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DILI (drug induced liver injury) associated drug, raises steady-state levels of NO in hepatocellular mitochondria (unpublished data).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 –
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.
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):
- “A reassessment of the peroxynitrite scavenging activity of uric acid.”
- “Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase.”
- “Nitrosation of Uric Acid by Peroxynitrite: FORMATION OF A VASOACTIVE NITRIC OXIDE DONOR”
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.
hello lisa, thanks for an answer. i live in Slovakia, mid europe. iv glutathione is not in our distribution. i got iv vitamin c administered and I had a strong flue like reaction to it. later i bought liposomal gluthatione, much cheaper then IV and i dint need to go to hospital to take it. i had flue like symptoms too. and worsening of my FQ symptoms. (muscle weaknes, its been three months since being floxed, it is getting better and better, finally i got back to work, although it is maybe only 70 percent of pre FQ condition) i read than many people with FQ have experienced flu like herxes after IV C or IV G but more they took it, less and less herxes and finally some possitive results came. I wonder if anyone knows science behind it. Is there too may ROS in our FQ damaged cells and even few Glutathione or vitamin C will cause strong inflamnation when they try to reduce them? i cant find an answer anywhere. is it somehow prooxidant for some of us when we fist take them? i really wonder what is it behind it.
well, there is no doctor i know who knows anything about FQ or IV vitamin C/ IV G herxes. There are few who recommend IV C for any condition and when a herx comes they say it is ok, it happens. but dont explain why is is so. none of them knows anything abouth glutathione, even nothing about G. preccursors, NAC or ALA. this supplements are not sold here and i need to buy them from abroad.
if i didnt speak english a bit i would know nothing about FQ. and yes, your site, thank you very much, when i first got FQ reactions, very strong ones, and found some sites about how cipro is deadly, your site gave me a lot of HOPE. thanks. i needed recovery stories.
it is very difficult to expalin my condition to my collegues and friends. whe i say i got an adverse effects of antiobitics, they look at them as if i was crazy. what i say know is that i got adverse effect of a medine which was first invedted as chemo drug and i unvoluntaliry went through small chemoteraphy. they dont understand a thing but word chempotheraphy is what they need to here to admit that there is something terribly wrong with me. 🙁
thanks again. dont worry, i dont think IV C or IV G are miraculous medication for me. i know i will get better without them. i was just curious why there are IV C and IV G herxes. that answer that it is a detox is not enough for me.
actually, i have been floxed twice. first time in april this year. i was diagonsed to have chronical chlamydia infection. my doc gave me ciplox and azi combination for a month and then azi doxy for later. three weks on ciplox i stareted to have muscle weaknes, i stayed home for a month. next month symptms slowly dispaeared. i thought i was a herx reaction of bacterail die off. then i was diagnosed to have streptococus and oflox was the only sensitive abx. i took oflox for two weeks, then stopped, i didnt like parestesias it gave me. few days later i got strong neuropathy. it went away in a week. than i got IV C, which put me into a bed. flu like symptoms and strong muscle weaknes. all muscles, not just legs. very strong. it was 3 months ago. my doc doenst believe quinolones can make such long term effect,l well, aparently it can. now, seeing similarities with april ciplox weaknes i realised it must be FQ, althought it seems to be 3 times worse than first time. of course, everything is fine with me. doctors cannot find anything wrong. i would mind taking iv c or iv g even with flu like herxes, but they make my symptoms much worse. so it is a no no.
thanks for links, i will read those articles.
it is shame, i cant find scientific infmraction why IV C and I G cause herxing.
lisa, thanks again. those articles are Great.
i just have some sort of flare up? i was doing ok, three months since i was floxed, getting back to my job. but i got flu like symptoms, fever, tremors, and my symptoms got worsen. it is similar to how i felt at the beggining, thought it is not as strong.
is is true, that with any kind od acute illness, FQT symptoms get worse and the illness is worse too?
This is an EXCELLENT post that goes over what I said above, better. 🙂
http://health-quest.proboards.com/thread/258/quinolones-ros-onoo-cycle
https://youtu.be/saZAwB9P2iQ
How to reverse this damage, are there still a path of regrowing or regenerate a terminated cells? Of is this mean loss?
Can course Cipro 500mg, 2x/day for two weeks could vanish the neurons in a brain to the point of permanent lost or is there any chance of natural neural regeneration for this heavy dose?
What about GABA with NSAID? Is that permanent?.
I remember took NSAID OTC two days after finishing my two weeks course of Cipro when I realize I can not sleep and did not help the sleeping problem.
Now its already 5 month without a wink of sleep 24/7 and Benzo only make 2 hrs sleep with nightmares. Benzo now giving a short breath plus to the Cipro adverse symptoms.
Life is tearing down without sleep as No sleeping no healing.
jiwa ,no idea but i am 2 1/2 months out ,only took 2 cipro 500 ,and 3 flagyl
1 hours after the 2nd does of cipro and flagyl taken together i had a severe reaction
uncontrollable shaking ,tremors, and spasms , tinnitus, severe metallic taste ,schitso thoughts severe insomnia , heart racing,chest pain , drenches in sweat
happened every night for over 3 weeks with zero sleep thought i would have a psychotic break , broke down crying at night ,every time i tries ot sleep it was like a n electric shock in my brain and i had convulsions for 3 weeks along with the insomnia
it went away but the extreme insomnia comes back
i tried theanine and melatonin melatonin did not work theanine works somewhat
but has bad side effects that last days , worsening brain fog and a sensation like my brain is vibrating in my skull ,i used jarrow formulas ,when i get insomnia bad i would crack open the capsule and take a little sublingually ,i only need a small amount
i just received jarrow uridine from amazon , i am about 2 or 3 days out from a bad relapse where i did not sleep for 6 days now i sleep but it’s broken but no racing schitso thought or electric shock feeling , also i just started mag supplements a week ago , 250 mg pills 1 1/2 a day plus natures calm mag drink at night seems to be helping me
i wish there was more discussion about the neurological symptoms here
they are the worst of all , my tinnitus NEVER goes away the metallic taste went away but comes back though not as bad but the insomnia if you can even call it that is the worst thing of all ,it is the one thing i can not live with
so i feel your pain ,at least the benzos work for you to get 2 hrs ,but i would try to refrain from GABA agonists ,my doc prescribed me lorazapam but i did not not even fill it i have every type of benzo in my med cabinet but i am afraid to take them, they stopped working for me years before being floxxed ,i had already developed a ridiculous sensitivity to drugs
years before and benzos just seemed to have the opposite effect even a mere speck
i like 1/32nd of a 1 mg pill , all pills make me get horrible anxiety like symptoms already
the 1st thing i did was to stop exposure to fluoride best i could ,i always drink bottle water but i used to cook with tap and make tea and coffee with it
now i avoid all caffeine and tea and roibos contain fluoride
i also switched to aluminum free deodorant and fluoride free tooth paste
i am also 99% sure that any type of MSG or free glutamate will cause a sever reaction and trigger me into a relapse of neurological symptoms
you MUST avoid any food with MSG, or ever any form of free glutamaic acid
i only eat organic now , nothing processed , no hormone no antibiotic no pestacide no herbacide only organic chicken fruits and veg
read every label if you cant identify the ingredient do not eat it, i have got triggered several times already a couple times i thought what i was eating was safe but it wasn’t
i been eating the same things over and over i am terrified to change my diet for fear of being triggered again but the last time i relapsed i think i did not eat anything to trigger me
also avoid any stimulation at night , and try to get to bed early , i noticed after i felt better i stood up too late a few nights and then i had a relapse not sure it was caused by food or by staying up too late, if i stay awake too late one night then i can not sleep for a week it seems ,makes sense ,since i read that the brain detoxes itself during sleep if you stay up too late then less time for the brain to detox itself
i plan on trying to add calcium, iodine , DHA and choline along with the uridine to my regimen
this week if i can afford it
iodine and calcium to chelate the fluoiride and the uridine DHA and choline to help repair the neurons and gaba receptors nto sure if it will help and i have not had time to do enough research i am just grabbing at straws out of desperation to try and feel somewhat normal again
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