effects of learning and memory
Multiorgan pain All components of cycle have a role, acting in part through nitric oxide and cyclic GMP elevation
Fatigue Energy metabolism dysfunction
Sleep disturbance Sleep impacted by inflammatory cytokines, NF-kappaB activity and nitric oxide
Orthostatic intolerance Two mechanisms:  Nitric oxide-mediated vasodilation leading to blood pooling in the lower body; nitric oxide-mediated sympathetic nervous system dysfunction
Irritable bowel syndrome Sensitivity and other changes produced by excessive vanilloid and NMDA activity, increased nitric oxide
Intestinal permeabilization leading to food allergies Permeabilization produced by excessive nitric oxide, inflammatory cytokines, NF-kappaB activity and peroxynitrite; peroxynitrite acts in part by stimulating poly ADP-ribose polymerase activity

Sounds pretty familiar, doesn’t it?

STOPPING THE NO/ONOO- CYCLE

What can be done to stop the NO/ONOO- cycle?  How can one heal when cells are reinforcing the damage done to them over and over again?

Here are Dr. Pall’s recommendations – http://www.thetenthparadigm.org/therapy.htm

Additionally, a very smart and appreciated floxie noted in a comment on this site, that uric acid has been shown to decrease peroxynitrite.  Per the article, “Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis,” “Uric acid, the naturally occurring product of purine metabolism, is a strong peroxynitrite scavenger, as demonstrated by the capacity to bind peroxynitrite but not nitric oxide (NO).”  (There has been some debate about whether floxies want to increase or decrease nitric oxide.  I think that we want to increase NO because too much of it is converted into peroxynitrite.  Here’s an article on how NO helps with tendon healing – “The role of nitric oxide in tendon healing.”)  Uric acid.  The stuff that causes kidney stones and gout – it’s a powerful antioxidant that scavenges peroxynitrite.

The role that uric acid plays in getting rid of toxic peroxynitrite makes sense to me on a personal level because of a couple of things that have made me feel significantly better post-flox – brewer’s yeast and uridine supplements.  Both brewer’s yeast and uridine are high in purines, which are converted into uric acid in the body.  I always thought that the purines and uric acid were a necessary evil and that the good done by brewer’s yeast had to do with its high amino acid and/or B vitamin content.  Now I’m thinking that the necessary evil was actually the active ingredient.

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Here are a couple more articles about the role of uric acid in peroxynitrite neutralization (thanks again to the floxie friend who pointed them out):

There is a very real risk of kidney stones and gout when consuming too many purines that lead to excess uric acid.  Even though brewer’s yeast has helped me immensely, I feel quite conflicted about it.  I don’t want a kidney stone and gout would probably make my flox-induced peripheral neuropathy look like a cake-walk.  Now that I’m feeling well, I’m probably going to cut way down on my brewer’s yeast consumption.  I really don’t know which are worse – the diseases of too much uric acid (kidney stones and gout) or the diseases of too little uric acid (“patients with MS have significantly lower levels of serum uric acid than controls” and peroxynitrite is associated with lots of other nasty diseases – like cancer and Alzheimer’s).  This isn’t exactly a great predicament.

Another consideration is that fluoroquinolones deplete cellular magnesium and proper amounts of cellular magnesium are necessary for 300+ enzymatic reactions.  (Fluoroquinolones may inhibit and deplete enzymes through means other than depletion of cellular magnesium too.)  If one doesn’t have the enzymes to metabolize uric acid, well, too much isn’t a good thing.  Too much peroxynitrite is bad too though.

I wish that the answers were more clear.  I hope that this post at least gave you some information with which you can make an informed decision!

In researching this post, I stumbled upon this interesting web site – http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/R/ROS.html  It is noted on the site that uric acid is an antioxidant and that, “Perhaps the long life span of some reptiles and birds is attributable to their high levels of uric acid.”  Bird shit and reptile blood are full of the stuff.  If there is a cure for fluoroquinolone toxicity, it’ll probably come from bird turds or alligator blood.  Great.

 

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Fluoroquinolone Antibiotics Damage Mitochondria – FDA Does Little

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The Pharmacovigilance folks at the FDA know that fluoroquinolones are damaging mitochondria.  Yet, they look the other way.  Adding a more severe warning about peripheral neuropathy to the warning label isn’t helpful.  People should know that they are increasing their risk of every chronic disease associated with mitochondrial damage and oxidative stress when they take a fluoroquinolone.  That would actually be helpful.

Here is the post, on Hormones Matter – http://www.hormonesmatter.com/fluoroquinolone-antibiotics-damage-mitochondria-fda-adds-warning/

 

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What Getting Poisoned Looks Like

People think that getting poisoned looks like this:

But in the real world, it looks like this:

People whose cells are being destroyed from the inside out, often look fine.  Looks can be deceiving.

Everyone with an invisible or mysterious illness should ask the question – Were you poisoned?

Something that everyone who suspects that they may have been poisoned should note is that much of the damage, the poisoning, is indirect.  Pharmaceuticals (fluoroquinolones included) and environmental toxins damage mitochondria and, after reaching their tolerance threshold for damage, the mitochondria respond by producing poisonous reactive oxygen species (also known as oxidative stress).  Those reactive oxygen species (peroxynitrite is a particularly toxic one) that result from mitochondrial damage cause multi-symptom chronic illnesses.  It should be noted by people with chronic fatigue / M.E., that mitochondria are the energy centers of our cells and that damage to them can result in debilitating fatigue.  It should be noted by people with fibromyalgia that mitochondrial damage and oxidative stress have been shown to damage nerves and cause body-wide pain.  Autoimmune diseases have also been linked to poisoning, and also to mitochondrial damage.

Mitochondrial damage is tricky in that the tests to show it are woefully new and under-utilized.  Muscle biopsies can show mitochondrial damage, but they’re invasive and not very reliable.  Lactate doublets are a sign of mitochondrial damage, but the research behind them is new and utilization of MRIs to test for lactate doublets are rarely used.

The fact that the tests don’t show anything means that the tests are inadequate (and that they don’t show mitochondrial damage / oxidative stress), not that the problem is “in your head” or that it’s not chemical, or that you haven’t been poisoned.

People who are poisoned are in pain, they are fatigued, they can’t think straight, they are unable to function at the level that they used to.  That should sound familiar to everyone with fibromyalgia, CFS/ME and even autoimmune diseases.  Were you poisoned?  When?  By what?  And by whom?

If doctors looked at the mitochondria, they would see the destruction of the poison.  But they don’t look at mitochondria.  As long as they don’t look at mitochondria, they can tell themselves that their drugs are safe; that they’re not poison.  Ignorance is bliss for the entire medical profession and the FDA.  Too bad their ignorant bliss isn’t reality.

Look around you.  The chronically ill people around you are telling you something.  This is what the poisoning of America looks like.

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Peer Reviewed Sources:

Molecular Nutrition and Food Research, “Medication Induced Mitochondrial Damage and Disease

Toxicological Sciences, “Mitochondria as a Target of Environmental Toxicants

Molecular Interventions, “Mechanisms of Pathogenesis in Drug Hepatoxicity Putting the Stress on Mitochondria

Biochemical Society Transactions, “Mitochondrial Matirix Reactive Oxygen Species Production is Very Sensitive to Mild Uncoupling

Science Translational Medicine, “Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

Cleveland Clinic Journal of Medicine, “Mitochondrial cytopathy in adults: What we know so far

Current Pharmaceutical Design, “Nitric Oxide-Derived Oxidants with a Focus on Peroxynitrite: Molecular Targets,Cellular Responses and Therapeutic Implications

Journal of Internal Medicine, “Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise

Biomed Central, “Central role of nitric oxide in the pathogenesis  of rheumatoid arthritis and systemic lupus erythematosus

JAMA Psychiatry, “Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder

Expert Opinion on Therapeutic Targets, “The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets?

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Same Disease, Different Symptoms: It’s all in the Mitochondria

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Fluoroquinolone toxicity affects everyone differently. Why? Because that’s how mitochondrial dysfunction works. WHY? Because mitochondrial produced ROS influence gene expression and we all have different genes. WHAT? Yup, ROS affect gene expression. Perhaps we should be more careful with our mitochondria. After all, our genes are at stake.

Same Disease, Different Symptoms:  It’s all in the Mitochondria

 

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Your Mighty Mitochondria

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

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

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

 

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Mitochondrial Dysfunction and Related Diseases

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This post, entitled “Some Doctors Don’t Believe In This Disease Yet it Predisposes Many Diseases” was published on Collective Evolution on 03/17/14.

http://www.collective-evolution.com/2014/03/17/mitochondrial-diseases/

Frustratingly little is known about mitochondria and the role that they play in human illness.  I hope that this will change soon.

 

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The Fluoroquinolone Time-Bomb – answers in the Mitochondria

Adverse reactions to fluoroquinolones are often delayed and people can tolerate a certain number of fluoroquinolones before they experience an adverse reaction. Delayed reactions and tolerance thresholds are perplexing mysteries until you take a look at mitochondrial dysfunction. Both delayed reactions and tolerance thresholds are actually typical for disease states that are caused by mitochondrial dysfunction. More details on the matter in this post. As always, thank you for reading and sharing!

http://www.hormonesmatter.com/fluoroquinolone-time-bomb-mitochondria-damage/

 

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Article Breakdown – “Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria”

Do you have a headache?  Do you want one?  If so, read this article –

Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria” written by

Dean P. Jones, John J. Lemasters, Derick Han, Urs A. Boelsterli, Neil Kaplowitz

If you want a headache that lasts a while, read these articles that give background information as to why what is in “Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria” is important.

Drug Metabolism and Disposition, “Acyl Glucuronidation of Fluoroquinolone Antibiotics by the UDP-Gulucuronosyltransferase 1A Subfamily in Human Liver Microsomes

and

Current Drug Metabolism, “Acyl Glucuronides: Mechanistic Role in Drug Toxicity?

Despite their headache inducing capabilities, the articles are actually quite interesting and important.  To highlight how and why they are important, here is my breakdown of “Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria.”  As I have done with other journal articles, I have taken quotes from the article and commented under them.

“Mitochondrial impairment is usually a final event common to pathways leading to necrotic and apoptotic cell death.”

Since mitochondrial impairment leads to cell death, perhaps it would be nice for the FDA to examine how pharmaceuticals affect mitochondria before approving them.  Sadly, they don’t think so, as “mitochondrial toxicity testing is still not required by the US FDA for drug approval.” (http://psychrights.org/Research/Digest/NLPs/DrugsCauseMitochondrialDamage.pdf)

“it is important to consider whether drug-induced participation of mitochondria in hepatocellular death is a direct result of drugs acting on these organelles (e.g., drug accumulation, inhibition of electron transport and fatty acid oxidation, or depletion of anti-oxidant defense) or an indirect result ensuing from mitochondrial participation in programs of cell death.”

They found that both were the case.  This stuff is very complex and not linear.  One reaction causes another reaction, on and on for a while.  It’s not an either/or situation.

“Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants; however, the finding that thiols [i.e., glutathione (GSH) and cysteine (Cys)] in plasma are not in redox equilibrium with their disulfide products [i.e., respectively, GSSG and CySS] (1, 2) and that their plasma concentrations are substantially displaced from cellular values (3) has significantly altered concepts of oxidative stress (4, 5). For example, the in vivo “balance” of pro-oxidants and antioxidants cannot be defined by any single entity, such as an equilibrium constant, and our growing knowledge of signaling mechanisms indicates that oxidative stress may be better defined as a disruption of redox signaling, rather than as an imbalance of pro-oxidants and antioxidants. The failure of large-scale, double-blind interventional trials with free-radical scavenging antioxidants may likewise reflect an oversimplified therapeutic approach.”

If you have too many oxidants/oxidative stress in your system, you should just add antioxidants to restore the balance of oxidants and antioxidants, right?  Well, it’s not that simple.  Once the signaling mechanisms within mitochondria start the process of oxidative stress and apoptosis (programmed cell death), you can’t stop the process or repair the damage by adding more antioxidants to the mix.  If it was as simple as a disruption in the balance between oxidants and antioxidants, we would all be cured by glutathione drips and vitamin C supplements.  Unfortunately, there are complex feedback loops that make the process much more difficult to fix than that.  I’m not saying that glutathione drips and vitamin C supplements aren’t worth a try, it’s just that adding antioxidants to make up for the excess of oxidative stress (in the form of Reactive Oxygen Species and Reactive Nitrogen Species) is an oversimplified approach.

“Cells that overexpress the mitochondrion-specific thioredoxin Trx2, however, have been found to be resistant to tBH-induced loss of mitochondrial membrane potential and apoptosis”

Mitochondrion-specific thioredoxin Trx2 (http://en.wikipedia.org/wiki/Thioredoxin) is protective.  I’m not sure exactly what the implications of this are, but I suspect that those of us who got “floxed” have low levels of mitochondrion-specific thioredoxin Trx2.  (We probably are deficient in cellular magnesium and have a genetic predisposition toward susceptibility to mitochondrial injury and oxidative stress too.)

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“Mitochondrial Trx2 responds to changes in the extracellular redox potential of Cys/CySS (http://en.wikipedia.org/wiki/Cysteine) (EhCys/CySS) over a range that is relevant to cardiovascular disease in humans.” and “Previous in vitro findings support a cause–effect relationship for plasma CySS in cell signaling pathways associated with cardiovascular disease.”

Cardiovascular disease is related to mitochondrial function and oxidative stress / antioxidants.

Every chronic disease that plagues humans has its roots in mitochondrial dysfunction.  That may be Lisa’s theory, or it may be the truth.  TBD.  But there are enough journal articles noting how mitochondria relate to all sorts of chronic diseases that you’d think that our regulatory agencies would require that the effects of pharmaceuticals on mitochondria be tested before they are released to the market.  But no, they don’t.  They’re incompetent fools.  And because of their foolishness the pharmaceutical companies really have gotten away with creating customers, not cures.

“Mass spectrometry-based redox proteomics show that several classes of plasma membrane and cytoskeletal proteins involved in inflammation respond to this redox switch (Trx2), including vascular cell adhesion molecule, integrins, actin, and several Ras family GTPases.”

This really cryptic, difficult to understand sentence may actually say a lot about FQ toxicity.  The Trx2 redox switch (http://en.wikipedia.org/wiki/Thioredoxin) is protective against loss of mitochondrial membrane potential and apoptosis (see above).  So, perhaps underexpression of the Trx2 redox switch  leads to inflammation of  vascular cell adhesion molecules, integrins, actin, and several Ras family GTPases.  What are these things, you ask?  Wiki will tell us!

Vascular Cell Adhesion Moleculeshttp://en.wikipedia.org/wiki/VCAM-1 – “The VCAM-1 protein mediates the adhesion of lymphocytes, monocytes, eosinophils, and basophils to vascular endothelium. It also functions in leukocyte-endothelial cell signal transduction, and it may play a role in the development of atherosclerosis and rheumatoid arthritis.” (I’ll let you look up all of the words you don’t know in this – ugh.)

Integrins http://en.wikipedia.org/wiki/Integrin and http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/CellAdhesion/integrinfunction.htm – “Integrins are cell-surface receptors that mediate cell-cell adhesion and are of great importance in binding and interactions of cells with components of the extracellular matrix (ECM) such as fibronectin (and cell-matrix). Importantly, integrins facilitate “communication” between the cytoskeleton and extracellular matrix, allowing each to influence the orientation and structure of the other.”  When your integrins are messed up, your cytoskeleton can get messed up.  Or something like that.

Here is an about how fluoroquinolones that mentions how they relate to integrins –

http://intl-vet.sagepub.com/content/38/2/143.full – “Lack of extracellular Mg2+ impairs the function of integrins.  These transmembrane proteins connect the cells to extracellular matrix”  This stuff has something to do with how fluoroquinolones mess up tendons.  Yeah.

Actinhttp://en.wikipedia.org/wiki/Actin  It’s important for cellular function.  (That’s all I’ve got for you – read the wiki :p )

Ras Family GTPases – http://en.wikipedia.org/wiki/GTPase  It’s important for cellular function.  (That’s all I’ve got for you – read the wiki :p )

You could get completely lost looking up all of the different systems described within this sentence.  Now that I have dug through it, maybe the authors of the study stated things as succinctly as possible.  This stuff is hard.

If someone significantly smarter than me wants to figure out how each of these cellular functions relate to magnesium, and, of course, floxing, that would be great.

Chelatable Iron, Oxidative Stress, and Cell Death

This whole section is about how iron relates to drug induced liver injury (DILI).  I’m not going to go over it piece by piece.  One thing that makes me curious about this section is that iron helped me to feel better than any other supplement.  I wonder why that is.  If the answer is in the article, I don’t understand chemistry well enough to get it from the article.

“In the mitochondrial permeability transition (MPT), high-conductance permeability transition (PT) pores open that make the mitochondrial inner membrane nonselectively permeable to all solutes of molecular mass up to approximately 1500 Da (59, 60). Calcium ion, oxidative stress, and numerous reactive chemicals induce onset of the MPT, whereas cyclosporin A (CsA) and pH less than 7 inhibit pore opening. After MPT onset, mitochondrial depolarize and undergo large-amplitude swelling driven by colloid osmotic forces, which are the hallmarks of the MPT. Swelling leads to rupture of the mitochondrial outer membrane and release of proapoptotic cytochrome c and other factors from the intermembrane space.”

Calcium + oxidative stress = apoptosis.  I’ve seen this elsewhere – https://floxiehope.com/2013/12/17/article-breakdown-mitochondrial-reactive-oxygen-species-control-t-cell-activation-by-regulating-il-2-and-il-4-expression-mechanism-of-ciprofloxacin-mediated-immunosuppression/

Interplay of Signal Transduction and Mitochondria in the Acetaminophen model

This section goes over how acetaminophen causes mitochondrial damage and drug induced liver injury.  It’s not a one-step process – it’s really complex and multiple things have to go wrong, at a cellular level, at once.  But it can happen.

As I mentioned above, I hypothesize that pharmaceutical induced mitochondrial injury is the cause of most chronic diseases.  Per Dr. Richard Boles, an expert in mitochondrial dysfunction and diseases:

these are partial defects. Mitochondrial dysfunction doesn’t really cause anything, what it does is predisposes towards seemingly everything. It’s one of many risk factors in multifactorial disease. It can predispose towards epilepsy, chronic fatigue, and even autism, but it doesn’t do it alone. It does it in combination with other factors, which is why in a family with a single mutation going through the family, everyone in the family is affected in a different way. Because it predisposes for disease throughout the entire system.”  (http://www.hormonesmatter.com/cyclic-vomiting-syndrome-mitochondrial-dysfunction/)

Is acetaminophen causing mitochondrial damage???  Is it damaging or depleting mtDNA?  Is that damage hereditary????  Because if ACETAMINOPHEN is leading to a variety of chronic diseases, ugh, well, we might just be fucked (sorry, I couldn’t think of another word for the situation).

Fluoroquinolones deplete mitochondrial DNA content – “Interestingly, as an inhibitor of bacterial topoisomerase II and an inducer of DNA double-strand breaks, ciprofloxacin was also shown to deplete the mitochondrial DNA (mtDNA) content, thus leading to mitochondrial dysfunction and retarded cellular growth (15–17).” http://www.jimmunol.org/content/184/9/4827.full.pdf  Awesome, huh?

I think that fluoroquinolone induced mitochondrial damage, both direct and hereditary, is responsible for the increase in every chronic disease that has increased in prevalence along with fluoroquinolone use.

“One of the most striking and puzzling clinical hallmarks of idiosyncratic (host-dependent) DILI is the delayed onset of the disease. In fact, the time between initiation of daily drug treatment and the presentation of biochemical markers and clinical symptoms of liver injury can vary from a few weeks to several months, sometimes even exceeding a year (89). The reason for the long lag, often followed by an abrupt progression to DILI, is currently not known. However, it is clear, for the vast majority of drugs, that the delayed time to onset is not related to a gradual accumulation (of drug or drug metabolite) that would eventually lead to critical and toxicologically relevant concentrations in the liver. Instead, the lag time could be explained by an accumulating effect of a drug. This notion, together with experimental findings, is in line with the concept that mitochondria are involved in the etiology of DILI, because damage to mitochondria often reflects successive chemical insults, such that no immediate cause for functional changes or pathological alterations can be established. There is indeed experimental evidence that prolonged injury to mitochondria, such as that which typifies oxidative injury to mitochondrial DNA or to components of the electron transport chain (ETC), has to cross a certain threshold (or a number of thresholds) before cell damage or cell death becomes manifest (Figure 4A).”

Underlining added by Lisa.  This paragraph explains both delayed reactions and the fact that most people have a tolerance threshold for fluoroquinolones.  If your doctor, or anyone else, tells you that your reaction that came months after you stopped administration of a fluoroquinolone “couldn’t have happened because of the FQ, because it was metabolized already,” or something like that, tell him or her to read this paragraph as many times as it takes to understand it.  Damage to mitochondria, whether related to DILI or not, is not linear and it is not (necessarily) immediate.  Unfortunately, this is not understood by anyone other than the authors of this study, and probably a few other scientists, so suing based on a delayed reaction to a drug that you have tolerated well in the past is difficult to impossible.

“This non-linear response can be explained upon consideration that the molecules that subserve mitochondrial function (e.g., mitochondrial DNA, mRNA, and ETC proteins) are present in excess of amounts required for normal cell function. This reserve (or buffering) capacity acts as a protective mechanism; however, at a certain stage of damage, the supply of biomolecules needed to support wild-type mitochondrial function becomes compromised.”

For each of us Floxies, the reserve capacity of our mtDNA has been depleted.  I have no clue if it can be built up again or not.

“a number of human mitochondrial genetic diseases that are clinically discreet are being diagnosed at unexpected rates”

It is REALLY IMPORTANT that it be determined whether or not pharmaceutical induced damage to mitochondria is hereditary.  Seriously scientists – important stuff – answers will be greatly appreciated.

“First, all the investigated drugs (including trovafloxacin, a fluoroquinolone) invariably decreased the activity of key mitochondrial proteins that are sensitive to oxidant stress (e.g., aconitase-2, complex I) and often decreased the expression of mitochondrial (but not nuclear) genes (120). Second, we found that these markers of mitochondrial injury became apparent only after four weeks, although a number of cytoprotective pathways were activated within two weeks. It thus appears that an initial adaptive response was followed by a toxic response (121), possibly also involving a threshold.”

What happens when expression of mitochondrial genes are decreased?  What are the implications of this finding?

The fact that there is an initial adaptative response followed by a toxic response (to pharmaceutical induced mitochondrial injury) may explain why there are so many different results to studies of fluoroquinolones (and other mito damaging drugs).  Long-term studies need to be done.  Studies that take into consideration that delayed reactions occur, need to be done.  Studies that take into consideration tolerance thresholds need to be done.  Please.

“First, superoxide that escapes dismutation to hydrogen peroxide cannot cross the inner mitochondrial membrane and can oxidize [Fe-S]-containing enzymes (e.g., aconitase and complex I/III subunits). Alternatively, superoxide can rapidly react with mitochondrial nitric oxide (NO) to form peroxynitrite (ONOO−). For example, the fluoroquinolone antibiotic trovafloxacin (TVX), a typical DILI-associated drug, raises steady-state levels of NO in hepatocellular mitochondria (unpublished data). The mechanisms are not known, but TVX also increases cytosolic (non-ferritin-bound) Ca2+, likely activating the Ca2+-dependent mitochondrial NO synthase (123) to produce ONOO−. Peroxynitrite is dangerous for a number of reasons: i) under acidic conditions, it can be degraded to form the extremely reactive hydroxyl radical; ii) it may directly cause the nitration of aconitase, Sod2, and the [Fe-S]-containing subunits of ETC complexes; and iii) it can induce mitochondrial permeabilization (Figure 4B) (124). This superimposed oxidative/nitrative stress could ultimately push the cell across the threshold to observable injury.”

Floxies – that’s what happened to you (and me).  It’s really hard to understand, I know.  I have a headache right now and I’m guessing that you do too if you’ve gotten this far in the post.  It’s important information though.

On a light note, I think that it’s funny that fluoroquinolones convert “NO” into “ONOO” in our cells.  Yup, that’s about what it feels like – “no” turning into “oh no” turning into “oh fuck” which turns into “fuck you Bayer / Johnson & Johnson.”  🙂

The end of the article and my comments.

Dean P. Jones, John J. Lemasters, Derick Han, Urs A. Boelsterli and Neil Kaplowitz are brilliant.  I thank them very much for this article.  It answers a lot of questions.  It still leaves many unanswered, of course – as any good article does.  I hope that they, and more scientists, are doing more work on the relationship between pharmaceutical induced mitochondrial injury and disease states.
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Article Breakdown – “Mitochondrial Reactive Oxygen Species Control T Cell Activation by Regulating IL-2 and IL-4 Expression: Mechanism of Ciprofloxacin-Mediated Immunosuppression”

I’ve read this article 14 times. I think that I understand it. It’s not an easy article to read. Actually, it’s a beast. I’m going to go over what I think are the interesting points of the article in this post. I’m also going to go over something that I think the researchers got wrong, and the implications of their false (IMO) conclusion.

Here is the article –

http://www.jimmunol.org/content/184/9/4827.full.pdf

Mitochondrial Reactive Oxygen Species Control T Cell Activation by Regulating IL-2 and IL-4 Expression: Mechanism of Ciprofloxacin-Mediated Immunosuppression

The Journal of Immunology, 2010, 184: 4827–4841.

Marcin M. Kamin´ ski,* Sven W. Sauer,† Claus-Detlev Klemke,‡ Dorothee Su¨ ss,*

Ju¨rgen G. Okun,† Peter H. Krammer,* and Karsten Gu¨low*

There is a lot of phenomenal information in the article, but I’m going to go over what I think they got wrong first. The researchers found that Ciprofloxacin had an immunosuppresive effect on T-cells, inhibited the production of ROS (Reactive Oxygen Species) and were anti-inflammatory. I don’t think that this is correct. Some of the results discussed in the paper, that I will go over later in this post, note that the effect of Ciprofloxacin on T-cells is one of activation of immune responses, not suppression. More on that later. As for the production of ROS, there are multiple peer-reviewed articles that note that fluoroquinolones (Ciprofloxacin and others) increase the production of ROS. Here are a few –

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249743/?report=printable

http://link.springer.com/article/10.1007/s00284-012-0094-7#page-1

https://www.jstage.jst.go.jp/article/tjem/226/4/226_4_251/_pdf

There are hundreds more.

I have no reason to doubt the intelligence, motives or methods of the Researchers who conducted this study, so why did they get a result that is the opposite result from most other Researchers? I’m not sure of the answer, but I think that it may have something to do with the fact that the cells that they studied were cultured in uridine. Supplementation of uridine, as well as consuming foods that have uridine in them, have seemed to help Floxies. Because of this, I wonder if uridine counteracts the production of ROS, and thus the results of the study were skewed. There may be a completely different answer for why the researchers who wrote the study that I’m reviewing concluded that ROS decreases with Ciprofloxacin, and all other researchers who have looked at the topic note that fluoroquinolones increase ROS production, but I think that the uridine direction is an interesting path. It leads to acyl glucuronidation and other headache inducing topics.

Anyhow, they got that wrong (as shown by the multiple articles that state the FQs increase ROS, not decrease it, not because I say so), so all conclusions based on the premise that fluoroquinolones decrease ROS or oxidative stress, should be disregarded. However, they still said some really interesting stuff about the effects of Ciprofloxacin on the cell.

Before I go into the good stuff from the article, I’m going to express my annoyance over the following paragraph:

Ciprofloxacin, as well as other members of the fluoroquinolone group of antibiotics, is characterized by immunomodulatory properties of an unknown mechanism. The effects of ciprofloxacin on T cell activation-induced gene expression remain vague. Numerous conflicting reports stated that ciprofloxacin activates or inhibits T cell activation-induced gene expression (e.g., for IFN-g, TNF-a, IL-2, and IL-4) (11–14).”

If a drug has immunomodulatory properties, perhaps it’s a good idea to figure out the mechanism. If more than 20 million prescriptions of these drugs are going to be given out each year in the U.S. Alone, perhaps it is a good idea to figure out the mechanism for how they effect the human immune system.

The effects of Ciprofloxacin on gene expression may be vague, but researchers recently found that another topoisomerase interrupter, Topotecan, triggered the expression of Autism related genes. So “vague” has consequences and they may not be pleasant ones.

“Conflicting reports?” Welcome to my world. But it really bothers me that Scientists can’t determine the direction of the arrow. It’s not a judgment call. It’s not a matter of opinion. It should be a matter of fact. How does Ciprofloxacin effect T-cell activation-induced gene expression? This should be a testable question.

Now onto the highlights:

Interestingly, as an inhibitor of bacterial topoisomerase II and an inducer of DNA double-strand breaks, ciprofloxacin was also shown to deplete the mitochondrial DNA (mtDNA) content, thus leading to mitochondrial dysfunction and retarded cellular growth (15–17).”

Why is this stuff on the market? Oh yeah, because the FDA systematically ignores the effects of drugs on mitochondria. Here is an article about how this is the case for many drugs: http://psychrights.org/Research/Digest/NLPs/DrugsCauseMitochondrialDamage.pdf

In this article, we show that prolonged ciprofloxacin treatment of preactivated human T cells leads to a loss of mtDNA content. This was accompanied by impaired activity of the mtDNA-encoded mitochondrial enzymes, such as complex I, whereas the activities of the nuclear-encoded mitochondrial enzymes, complex II (succinate dehydrogenase) and citrate synthase, were unaffected.”

I’m pretty sure that loss of mitochondrial DNA (mtDNA) content is bad.

Because complex I is central to energy production in the cell, its malfunction results in a wide range of neuromuscular diseases.” (http://www.mrc-mbu.cam.ac.uk/research/mitochondrial-complex-i) Does the finding that Ciprofloxacin impairs complex 1 mean that Ciprofloxacin can cause neuromuscular diseases? I’m pretty sure that most Floxies would sadly say, “It sure does!”

Per http://www.ncbi.nlm.nih.gov/gene/51103, “Complex I (NADH-ubiquinone oxidoreductase) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane.” Basically, this is an explanation as to how glutathione is massively depleted by fluoroqinolones (FQs). The FQs impair mitochondrial enzyme complex 1 which is responsible for the production of ubiqunone (coenzyme Q) which is responsible for the production of glutathione. This finding is also consistent with an increased production of ROS, not a decrease in ROS. Antioxidant production is inhibited because Complex 1 is inhibited – therefore an increase in ROS would make sense. 

Thus, the current study demonstrates for the first time that mitochondrial complex I-derived ROS control T cell activation.”

Does it mean that mitochondrial complex 1 damage has something to do with autoimmune diseases? It certainly means that it’s REALLY IMPORTANT that it be correctly determined whether Ciprofloxacin (and other fluoroquinolones) increase or decrease ROS production. As I noted above, all other studies that I found said that ROS increases with administration of fluoroquinolones.

Ciprofloxacin treatment was shown to exert various effects on activation- induced gene expression in T cells (10). Stimulatory effects of immediate ciprofloxacin treatment (incubation time up to 72 h) on basal expression of IL-2, TNF-a, or IFN-g in mitogen-activated T cells have been reported (11, 12, 24).”

Stimulating the expression of IL-2, TNF-a and IFN-g is really bad news. Basically, if those are stimulated, an autoimmune-disease, or at least an autoimmune-disease-like state, will ensue. IL-2 is a protein signaling molecule found in the immune system – especially white blood cells. TNF-a is Tumor Necrosis Factor (a) and it also regulates immune system cells. It should be noted that drugs that are used to fight autoimmune diseases are TNF inhibitors. Enbrel and Humira work by suppressing the expression of TNF. If Ciprofloxacin (and other fluoroquinolones) increase the expression of TNF, well, they will induce an autoimmune-disease-like reaction, if not an actual autoimmune disease. IFN-g is interferon gamma, it’s a protein signal that is critical for the operation of the immune system. Again, over-stimulating it is probably a bad idea – unless an autoimmune disease is the goal.

To be fair, it should be noted that the Researchers who authored this particular study did not find that Ciprofloxacin had a stimulatory effect on T-cells. Rather, they found that, “Ciprofloxacin treatment led to a moderate increase in basal IL-2 and -4 expression levels in PHA-preactivated T cells (Fig. 1A). However, prolonged ciprofloxacin treatment clearly inhibited anti-CD3–induced IL-2 and -4 expression in a dose-dependent manner (Fig. 1B).”

They also found that:

Ciprofloxacin treatment induces mtDNA loss, impairs mitochondrial function, and inhibits cellular growth in cultured preactivated human T cells.” (Italicization and emphasis added by them.)

What are the consequences of mtDNA loss? What are the consequences of impairment of mitochondrial function? What are the consequences of inhibiting cellular growth in human t-cells? These are questions that should be asked. The questions should be asked both for the subject human that has consumed the damaging drug and intergenerationally. After all, we are talking about DNA.

In addition, ciprofloxacin induced mtDNA depletion in cultured PHA-preactivated T cells by up to 50%, as estimated by real-time PCR analysis (Fig. 1E). Moreover, mtDNA loss resulted in an impairment of mitochondrial function. This is reflected by significantly decreased activity of the mtDNA-encoded respiratory complex I (Fig. 2A).”

This is a partial answer to the questions about the consequences of mtDNA depletion. What are the consequences of impairing mitochondrial function? What are the consequences of decreasing activity of the mtDNA encoded respiratory complex 1? (Again, I question the result of “decreasing” the activity – it might increase it – there are so many conflicting reports that it’s just obnoxious.)

Genes located on mtDNA encode crucial components of the mitochondrial ETC, such as complex I, III, and IV and ATP synthase. Thus,the loss of mtDNA results in a decreased activity of the ETC (25).”

ETC is the electron transport chain – the process through which mitochondria create energy. Decreasing mtDNA and the activity of the ETC doesn’t seem like a very good idea. What are the consequences of doing so? It doesn’t seem like an unreasonable question to ask.

This indicates that the IL-2 and -4 promoters depend on the simultaneous presence of the increased cytosolic Ca2+ concentration and the PMA-induced oxidative signal. Selective blocking of ROS (with the antioxidant NAC) and the Ca2+ influx (with the intracellular Ca2+ chelator BAPTA-AM) (Fig. 4A, 4C) led to a significant inhibition of IL-2 and -4 promoter activities (Fig. 4B, 4D).”

If one assumes that Ciprofloxacin is a promoter of IL-2 and IL-4 (the opposite of the conclusion of the Researchers, it should be noted, – but I really think that they got the direction of the arrow as to the effect of fluoroquinolones on immune system cells wrong – and my thinking this is backed up by other studies), does this mean that a combination of too much Ca2+ (calcium) and ROS (oxidative signal) within our bodies was part of the equation that made us have the reaction that we had (getting Floxed)? If so, would a combination of NAC as an inhibitor of ROS, combined with a calcium chelator be a cure if applied early on?

I also interpreted this as meaning that Floxies should avoid calcium, but I’m not sure about that.

The immunomodulatory properties of ciprofloxacin and other drugs of the fluoroquinolone group are well documented (10). Most of the in vitro studies showed stimulatory effects of immediate or short-term (up to 72 h) ciprofloxacin treatment on basal gene expression in peripheral mitogen-preactivated human T cells (11, 12, 24). However, several in vitro and in vivo studies suggested that ciprofloxacin has inhibitory properties toward T cell activation (10, 13, 14, 28). In addition, in vitro experiments demonstrated that prolonged ciprofloxacin treatment retards cellular growth (25). This cytostatic effect is mediated by inhibition of the putative mitochondrial topoisomerase II in proliferating cells, resulting in a gradual mtDNA loss and energy shortage (16, 25). Our previous work showed that the mitochondria-generated oxidative signal, in the form of H2O2, is indispensable for T cell activation induced expression of CD95L, a crucial AICD mediator (9). Thus, it is important to clarify whether ciprofloxacin-induced mitochondrial dysfunction could account for differential effects of ciprofloxacin on activation-induced gene expression in T cells.”

This paragraph is both interesting and infuriating because it is abundantly clear that too little is known about these drugs.

The last sentence in the paragraph is interesting. It makes me wonder, do the effects of Ciprofloxacin and other fluoroquinolones depend on which genes are activated/depressed and how t-cell gene expression is influenced (and it’s influenced differently in different people)? Perhaps in some cases/people, genes that inhibit the immune system are expressed, but in other cases/people, genes that stimulate the immune system are expressed. Fluoroquinolones adduct to DNA (http://www.jbc.org/content/273/42/27668.full). Maybe where the quinolone molecule inserts itself into the DNA makes the difference between inhibition and stimulation of the immune system. That could also be an explanation as to why there are such dramatically differing results from study to study. These drugs don’t influence all cells in the same way – making scientific experimentation and conclusions difficult. But if these drugs were looked at from the perspective of being DNA adducts, perhaps the mysterious discrepancies in results could be explained.

Our previous work demonstrated that in the case of CD95L expression, the IP3/Iono induced Ca2+ signal is complemented by a DAG/PMA-induced H2O2 signal. The combination of a mitochondria-generated H2O2 signal with a simultaneous Ca2+ influx into the cytosol constitutes the minimal requirement for induction of CD95L expression (8).”

CD95L is a transmembrane protein that belongs to the TNF family and induces apoptosis – programmed cell death.

Fluoroquinolones have been repeatedly shown to induce apoptosis. This paragraph again makes me think that calcium is an important part of the equation of Floxing. Perhaps it is part of what makes the apoptosis occur.

However, the ability of ciprofloxacin to induce delayed-type hypersensitivity via direct TCR triggering (51) may pose difficulties to the topical application of ciprofloxacin to alleviate skin inflammation.”

The acknowledgement of “delayed-type hypersensitivity via direct TCR (t-cell receptor) triggering” is important.

Applying Ciprofloxacin to the skin in order to reduce inflammation is a dumb idea for multiple reasons, one of which being that the microbiome on the skin is really important and disturbing it by killing all the bacteria on the skin is a really bad idea. Also, an adverse reaction to the Ciprofloxacin can induce more inflammation.

Furthermore, it was demonstrated that the malfunctioning of complex I leads to excessive generation of ROS (54). Thus, it seems interesting that Leber hereditary optic neuropathy, caused by deficient function of mitochondrial respiratory complex I, is often associated with T cell-mediated autoimmune multiple sclerosis-like syndrome (55).”

Cipro leads to the malfunctioning of complex 1 which leads to excessive generation of ROS.

Perhaps Floxies should ask their Rheumatologists if they have T-cell-mediated autoimmune multiple sclerosis-like syndrome.

This article has some really interesting points, that’s why I’m dissecting it, but the internal inconsistency within the article is annoying to say the least. Which direction do the arrows go? Does Cipro lead to an increase in ROS or not? Answer – of course it does. But this article concludes otherwise, despite statements like the direct quote above.

In addition, recent epidemiologic studies on a cohort of patients with mitochondrial disorders showed a high statistical association between these pathologies and lymphoid malignancies (56).”

Insert profanity here.

Written by me for another post that has yet to be published, “Destruction of mitochondrial DNA can result in mass apoptosis. When this occurs, an autoimmune-disease-like reaction can occur (14). However, if cell damage occurs but the cell does not die, but rather replicates the DNA errors, cancer can result (30, 31). Additionally, drugs that inhibit CYP450 liver enzymes leave people more susceptible to cancer-causing pathogens (32) and fluoroquinolones inhibit CYP450 enzymes (8, 33). How ironic, isn’t it? Cancer can result from DNA damaging drugs that, when used in doses that cause apoptosis, can be chemotherapeutic (and have all of the drawbacks of chemotherapy drugs).”

To explore how mitochondrial damage effects cells, the researchers compared the effects of Ciprofloxacin to the effects of Rotenone (Rot), a pesticide, insecticide and piscicide. http://en.wikipedia.org/wiki/Rotenone That should at least imply something.

I am not a Scientist. I am not an expert in mitochondria, cellular function, autoimmune diseases or anything else. However, I have experienced being floxed and I have been doing research on the topic of fluoroquinolone toxicity for the past 2 years. I’m sure that doesn’t count for much, but I think that I’m right in my assessment of the article reviewed above. (Of course I do, I wouldn’t have written what I wrote if I didn’t think I was right – but I could still be wrong – it has happened.) I encourage you to read the article yourself – preferably multiple times because it really is a beast of an article. I hope that this post clarified things and that it didn’t make you glaze over completely.

Fluoroquinolones are damaging human mitochondria. Though I disagree with the researchers who authored this study about the effects of fluoroquinolones on ROS and inflammation, they do note much of what fluoroquinolones can do to mitochondria and mtDNA. The consequences of damaging mtDNA are yet to be determined. I hope that they’re not too catastrophic.

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