Additional Targets of Fluoroquinolone Antibiotics: Examples and Research (Part 2)

This page is a continuation of the previous page (Part1) and contains the following topics: 

  • CYP1A2/3A4:   Unintentional Targets / Adverse Effects
  • Flowchart:  CYP1A2 Suppression, and, Living in a Windows 10 World While Running on Windows 3.1 
  • Phosphodiesterases:   Target for Studies / Unintentional Targets / Adverse Effects / Flowchart PDE inhibition
  • Immunomodulatory / Kinase Inhibitors:  Target for Studies / Unintentional Targets / Adverse Effects
  • Cytotoxicity and Oxidative Stress Related:   Unintentional Targets / Adverse Effects
  • Cardiac:   Unintentional Target / Adverse Effects
  • Aldehyde Dehydrogenases:   Unintentional Target / Adverse Effects
  • Viral DNA/RNA and proteins:   Target for Anti-viral / Adverse Effects
  • Fungal DNA and proteins:   Target for Anti-fungal / Adverse Effects
  • Plant DNA:   Target for Herbicide / Adverse Effects
  • Environmental pollution:   Resistance / Adverse Effects

 

 

CYP1A2/3A4: Unintentional Targets / Adverse Effects

It’s very well known that FQs inhibit some of the Cytochrome p450 enzymes.  Here, I look at one of the most studied ones:   CYP1A2.    I think some pretty big helpful hints about mechanisms can come from studying the “FQ-Theophylline” (or methylxanthine) connections.   FQs inhibit CYP3A4 too, and probably interact with other CYPs as well.

There’s a lot to go through from the CYP angle, and I think it’s very worth studying.   I don’t know when or if I’ll get around to it, so here, I present what I’ve come up with so far, which is just one small targeted hypothesis relating a rare genetic haplotype that I have to a possible association with my FQT/FQAD.   But I think there’s a tremendous amount more to be learned from this angle, especially because there are such huge variations in CYP metabolism that occur between individuals.

The good news is, there’s actually quite a bit of research available in this area.   I think the only reason the “FQ-CYP1A2” connection has been studied so much is because of the “FQ-Theophylline” connection, or drug-drug interaction.  Theophylline is a methylxanthine drug that historically has been used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).   Its use is limited now because of its high rate of side effects, which includes “FQ-Induced Theophylline Toxicity” (which I guess is one reason why the FDA is only now in 2016 getting around to recommending against FQ use in patients with COPD).   In this case, the consequences of concomitant use of FQs and Theophylline are clear, and serious enough for patients that medical professionals and Pharma can be liable if this knowledge isn’t clearly stated on the labels and addressed.   Consequently, this one aspect has been studied quite a bit for “cover your ass” purposes.   However, from an FQT/FQAD perspective, I think the studies done on the “FQ-methylxanthine” connection can be used to help elucidate some mechanisms that might be coming into play with FQT/FQAD as well.

FQs are known to inhibit both CYP1A2 and CYP3A4, both of which participate in the metabolism of Theophylline.   In this great little flow chart on Theophylline metabolism, note that Theophylline is demethylated  to 1-methylxanthine and 3-methylxanthine via CYP1A2.   Research has shown that FQs potently selectively block these two demethylations.     We’ve come across FQ-Inhibiton of Demethylase enzymes before:  the two dioxygenase enzymes JMHD and TET1 discussed in “Dioxygenases: P4H, LH1, PHD, JMHD, TET1:   Unintentional Targets / Adverse Effects” are demethylase enzymes too.   Inhibition of JMHD and TET1 may be a mechanism to consider in global epigenetic changes contributing to long term or permanence of FQT/FQAD.   With inhibition of CYP1A2, blockage or inhibition of a demethylation reaction again appears to be playing a role.   FQ-Inhibition of demethylation may therefore play a role not only in CYP1A2 inhibition, but in epigenetic changes making CYP1A2 suppression permanent.

Also note that Theophylline is hydroxylated to 1,3-dimethyluric acid.   Research has shown that FQs selectively blocked this hydroxylation as well, but only at high concentrations — such as what might occur in the “Overdose Hypothesis” (discussed in Part 1 of this topic, see previous page).

As a matter of interest, note that cruciferous vegetables such as broccoli, cauliflower, and cabbage, induce CYP1A2 (and in very large amounts might help tame an overactive thyroid, or hyperthyroidism, as well).  The popular Wahl’s Diet (and other Paleo diets) include a large amount of cruciferous vegetables.  As to whether or not CYP1A2 induction plays a role in their huge health benefits, I can’t say, but I thought it was of interest to note.

Here is the PharmGKB information for caffeine metabolism, which also shows the involvement of CYP1A2 and CYP3A4, along with others.   There are not many drug studies done in general on differences in metabolism between males and females, but here are a couple in regard to the FQs:    Influence of sex on the pharmacokinetic interaction of fleroxacin and ciprofloxacin with caffeine  and Organic Anion Transporter 3 (Oat3/Slc22a8) Interacts with Carboxyfluoroquinolones and Deletion Increases Systemic Exposure to Ciprofloxacin.    I have a tall, slender build, and have always felt this phenotype somehow contributed to my reaction.   Additionally, there is no doubt I have some sensitivities to some drugs.  The most notable were with two over the counter cold formulations, a trial of a few days of Prozac, and a couple of short-lived trials of taking birth control pills, once in the early eighties and a second time in the early nineties.   I rarely, if ever took any medication when I had a cold, but on a couple of occasions, decided to try some OTC meds.   Both times I experienced symptoms very similar to some of my CNS flox symptoms, what one would call “extreme anxiety”.  I call it the “I’m afraid I might jump out the window” feeling; I didn’t know what was happening, and was afraid I was “losing my mind”.   I wish I could remember exactly which meds I took now, so I could confirm the ingredients, but I *think* that one time it was pseudoephedrine (adrenergic, “fight or flight” response, inhibit CYP1A1/2 and CYP2E1), and the second time, chlorpheniramine (anti-cholinergic, metabolized by CYP2D6 and inhibitor of CYP2D6 as well) were the ingredients that stood out for me.  Additionally, the vasoconstriction / drying up my sinuses only felt uncomfortable to me at the time I took those drugs, and is a pretty familiar chronic feeling now, with my FQT/FQAD reaction.   As far as the BC pill trials, I developed all of the symptoms of “too much estrogen” pretty quickly, and couldn’t tolerate them both times I tried them.  There may have been higher doses of hormones back then in the pill, which might have been part of my problem.  As a tall, slender phenotype, knowing what I know now, that was to be expected.  I suspect I have a very, very narrow  “therapeutic range” for estrogen (and other hormones).  In my early forties, I started taking a very lose dose synthetic estrogen/testosterone medication, and that actually made a very noticeable positive difference for me both physically and emotionally.  I had been on this medication without a problem for several years, and was on it at the time I took the Cipro.   Estrogen is also metabolized by CYP1A1/2 and 3A4, and I suspect that FQ inhibition of CYP1A2 and 3A4 probably contributed to an “estrogen toxicity” and FQT/FQAD symptoms during the acute phase.   Currently, as with TH and all other substances, I can no longer tolerate the slightest increases (microgram amounts) of any of the steroid hormones.    Although there could be any number of reasons for this, permanent suppression of one or more CYPs could be one of them.

Interestingly, in my case, I could tolerate taking Ibuprofen (PharmGKB pathways 1 and 2), and relatively high doses (600 mg three times a day) without a problem – even post my FQ reaction. I had taken plenty of Ibuprofen in my life before my FQT/FQAD reaction to help me deal with my back pain flare ups.   After my FQ reaction, I tried hard not to take any, but it seemed to really help during the worst of some of my severe vertigo “PGL/Pheo-like” flares I experienced for a while.   Desperate for relief, I resorted to Ibuprofen once again, and not only was it not a problem, it did seem to help.   In terms of CYP functions, I think I can assume my CYP2C pathway was intact, at least for the first several years.   I think I’ve noticed over time, as my condition progresses overall, that this has changed, and I felt some changes after taking it for more than a few days.   At this point in time (Year 7), I haven’t taken any Ibuprofen in probably over a year, so I don’t know how I would tolerate it now.   My sensitivities have increased to “everything” overall, so I suspect I would feel the effects of Ibuprofen more as well.  I also have the CYP2C9Ht∗1/∗3 – CYP2D6Ht ∗1/∗4 haplotype which has a drug allele response to NSAIDS such as diclofenac and warfarin sensitivity, and, according to this interesting paper here, puts me at increased risk for MCS (Multiple Chemical Sensitivity), FM (Fibromyalgia), and Chronic Fatigue Syndrome/ME.

Below, I wrote up this example hypothesis upon request for someone not familiar with FQT/FQAD.   In it, I suggest a rare genetic CYP1A2 haplotype that I have to a possible association with my FQT/FQAD.  Rather than write up something else for this section, I’ll just supply this write up as is (which is why there’s a lot of repeat and background information here that is covered several times over in this website already).   It should give some idea of the types of things I was thinking of with the CYP hypotheses.   How likely is my thinking process on this hypothesis to be correct?   I don’t know.   No one knows, until and unless someone starts doing some real research with FQT/FQAD population genetics and trying not only to associate the findings with symptoms within the FQT/FQAD population, but then to confirm whatever is found with additional studies.   All I have to work with are my own symptoms, my own 23andMe data, and available research on the internet.   And until the FDA, Pharma and the scientific research community decide to step in, that’s all I’ve got.   I don’t have anyone else’s data for comparisons.   I throw this example out there not necessarily because of the specific CYP SNP’s I focused on, but rather to use it as an example of how to look for connections between our genetic data, available FQ research, and our symptoms of FQT/FQAD.   The SNPs of interest could be anything (not just the CYP ones that I focused on), in any gene, and I hope that as time goes on, more connections like this will be considered by others within the FQT/FQAD community as well.

 

Example of Hypothesis Questions:

  • Is there an association between the CYP1A2*1K haplotype and the development of long term or permanent methylxanthine intolerance in patients with Fluoroquinolone Associated Disability (FQAD)?
  • Is there an association between the CYP1A2*1K haplotype and Fluoroquinolone Associated Disability (FQAD)?

 

  • Caffeine, theobromine, and theophylline are among the most widely consumed compounds in beverages and in pharmaceutical preparations. Some fluoroquinolone antibiotics (FQ’s) are potent and selective inhibitors of specific isozymes of CYP1A2 responsible for methylxanthine metabolism.   This can result in patients experiencing adverse effects to methylxanthines during concomitant administration of FQ’s. The most notable and clinically significant example of these is theophylline toxicity, which can include seizures and fatalities.
  • A significant number of people who have experienced a severe, long lasting or permanent syndrome of adverse effects due to taking FQ’s (described as “Fluoroquinolone Associated Disability, or FQAD), also experience long lasting or permanent intolerance to methylxanthines post antibiotic, even if they were users prior to taking the antibiotic.   In an informal poll taken of FQ-affected, about 35% reported they cannot tolerate any caffeine post antibiotic reaction.
  • My own 23andMe CYP1A2 results show that for the CYP1A2*1K haplotype I carry the rare rs2069526 G/T (0.9%), rs12720461 C/T (0.0%), and rs762551 A/A (53%) variants (HapMap CEU data).   Additionally, I am rs4646425 C/T and rs4646427 C/T, which HapMap-CEU lists as about 0.9% frequency for each.   CYP1A2*1K allele has significantly reduced CYP1A2 activity in nonsmokers compared with *1A or *1F, using caffeine as a probe substrate. This haplotype occurs in very low frequencies overall, and in particular, in the European populations tested. So not only do I have this very rare haplotype that has revealed reduced CYP1A2 activity with caffeine, I also appear to have two additional very rare SNPs within my 23andMe CYP1A2 data. (see PharmGKB Summary:  Very Important Pharmacogene Information for CYP1A2 about this haplotype).
  • Allele frequency and genotype frequency statistics may vary with different databases, and may differ from the NCBI HapMap data. Obviously, I’m working with pretty limited data, only my own data, and rarer alleles/genotypes don’t necessarily translate into problems (we all have plenty of them in our genome).   Still, this is what I have to work with, in terms of trying to find an association between my symptoms, the available research, and my genetic data.
  • If there is an association, what might the significance be?    A suggested mechanism for long term or permanent methylxanthine intolerance in patients with FQT/FQAD may start, or be exacerbated by, with a genetic, and/or environmental predisposition for such patients to have a reduced ability to metabolize or clear FQ’s (hepatically, renally) leading to toxic doses of the drug.  This results in increased inhibition of CYP1A2 (and CYP3A4), as well as other unknown responses of unintentional targets of FQ’s while on the drugs. Increasing serum and cellular concentrations of FQ’s may increase the potential for long term or permanent inhibition of CYP1A2 post antibiotic due to FQ-Induced de novo mutations, epigenetic changes of CYP1A2, or initiation of autoimmunity to CYP1A2.   This might be particularly true for people who start out with lower levels or functionality of the enzyme to begin with.   For FQ-Affected patients with CYP1A2*1K variants with two living biological parents, testing their genotype could help determine a predisposition versus new mutations post antibiotic.   Patients with the CYP1A2*1K variants may want to avoid FQ use if possible, or avoid FQ’s with co administration of theophylline, caffeine, or chocolate.

 

Additional Information

My own 23andMe CYP1A2 results show that for the CYP1A2*1K haplotype I carry the rare rs2069526 G/T, rs12720461 C/T, and rs762551 A/A alleles.   Additionally, I am rs4646425 C/T and rs4646427 C/T, which HapMap-CEU lists as about 0.9% frequency for each.   I am a 57 year old first generation American female of German/European parents, grew up exposed to second hand cigarette smoke from both parents but never smoked myself, and have a history of not tolerating much caffeine in coffee or other beverages due to the “anxiety/jittery” symptoms.   Although I could tolerate chocolate mixed with other foods (chocolate chip cookies, chocolate cake, chocolate milk), I never really ate “too much” straight up chocolate, which in my case, might be a couple of Hershey bars, or a lot of chocolate kisses, for the same reason.   I never tried Melatonin before taking the antibiotic, but post-FQ, feel quite groggy for a couple days after taking 1 mg of Melatonin.

In March 2010 I took a fluoroquinolone (FQ) antibiotic for a simple UTI and experienced a rare, but characteristic severe multi-symptom ADR, which completely disabled me within days, and left me with permanently progressive symptoms of multiple systems.   Prior to taking the antibiotic, I was a healthy, athletic person with no known comorbidities or predisposition, and no known allergies.  There’s been a lot of media attention this past year or so because of these severe FQ-induced ADR’s, and the FDA has recently coined the term “Fluoroquinolone Associated Disability” (FQAD) to describe these reactions and added additional label warnings as a result.   There are thousands of others just like me, who became disabled within days or weeks of taking these drugs.   Many of us were healthy and athletic, of all ages and both genders, with no known co-morbidities or allergies, not on any other medications, no known predispositions for any other diseases or conditions.  We took the drugs for a simple UTI or case of bronchitis, or suspected ear infection or even prophylactically to prevent potential infection for a knee surgery, for example. Millions of people appear to take these drugs safely; however, for the affected population, the results are catastrophic and devastating to quality of life.   Recovery, if it occurs at all, is in the time frame of months to years.   Symptoms are widespread and varied, yet characteristic among the group, implying a common underlying mechanistic problem.  Something is different within the affected population that we have been so severely affected, and that “something” may very well be genomic or epigenomic in nature.

No one knows how or why this happens in some people, or who is susceptible. However, there are cases of multiple family members which have been affected:  parent/child as well as sibling pairs, and even people with a twin.  In my particular case, my parents are also first cousins; their mothers were sisters, so there is a small, but increased chance of me carrying rare or significant genetic variants.   If minute differences in FQ molecular structure can make such a difference between drug-protein interactions, then minute differences in our DNA/protein structure could equally do the same, possibly accounting for the small percentage of the population who react so adversely and extremely to this class of drug.

One hypothesis to consider would be that those of us who react so strongly to this class of antibiotic are lacking one or more enzymes to metabolize them, which effectively “overdoses” us, resulting in a cascade of adverse effects.   A model example of this would be the drug 5FU, where approximately 0.2% of individuals lack the dihydropyrimidine dehydrogenase enzyme needed to metabolize it.  Unfortunately, no such enzyme (or lack of it) or other unifying mechanism has been identified yet in FQAD.   As a class, FQs structurally look like purine (adenine, adenosine, ATP and xanthine derivatives) and indole/tryptophan derivatives.  As part of their mechanism of action, they also can intercalate DNA, form DNA adducts, and interact with phosphodiester bonds, as well as chelate metal ions and inhibit a variety of other human/mammalian proteins.   One of the more well studied interactions of FQs is the “CYP1A2-FQ-Methylxanthine” connection.

Inhibition of CYP1A2 by quinolone drugs is a well known and clinically significant interaction that appears to interfere with methylxanthine metabolism.   Numerous case and research studies describe the effects of Theophylline toxicity secondary to concomitant FQ administration, as well as effects on caffeine metabolism.  (References 16).   Interestingly enough, for the FQAD group, many people develop moderate to severe intolerances to food, supplements, and drugs that did not exist prior to taking the antibiotic.   In an informal poll taken of FQ-affected, about 35% cannot tolerate any caffeine post antibiotic reaction, even if they had no problem with this before.  In my particular case, I am even more sensitive now to small amounts of chocolate than before I took the antibiotic (and I can’t even imagine ingesting any caffeine).   I’m also extremely sensitive to polyunsaturated oils, fat soluble vitamins, and the tiniest doses of steroid and thyroid hormones.   Women who are still cycling say their symptoms fluctuate with their hormonal cycles, and steroids, either endogenous (cortisol) in the form of “stress” or exogenous in the form of Prednisone, often exacerbate or exaggerate these reactions, as do NSAIDs .   Although any number of mechanisms could account for these symptoms, it seems to me that one of them could be a long term or permanent loss of one or more CYP p450 functions, in particular, those who started out with low levels to begin with.  I suppose long term or permanent induction of one or more CYPs is also a possibility, perhaps as a compensatory mechanism in response to such a loss.  Wide inter-individual differences in CYP1A2 activity have been found (10-200 fold, according to various references), so for those at the lower end of the spectrum of activity, an inhibitor of this pathway could be highly significant when it comes to methylxanthine metabolism.  The very narrow therapeutic range of theophylline might be a reflection of this inter-individual variation to some extent.

FQ’s are topoisomerase inhibitors, and therefore, are studied for their anti-neoplastic potential.  The success of the FQ class of antibiotics are based on the premise that “in general”, and in “therapeutic concentrations”, the FQ’s only target the bacterial topoisomerase enzymes, not the human topoisomerase enzymes or any other human enzymes or proteins.  However, in vitro studies have revealed that with increasing concentrations, and presumably, supra-therapeutic levels, these drugs will bind to mammalian/human topoisomerases as well.   They therefore have the potential to be highly mutagenic and clastogenic drugs in toxic concentrations.   For those of us adversely affected, it’s obvious the FQ’s are interacting with or affecting one or more of our human proteins.  CYP1A2 is already a well known target, and further studies have revealed that CYP3A-s may be inhibited as well.   Additionally, they also are known to inhibit various kinases, Tdp1 phosphodiesterase, HIF1 α, V-ATPase subunits, dioxygenases P4H, PHD, JMHD, TET1, and to enhance miRNA in vitro, contributing to interest in using them as anti-neoplastic (chemotherapeutic) agents.   Supra-therapeutic levels of FQ’s resulting in toxicity could conceivably occur in people with genetic predispositions for impaired hepatic and renal clearance for this particular class of drug.   Once that occurs, FQ’s may act more as an anti-neoplastic or chemotherapeutic agent than as an anti-infective agent simply due to a toxic concentration.   This might explain why some of us lose our hair and nails, are chronically nauseated and lose 20-50 pounds, have severely dry eyes, mouth, and skin, strange skin rashes, lose the ability to sweat, have permanent peripheral neuropathy, muscle aches, headaches, fatigue, endocrine and neuroendocrine symptoms, and “chemo brain”/ “brain fog” CNS symptoms during the acute stage or as delayed symptoms.   This is in addition to the well known but peculiar FQ-Induced adverse affect of targeting collagens, resulting in documented tendon pain and ruptures, detached retinas, and aortic aneurysms.

Acute supra-therapeutic levels of FQ’s secondary to a metabolism/clearance issue could also have numerous effects on other enzymes or receptors as well.   Some of these studied include the GABA and NMDA receptors implicated in the CNS reactions, matrix metalloproteinases implicated in the tendon issues, and anti-oxidant enzymes and tyrosinase in the phototoxicity issues, among others.  Individuals with unique genetic, epigenetic, or metabolic variations and vulnerabilities in these areas or elsewhere (such as CYP1A2*1K) might also be more susceptible to elevated FQ levels.  Rare genotypes don’t necessarily translate to vulnerabilities, however, I have come across several fairly rare genotypes in my own 23andMe data for relevant genes (allele frequency < 10%, genotype frequency 0-5% of HapMap EUR ancestry) that I flagged for consideration.

The permanency and continuing worsening of these reactions is another idiosyncratic phenomenon of these drugs for those of us affected.  Numerous hypotheses exist, however, it could be due to permanent epigenetic changes, or even new mutations due to the topoisomerase mechanism or as a result of FQ-Adduct formation.  Because so many FQ-Affected people seem to have a problem with methylxanthine metabolism post-FQ, I wonder if either of these has occurred with the CYP1A2 enzymes, in addition to a possible predisposing polymorphism within the enzyme as well.  FQs inhibit CYP1A2 and CYP3A4, and KEGG information lists FQs as substrates of CYP1A2 as well.  This seems to me to set up the scenario where FQs have the potential to inhibit their own metabolism so some degree, further contributing to potential supra-therapeutic levels while on the drugs.

The various FQ’s are considered to be cleared unchanged from the parent compound to various extents (example: 20-80%).  However, it’s known that metabolism does occur via glucuronidation, and renal clearance via transporters.  In my own data, I have found a few of the rarer frequency variations in glucuronidation enzymes as well.

CYP and Glucuronidation enzymes are heavily involved in metabolism of xenobiotics, steroids, thyroid hormones, fat soluble vitamins, retinoids, fatty acids, and more.   Permanently decreased function in one or more of these pathways could account for the extreme sensitivities to various foods, drugs, supplements, and endogenous hormones and substances that FQAD patients often develop.   I often experience this sensitivity as a “block” or “bottleneck”, as to how much I can eat, exercise, or change my “internal climate” in any way.   It just “feels” like I “don’t have enough” enzyme or protein, and many affected people often talk of that “invisible line” they can’t cross when it comes to foods, drugs, supplements, or exercise.  Tendon pain and disorders are also correlated with hormonal disorder and fluctuations, and a significant number of FQAD patients report hormonal disruptions of all types post reaction, such as with sex hormones, adrenal hormones, thyroid hormones, dysglycemias presumably in association with insulin hormone, Vitamin D/parathyroid hormone, Vitamin A and other fat soluble vitamins.   Might disruptions in one or more of the CYP/Glucuronidation enzymes potentially play a role in tendon disorders as well via decreased ability to metabolize these endogenous substances?

Another reason the “FQ-CYP1A2-Methylxanthines” connection may be significant is because it also opens the door to looking at purine metabolism and salvage pathways.   Structurally, FQs as a class resemble purine derivatives, which include not only adenine, guanine, isoguanine, xanthine, hypoxanthine, caffeine, theobromine and uric acid, but ATP, GTP, cAMP, cGMP, NAD, FAD, NADH, coenzyme A and more.   Disorders of purine metabolism are being studied for many conditions, and have been implicated in Autism and Alzheimer’s, and most recently, in CFS/ME.   Although purines are essential in all cells of the body, the clinical manifestations of these disorders often suggest the nervous system to be more seriously affected than other organs, both peripherally and centrally.  Several pathogens are known to rely on their mammalian host for salvage of purine bases for their survival as well, such as B. burgdorferi (Lyme’s disease), Plasmodium spp (malaria), and H. pylori (gastritis/peptic ulcers).   Purine metabolism, salvaging, and signaling dysfunction may be a common denominator to consider in FQT/FQAD and these disorders, as well as other “chronic invisible illnesses”.

These antibiotics aren’t going away soon, and in fact, more quinolone derivatives are being developed every day as possible drug candidates for any number of conditions due to their anti-viral, anti-fungal, anti-inflammatory, and anti-neoplastic abilities in addition to their antibiotic abilities.   As this occurs, the number of those adversely affected will continue to increase as well.    If there’s any way to figure out who might be susceptible to these reactions other than finding out by taking the drug and becoming permanently disabled, that would be great.  This includes any possible genetic markers which might exist, which in this case, might include the CYP1A2*1K haplotype as one example .

References 16 :  CYPs, mostly FQs with CYP1A2/Theophylline and Caffeine

Update:    According to KEGG information, Ciprofloxacin is a substrate of CYP1A2, therefore it does inhibit its own metabolism to some extent.   For people who might have decreased CYP1A2 functionality to begin with, this is alarming, and increases the chance substantially that in these people, supratherapeutic levels of Cipro could occur while on the drug.  Note that Cipro is also listed as CYP3A4, 3A5, and 3A7 inhibitors, and that transporters SLC22A6 and SLC22A8 are involved in Cipro metabolism.   Also note that KEGG lists CYP1A2 metabolism as involved in steroid hormone biosynthesis, linoleic acid metabolism, tryptophan metabolism, retinol metabolism, caffeine metabolism, xenobiotics metabolism, and drug metabolism.    From a symptoms approach, I had suspected all these as being affected in me post FQ.   From a research perspective, I would put looking for unique polymorphisms within the CYP1A2 gene in its entirety on the list as a candidate for harboring potential genetic vulnerabilities within the FQT/FQAD population.   Searching for epigenetic changes that would modify or attenuate CYP1A2 activity would also be on my list.  Additionally, autoimmunity to CYP1A2 could be yet another mechanism for compromised protein function.

Having said the above, I think it’s also important to note that several studies done in mice lacking expression of CYP1A2 do not differ from wild-type mice, indicating that CYP1A2 is not required for development and physiological homeostasis.  This discovery may or may not be true in humans, but needs to be considered when thinking about any of the hypotheses I am throwing out here about potential attenuation or abolishment of CYP1A2 activity in FQT/FQAD.   However, these mice lacking CYP1A2 expression do have altered responses to the toxic and carcinogenic effects of chemicals as compared with wild-type mice.  Specific references regarding CYP1A2 knockout mice are on Pages 53-54 of References 16.

 

 

Flowchart: CYP1A2 Suppression, and, Living in a Windows 10 World While Running on Windows 3.1

FQ-CYP1A2 Flowchart  (Note:  this flowchart does not include the updated information I provided above from the KEGG info on Cipro.   With the confirmation that Cipro is a substrate, as well as inhibitor of CYP1A2, the flowchart possibilities become even more alarming.)

I made a simple flow chart model of how of FQ-Induced CYP1A2 permanent suppression might have occurred in me.   I haven’t taken the time to learn how to make a more complicated flowchart in Word (with feedback mechanisms), so these flow charts are “one way” only, and don’t reflect all the possible outcomes.   If I ever get the time or energy, I’ll figure out how to make a better flow chart, but for now, these will have to do.

Several assumptions are made with these models:

  1. FQ inhibits a protein directly for as long as the person used the FQ.   In this case, I’m using CYP1A2 as the protein that is directly inhibited.   However, the same concept would apply to any protein that FQs target.   Here, in this particular flow chart, this could include demethylases and TOPO itself, as well as additional targets not on this flow chart but discussed in this website, such as V-ATPase, other dioxygenases, Tdp1, and numerous others as revealed by available research.   Even with this simple flow chart, possible variations in outcomes are greater than what’s seen on the flow chart, depending on if and how much inhibition is occurring where.   In my own case, I have found multiple rare SNP variants in CYP1A2, and less rare, but potentially significant multiple variants inTOPO2B in my 23andMe data, so that influenced how I drew up this flow chart.   I also suspect I was “overdosed” (see “Overdose Hypothesis” in Part 1, previous page), which may increase the chances of inhibition of any one or multiple enzymes regardless of my genetics.  From an individual protein perspective, “recovery” and time frame of recovery would depend on multiple factors, including half-life of the protein and the amount of epigenetic suppression, as well as individual genetic SNP variations.  If development of autoimmunity to CYP1A2 or any other proteins are involved, that would add yet another dimension to consider in all this.
  2. I’m also making the assumption that FQ-topisomerase “crossover” is occurring as well. This could be due either to unique Topo genetic polymorphisms, or the “Overdose Effect” (see “Overdose Hypothesis” in Part 1, previous page).   TOP2A promotes replication, transcription, chromosome structure and chromosome segregation, and is essential for cell proliferation and expressed mostly in dividing cells.   In contrast, TOP2B participates mainly in transcription and is expressed in both dividing and non-dividing cells, involved in neuronal differentiation, regulation of several ion channels and transporters, vesicle function, and cell calcium metabolism as well.   I’m emphasizing the transcription aspect of TOP2B because I felt I found potentially significant variants in a number of my TOP2B SNPs as well, not to mention that I have symptoms which could be indicative of “neuronal dysfunction, ion channel and transporter dysfunction, vesicle dysfunction, and cell calcium metabolism”.  The important point to remember here, is that if a gene needs to be upregulated to meet the needs of the cell, more TOPO will be needed there.  This would include upregulation for drastically depleted proteins, such as CYP1A2 in this case.   Although I focus on CYP1A2 here, note that the same might be true of TOPO as well.

 

Looking at this flowchart, a legitimate question with this hypothesis is:    Shouldn’t we be able to see a buildup of one or more metabolites with blood testing, if there’s a block in CYP1A2 or elsewhere?   It’s a logical question, and normally I would say “yes” (this is the case with FQ-Induced Theophylline Toxicity, where one can see objective evidence of elevated theophylline levels in blood while on the FQ).    But I think there may be other possibilities.    For starters, there are thousands of metabolites fluctuating at an intracellular level, and at a tissue specific level, that we’re unable to test for and won’t see in blood samples.   “Serum homeostasis” — the level of thyroid hormones in my blood, for example, is not equivalent to “cellular homeostasis” — the amount and activity of the thyroid hormones within each cell.  So having “normal blood levels” of thyroid hormone, doesn’t guarantee that everything is working “normally” within my cells, or that I don’t have “too much” or “too little” within the cells when it comes to utilizing thyroid hormones — especially if one or more intracellular or intranuclear mechanisms is disrupted.  The same is true of other hormones, neurotransmitters, and metabolites.

Another example, is that there are also thousands of metabolites that simply can’t be tested for yet (no clinically available testing).   For example, I would love to test for reactive aldehyde intermediates, because “Aldehyde Toxicity” is on my list of possibilities for FQT/FQAD.   But there’s no simple blood testing available for all the different aldehydes and intermediates available.  And it’s obvious that different tissues are being differentially affected in me as well.  For the metabolites we are able to test for, my guess would also be that the best time to catch elevated levels in blood tests would be during the acute phase of a reaction, before the body has a chance to systemically adjust via numerous compensatory mechanisms.    Once a systemic or global compensatory response takes place, serum levels of metabolites might level out in normal ranges again, despite there still being a “block” somewhere.

If there’s a block somewhere in metabolism, there are probably several different responses to that.  One is that alternative pathways will upregulate, to try and compensate, and this may be enough to take care of the excesses to an extent or for a short duration (ie, during the acute phase of the block).   Another possibility is that the body tries to compensate by slowing down / shutting off everything related to that, so all metabolites will lower systemically.  I would expect this option to occur more in chronic, long term cases, such as what I’m now experiencing.   In fact, I actually attempt to help this processs “manually” by limiting my exercise, eating the same foods, in the same amounts, at the same times every day, in my own desperate attempt to “maintain homeostasis and not create a buildup” somewhere.   If I do cross that “Invisible Line”, I pay for it dearly with horrific symptoms, and my body goes haywire trying to get back to some semblance of “homeostasis”.

The best chance I would probably have at looking at a serum “buildup” of something now would probably be to do a “stress test” of sorts, by exercising, eating certain foods, taking certain drugs or supplements, and then running multiple serial blood work while I’m highly symptomatic, trying to see what’s “building up” in me.   As an example, at this point in time, if I try to walk a couple of blocks, I can feel “something” building up in me.  The first day, it’s a “good thing”, because some of my symptoms will improve a bit (which actually leads me to suspect that enzymes which are supposed to be constitutively expressed at low levels are too low in me).  But if I continue to try walking a couple of blocks a day, by Day 4-5 I start “running out of something”, and whatever is “building up” in me as a result feels like it goes to excess.  I develop a severe, all over body “electric buzzing” sensation and burning that won’t turn off, while feeling like “the bottom has fallen out” for some other substance, all my other symptoms worsen, I feel like I’m dying, and the CNS symptoms are even worse if that’s even possible.   I have to stop, not move, not eat anything new, decrease the amount of food, and slowly wait for the excess “something” to metabolize off, while whatever I ran out of “replenishes” itself (and there’s a hell of a lot of physical and emotional suffering in that process while I wait).  This cycle repeats itself with virtually anything I do or ingest anymore, so whatever is “building up” is pretty fundamental and common to a lot of processes  (like intracellular cAMP is one example I always think of, which probably can’t be measured in serum).   As my condition continues to deteriorate, it’s getting harder and harder to control this all over “electric buzzing” though; for the most part, I always have a little of that going on anymore, which is why I can’t “exercise” and I try to move less and less.   I do feel better whenever I run blood tests, which suggests that “something toxic” is being removed from me every time I give blood (in this case, perhaps autoantibodies).   So there’s probably something in my bloodstream that could conceivably be tested, but what it is, and if a test is actually available to measure it, is anyone’s guess.

As another example, I’ll use my own experience of taking thyroid hormone (TH) and monitoring multiple serial serum levels of T4/T3.   As time has gone on, my sensitivities to everything, including TH, have increased.   At this point in time, I am highly sensitive to the slightest increases in TH, in particular, T3.   A microgram or two can throw me into a “hyperthyroid state” now within hours – but this tiny “elevation in dose” would not be reflected in serum levels.   In fact, my serum levels of T4 have remained steady even as I am forced to continually lower my dose to reflect an increasingly lower metabolic status.  This is one reason why I suspect I have one or more receptor or transporter problems at an intracellular level, as discussed in “It Felt Like a Homeostasis Problem”.

I’m on Year 7 of this ordeal, and although TH originally helped me quite a bit, it’s become apparent that my FQT/FQAD problems lie elsewhere in addition or instead of with just TH.   In the past several years, as my condition continues to slowly deteriorate, my TH needs – and therefore my TH dose – has been slowly but steadily decreasing.   It was never high to begin with – I started out at about half the dose most people take.   But over time, I am being forced to slowly decrease that dose even more, to the point I’m now only on about a quarter of the dose most people take.   My body is “metabolically shutting down” because I’m “running out of something”, and I don’t know what that “something” is yet.   It could be an enzyme, it could be mitochondria, or it could be proteins “piling up at the ER” – but whatever the problem is, the rest of my body is trying to compensate for the block by slowly shifting “everything else” down too on a global scale.   For people not on TH medication, this process is occurring automatically with the HPT axis.  For people like myself, on medication, I have been forced to adjust my TH dose down, since my HPT axis is “shut off” and unable to do it for me.   Increasing TH is like giving the signal to “increase metabolism”.   In my case, my “metabolism” is “shutting down” due to one or more blocks somewhere, and my lower TH dose needs are a reflection of that.   But my serum TSH and TH values are not a reflection of that – they remain in the same range they always were.   Yet, I’m on half the TH dose I started out with, and on a quarter of the TH dose most “normal” people are on (based on all my experience with TH in the past several years, I’m pretty confident my axis remains “shut off” and there is no TH contribution coming from my thyroid gland).

As with my TH example, these are some of the reasons I can think of that we might not see elevated levels in other hormones or metabolites we can test for, especially in the chronically ill.   But it doesn’t mean that toxic metabolites aren’t building up at a cellular level or in specific tissues.   It just means we can’t see them or test for them yet.  Most people with severe or permanent FQT/FQAD experience some level of fatigue and weakness, similar to what CFS/ME people experience, and this is true of me as well.  I’m convinced that for both of our groups, we are “missing” or there is suppression of one or more important enzymes or proteins, creating a “block” somewhere.  This appears to have been confirmed in the study “Metabolic features of chronic fatigue syndrome” where patients with CFS showed abnormalities in 20 metabolic pathways.  Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome”.   Many, if not most, of these metabolites are not ones the average patient would be tested for.   With the advent of this particular study, I hope this changes, and that clinically available testing for the markers they found will become available soon.   It would at least provide an objective way to diagnose CFS/ME, something that community has been waiting for, for a very long time.

CFS/ME is a devastating, life altering condition that has been dismissed, denied, and even ridiculed by the medical profession and the general public forever.  Describing the severe lack of energy (possibly ATP) as “fatigue” hasn’t done anyone any favors either, as this word doesn’t even begin to describe the reality of whatever is physiologically going on within every cell of the body.   “Millions Missing” is an apt description for the millions of people who simply drop out of life due to this horrific condition; and “Millions Missing” is also an apt description for the millions of dollars missing that are needed for research to diagnose and effectively treat this population.   About the only thing to come out of the “research” for these poor CFS/ME folks in the past 30 years is a couple of name changes, along with the incredibly ignorant and insane recommendation that “exercise and a positive outlook” will cure you.   It’s clearly obvious that whoever made those recommendations are lucky enough to have not ever experienced even remotely what some of the CFS/ME people live with daily.   What a horrifically medieval and abusive response (just because you as a healthy person can’t see it or feel it, it doesn’t exist) to a population who has suffered so tremendously.

At this stage of the game, seven years out, I very much fit into a CFS/ME diagnosis as well as FQT/FQAD.   The difference with me, is that I know exactly what the initial insult was that initiated and caused this downward cascade of events.  In fact, the very first symptom I experienced on Day 5 of my acute reaction was a mixture of profound “weakness / fatigue” unlike anything  I had ever experienced before in my life.   That profound “shut down” on Day 5 was when enough of the drug bound up enough of one or more enzymes, or ATP derivatives, or some specific place within my DNA directly, that I felt like “everything just stopped”.   And here, in this very long section about these “Dirty Drugs”, we can see the long list of already known additional targets of FQs, giving us clues as to where that might have occurred in me, in other FQT/FQAD victims, and possibly in numerous other chronic illness conditions too.   As I wrote on the webpage  Is it Lyme’s Disease, Sjogren’s Syndrome, Mitochondrial Disease, Chronic Fatigue Syndrome, Fibromyalgia, Fluoroquinolone Toxicity Syndrome, or . . . The Commonalities of Post-Viral, Post-Bacterial, and Post Fluoroquinolone Syndromes,   “An underlying theme in this section is that FQ ADR’s appear to cause, trigger, or mimic many other “Chronic Invisible Illness” symptoms.   If FQ’s can cause the same or similar symptoms as these other conditions, then it only makes sense that some of the underlying biochemical, genetic, or epigenetic causal mechanisms may be similar as well.   In my opinion, studying FQ adverse effects and the underlying mechanisms could probably teach us a lot about many of these other conditions as well . . . Viruses hijack host DNA, spirochetes with their limited genome depend on host cell metabolism, and both chemo and FQ drugs target specific proteins and DNA causing similar adverse effects.   Surely there is something to be learned from this.”

One of the reasons I think the “FQ-CYP1A2-Methylxanthines” connection is so important, is because it opens the door to looking at purine metabolism and salvage pathways.  Structurally, FQs as a class resemble purine derivatives, which include not only adenine, guanine, isoguanine, xanthine, hypoxanthine, caffeine, theobromine and uric acid, but ATP, GTP, cAMP, cGMP, NAD, FAD, NADH, coenzyme A and more.  Disorders of purine metabolism are being studied for many conditions, and have been implicated in Autism and Alzheimer’s, and most recently, in CFS/ME.   Although purines are essential in all cells of the body, the clinical manifestations of these disorders often suggest the nervous system to be more seriously affected than other organs, both peripherally and centrally.  Several pathogens are known to rely on their mammalian host for salvage of purine bases for their survival as well, such as B. burgdorferi (Lyme’s disease), Plasmodium spp (malaria), and H. pylori (gastritis/peptic ulcers).   Purine metabolism, salvaging, and signaling dysfunction may be a common denominator to consider in FQT/FQAD and these disorders, as well as other “chronic invisible illnesses”.

I often feel like I’m “running on a Windows 3.1 version” while living in a Windows 10 world.    And everyone who is old enough can understand how many glitches, and how slow, a computer running on an old Windows program like 3.1 would be today.   You can’t play today’s computer games, watch HD videos, or even access much of the internet using some of those old programs, and just imagine trying to use dial-up for connecting.  In the same way, I’m barely functioning in survival mode, but that’s about it.   As with CFS/ME, any quality of life has been robbed from me by FQT/FQAD.  When it comes to research, I think there’s a lot to be learned for both conditions that both populations can learn from.

CFS/ME research appears to be gearing up and finally getting the attention (and funding) that it deserves.   I would like to acknowledge the great work and progress of all the various CFS/ME research groups in attempting to tackle the problem of CFS/ME.   They are stressing collaboration, sharing, and openness as the approach to solve this problem and get to answers faster.  Thank you for your hard work and dedication.  I hope that others from outside specialties will take an interest and join them in their endeavor.  My heart goes out to everyone with CFS/ME, and the family members who love and care for them, and I sincerely hope that effective diagnoses and treatments will be found soon.   Some excellent patient resources on “everything CFS/ME”, including the latest research, are the “HealthRising” and “Phoenix Rising” websites.

FQs are known to inhibit CYP1A2, 3A4, and possibly other CYPs as well, interfering with metabolism of numerous other endogenous and exogenous substances while on the drug.   Epigenetic modifications or autoimmunity may potentially contribute to permanent changes in CYP metabolism post FQ.  CFS/ME is a another devastating, life-altering chronic condition with what appears to be multiple causes or triggers.   I developed CFS/ME after taking an FQ, so in my opinion, FQs are one of them.

If you have cancer, or are on your death bed due to sepsis nothing else will get, you might want to consider an FQ.    But for anything and everyone else — why take the risk?

References 16:  CYPs, mostly FQs with CYP1A2/Theophylline and Caffeine; some Purines/Purine Metabolism

FQ-CYP1A2 Flowchart

 

 

Phosphodiesterases:   Target for Studies / Unintentional Targets / Adverse Effects

Phosphodiesterases (PDEs) are enzymes that break phosphodiester bonds.    Phosphodiester bonds are really important components in DNA and RNA molecules, and in cAMP/cGMP molecules, among others.   A phosphodiesterase inhibitor (PDEi) is a drug that inhibits, or stops PDE enzymes from breaking phosphodiester bonds.   It turns out FQs appear to function as PDEi’s, which leads to a cascade of effects.   From the references available, the speculation is that FQs inhibit PDEs –> prevent breakdown of cAMP –> accumulation of intracellular cAMP –> enhanced cAMP-Protein kinase A activity –> inhibit TNF-α production.   TNF-α is a cell signaling protein (cytokine) involved in systemic inflammation and in the regulation of immune cells (ie, it’s considered “pro-inflammatory”).   Consequently, lowering TNF-α is a goal of many drugs already on the market for numerous “inflammatory” conditions, including “autoimmune” ones, as well as the inflammation that can occur with viral or other infections.   There are many different kinds of PDE’s in the “PDE family”, and it looks like FQs are now in consideration for “selective inhibition” of specific PDEs as anti-inflammatory medications now too.

Way back in Part 1 of this very long section, we’ve already seen another example of PDEi, in that FQ derivatives have been discovered to inhibit a specific phosphodiesterase called Tdp1 for use as anti-cancer agents (see Part 1, previous page, under “Tdp1 (Tyrosyl-DNA Phosphodiesterase):  Target for Cancer”).  In this case, Tdp1 is involved in repairing DNA via phosphodiester bonds, so by preventing this repair from occurring, cancer cells can be killed more effectively.

With the exception of the above regarding Tdp1, most of the references I could find on FQs acting as phosphodiesterase inhibitors (PDEi’s) seemed to mention this effect almost in passing, as a suggested mechanism for other aspects of the study.    I could not find studies dedicated to researching this effect, although I’m sure they must have occurred somewhere, as the next paragraph suggests.

There is a patent publication for utilizing quinolone derivatives as selective phosphodiesterase inhibitors (PDE4i’s) for a very long list of diseases (see references below).   I also supply a patent application for a non-FQ – PDEi, and, as the author states:    Inhibitors of each type [of PDE] can have a crossover inhibition of other types [of PDE’s].    I’d be willing to bet that in those of us with FQT/FQAD, some of this “crossover inhibition” with PDEs was occurring in us while on the FQs, and to some extent, is continuing in those of us with permanent FQT/FQAD.

In the article “Warning to Floxies: Beware of New Med for Psoriatic Arthritis”, the author describes how her husband, who initially had a mild FQ-ADR three years prior, appeared to develop symptoms very similar to FQT/FQAD after just a few days of starting a PDE4 inhibitor.   This sounds like it could have been an “accumulative effect”, with the first hit due to an FQ PDEi, and the second hit due to a drug specifically given as a PDE4i.

If I had any money to bet, I’d bet that FQs are acting as non-selective phosphodiesterase inhibitors (PDEi’s) as part of their “dirty drug” profile.    Note that methylated xanthines and derivatives (discussed above in CYP1A2/3A4:  Unintentional Targets / Adverse Effects) also act as non-selective PDEi’s.    For FQT/FQAD victims who can no longer tolerate caffeine or chocolate, this is another mechanism of PDE inhibition to consider.

For a variety of reasons, I had long considered some kind of “secondary messenger dysregulation” as something to consider as being fundamental to my sensitivities and problems in general.  These secondary messengers would include cAMP, cGMP and intracellular calcium.   The cyclic AMP (cAMP) pathway is a secondary messenger pathway used by a lot of endocrine hormones to cause an effect in their cells.   In this video here, notice all the different hormones that utilize this pathway.   In other words, this cAMP signaling pathway is a common denominator for all these different hormones (More videos here and here).   Cyclic AMP, cGMP, and calcium are fundamental to so many processes and pathways, that a problem at this level could account for the extreme “on/off” and homeostasis symptoms I felt with all the hormones and so many substances in general (see “It Felt Like a Homeostasis Problem”).   But there was no way at all for me to test this, so it’s just another guess.

However, for some reason, I came to think of that all over “neurological buzz”, the “electric fence feeling” throughout my body, along with the “anxiety” and tinnitus, as being cAMP related.   Again, I had no way to test this or confirm it, although there are cAMP (as well as ATP) supplements one can purchase.   I bought a cAMP spray, and tried a little spritz sublingual and again up the nose just to feel what happened.   I definitely developed what I called my “cAMP buzz” within minutes, which I suppose one could say helped support this hypothesis.   But I developed that buzz with lots of other things too, so it’s not confirmation of anything.   Still, once I started looking at PDE’s, and inhibitors of PDE, this not only kept “cAMP dysregulation” on the list for me, but moved it up quite a bit.   PDE activities are modulated in coordination with adenylyl cyclase (AC) and guanylyl cyclase (GC) activities through direct effectors and feedback pathways, thereby maintaining cAMP and cGMP levels within optimum ranges for responsiveness to signals.  Therefore, if there’s a problem or dysregulation with PDE’s, that’s going to affect everything downstream of that too.  As I’ve mentioned before, I’ve tested TNFa serum levels, and they’ve always been plastered down at the very bottom of the range, about as close to the bottom of the range as can get.   Might this be a reflection of permanent PDE inhibition?   I don’t know, but it’s something to consider.

The other horrific symptom that occurs with my “cAMP buzz episodes” is severe weakness, and a feeling that is pretty indescribable, but I can only try and describe as feeling like “every cell of my body is dying”.   cAMP is an ATP derivative, and I always tend to think of these episodic reactions as “losing ATP” as it’s converted to cAMP.   It’s a combination of feeling like “the bottom has dropped out” in terms of energy, and the worse that is (ie, the weaker I am), the stronger (ie, worse) the neurological buzz and “cold from the inside out” is.   If I don’t have enough ATP to begin with, there’s less available to convert to cAMP, although if PDE is permanently suppressed, a buildup of cAMP could occur anyway.   The enzyme adenylyl cyclase catalyzes the conversion of ATP to cAMP, requiring magnesium ions, so a problem with this enzyme would also contribute to ATP/cAMP problems.   Again, I have absolutely no way to determine if this is going on, but this is one of the mechanisms I think of when I try to make sense of these symptoms and correlate them with the available research we have on FQs.

When I develop my “cAMP buzz” after eating, or moving, it lasts for varying lengths of time (minutes, hours, depending on the stimulus).   But I know it when it “turns off” or “drops down” to the next level, because I can feel it.   It’s a very “on/off” type of thing:   I’ll feel that buzz, and then suddenly, within seconds, it will “turn off”, or “drop down a level” (that’s because for the most part, it’s never really “turned off” completely anymore; I always have some amount of that “buzzing” going on now).  Interestingly enough, about the only time I haven’t felt this “buzz” post flox was during my “iodine trial”, when I had extremely low levels of thyroid hormone, but higher levels of iodine.  My body — and mind — felt . . . quiet.  No “CNS buzz”, no “tinnitus”, no “buzz” throughout my body . . . just . . . quiet.  It was an amazing relief and experience, and is part of what prompted me to start writing up this website in the first place.    Whatever is causing that “buzz”, it’s more active at night too (the regular fluctuations of hormones, neurotransmitters, amino acids, etc that occur at night), and I can literally feel various pathways “turning on and off” throughout the night.   There’s nothing wrong with my “circadian clock” and rhythm, because it’s all very regular, like clockwork.    I could tell you what time it is by the hourly changes in my symptoms.  When scientists say there’s a lot going on at night when we sleep, they’re not kidding, because I feel a hell of a lot of it happening now.   I can really see how sleep is a time for innumerable bodily processes to undergo all kinds of  “regenerative fluctuations” while essentially “knocking us out” while the worst of it is happening, but no such luck with me being konked out or sleeping anymore while all this is going on since being floxed.   These are normal and necessary hormonal and neurotransmitter cycles as we sleep, but as I said in “It Felt Like a Homeostasis Problem”:    “Note that there is a difference between saying something like “Excess hormonal surges are occurring and my body is spitting out “too much hormone”, versus “The receptors to certain hormones are disrupted or hypersensitive, and so normal hormonal surges now feel exaggerated due to these receptor malfunctions”.  Either or both of these situations could have been occurring in me”.   Part of those “receptor malfunctions” could include cAMP/cGMP dysregulation secondary to PDE dysregulation.

The worst examples and experiences of this are being abruptly awakened at 4 am with heart pounding and racing, dripping in sweat, severe chest pain, feeling the extreme neurological buzzing throughout my body, while my body becomes ice cold. I’ve provided a list of differentials for these symptoms in this section (see previous page Part 1, under “HIF1a (Hypoxia-Inducible Factor 1-alpha):   Target for Cancer”) and throughout this website.   Here, another consideration might be “cAMP stuck on the “ON” position” for too long, due to excessive PDE suppression or dysregulation.   On the other hand, I might not have enough cAMP/cGMP when I need it also; with this potential mechanism, it’s like the “fine tuning” of the interplay between PDE and cAMP/cGMP is disrupted, and it takes a lot more of either for anything to happen anymore.

There isn’t any way for me to determine how much, if at all, cAMP is playing a role in my FQT/FQAD.    And there’s no way for me to confirm whether PDEs are as well.   However, based on what I know, I’d put PDEs high on the list of additional unintentional promiscuous targets of FQs.    Cell signaling involves such a huge cascade of events that all it would take is a problem in one part of the maze to mess the whole thing up (which is why targeting one aspect of it with drugs so often has so many side effects).   cAMP and PDEs are only part of that cascade, but I’m focusing on it here because we do have evidence in the form of available published research of FQs interacting with one or more PDEs.   As usual, I would suspect that people with specific genetic or epigenetic variations within the various PDEs would be the most vulnerable to developing long-term or permanent FQT/FQAD.

FQ-CYP1A2-PDE Flowchart:    Under “CYP1A2/3A4:   Unintentional Targets / Adverse Effects” on this page, I provided a flowchart for CYP1A2 suppression by FQs.   Here, I provide a second flowchart, combining CYP1A2 and PDE suppression by FQs.   See the description of the assumptions I made with the FQ-CYP1A2 flowchart for more information.  As with the FQ-CYP1A2 Flowchart, possible variations in outcomes with this flowchart including PDEs are greater than what’s seen on the flow chart, depending on if and how much inhibition is occurring where.

An antibiotic that you take for a simple infection shouldn’t be targeting all important phosphodiester bonds within your DNA or involved with the ATP/AMP energy metabolism in your body.    If you have cancer, or are on your death bed due to sepsis nothing else will get, you might want to consider an FQ.   But for anything and everyone else — why take the risk?

Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone.    “With ciprofloxacin, it occurs in very early stages of TNF-α synthesis, probably due to the quinolone effect as a phosphodiesterase inhibitor, leading to cyclic AMP accumulation in the cells, resulting in enhanced cyclic AMP-protein kinase A activity, which in turn is known to inhibit TNF-α production.”

Fluoroquinolone-Induced Motor Changes in the Guinea Pig Isolated Ileum.   “This hypothesis is supported by the observation that drugs with quinolone structure may inhibit phosphodiesterase activity in rat mastocytes and in the human isolated myocardium.”

Ciprofloxacin-Induced Antibacterial Activity Is Attenuated by Phosphodiesterase Inhibitors.     Ciprofloxacin is a commonly used antibiotic for urinary tract infection that interacts with bacterial topoisomerases leading to oxidative radicals generation and bacterial cell death.   Phosphodiesterase inhibitors (PDEis), on the other hand, are commonly used drugs for the management of erectile dysfunction.  The group includes agents such as sildenafil, vardenafil, and tadalafil.   We investigated whether PDEi could interfere with the antibacterial activity of ciprofloxacin.   PDEis were tested in several reference bacteria, including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Acinetobacter baumannii, Proteus mirabilis, and Klebsiella pneumoniae utilizing a standard disc diffusion method and measuring both zones of inhibition and MIC.   Results from both assays indicated that ciprofloxacin demonstrates potent activity against the tested reference bacteria.  Additionally, when bacteria were treated with a combination of ciprofloxacin and sildenafil, tadalafil, or vardenafil, the zones of the combination inhibition were significantly reduced, whereas the MIC values were significantly greater than those of ciprofloxacin alone for all tested bacterial strains.   In an attempt to examine the mechanism by which PDEis interfere with the action of ciprofloxacin, we utilized the in vitro E coli DNA gyrase cleavage assay. The results showed that PDEi drugs had no effect on ciprofloxacin’s inhibition of E coli gyrase activity. Pretreatment of various reference bacterial cells with PDEis largely inhibited the antibacterial activity of ciprofloxacin. . . . Our present results indicate that combining ciprofloxacin with a PDEi results in inhibition of the antibacterial activity of ciprofloxacin against a panel of reference bacterial strains. To our knowledge, this is the first report of such effect or drug-drug interaction. This could point out that concurrent use of ciprofloxacin with any of the PDEis we tested might oppose the antibacterial activity of this antibiotic. Therefore, PDEi use might need to be closely monitored in patients who are receiving ciprofloxacin. The mechanism for this interactive effect of ciprofloxacin and PDEis is unknown. Quinolones exert their bactericidal actions through the inhibition of DNA gyrase, bacterial type II topoisomorase.  Yet multiple other effects were related to quinolones, such as inhibiting the growth of other types of cells via interference with cell cycles, reducing cell size, inhibiting de novo synthesis of pyrimidine, and interfering with mitochondrial enzymes that are involved in energy metabolism21 and oxidative stress.”

Inhibition of rat parotid and submandibular gland functions by ofloxacin, a fluoroquinolone antibiotic.     “While fluoroquinolones are widely used in the treatment of various infectious disease, not enough attention has been paid to their adverse effects on salivary glands functions. In the present study, the effects of ofloxacin, a fluoroquinolone antibiotic, on rat parotid and submandibular gland functions, were examined in an acute experiment . . . It is concluded that ofloxacin inhibits rat salivary gland functions, which might be observed as a side-effect in humans. Properties of fluoroquinolones alter intracellular cAMP and calcium levels and their ability to suppress DNA, RNA and protein synthesis of acinar cells might be possible reasons for the observed changes.”

Inhibition of rat parotid gland growth response induced by chronic isoproterenol following treatment with quinolone antibiotics.     “While antibiotics are broadly used in dental and medical therapy, little attention has been directed towards the potential toxic side effects of antibiotics on tissue regeneration. Here we examined the effect of a quinolone antibiotic, pefloxacin (Rhone Poulenc) on rat parotid gland responses to chronic isoproterenol treatment. Groups of rats received injections of isoproterenol to induce glandular growth, saline (controls), pefloxacin, or isoproterenol and pefloxacin in combination. Parotid gland weight decreased significantly after pefloxacin treatment for 7 days as well as inhibiting glandular enlargement provoked by isoproterenol. The same trend was observed for the rates of DNA synthesis, with the incorporation of [3H]-thymidine in isoproterenol/pefloxacin-treated rats reduced to 49% of isoproterenol treatment alone levels. Saline-treated animals were 42% of the rate of [3H]-thymidine incorporation into DNA observed in isoproterenol treated rats. While isoproterenol treatment increased steady-state mRNA levels for fos, jun, myc, src, c-erbB-2, ras and topo II, inclusion of pefloxacin with the isoproterenol regimen blocked these increases. Pefloxacin treatment by itself did not alter proto-oncogene mRNA levels in the parotid gland. Glandular amylase activity was decreased in the pefloxacin treated group, while the combination of isoproterenol with pefloxacin did not decrease glandular amylase levels to the extent of that observed with β-agonist treatment alone. In acute experiments, pefloxacin significantly decreased the volume of saliva secreted by the parotid gland. These results suggest that quinolone-based antibiotics disturb the secretory function of the parotid gland and can inhibit cell proliferation and regeneration.”

Analysis of protein synthesis in rat salivary glands after chronic treatment with β-receptor agonists and phosphodiesterase inhibitors.   “The phosphodiesterase inhibitors (theophylline and caffeine) were able to induce de novo PRP (proline rich protein) biosynthesis at drug doses of 20 mg/200 g animal.”

Morphological Changes in Salivary Glands Induced by Theophylline in Rats.   “Theophylline, a phosphodiesterase inhibitor, is known to induce enlargement of the salivary glands.  This enlargement has been thought to be associated with enhanced cellular levels of cyclic AMP as a result of inhibition of phosphodiesterase. . . . these results suggest that inhibition of phosphodiesterase is primarily involved in the discharge of secretory granules, and that the salivary hypertrophy previously reported is an adaptive response caused by the repeated stimulation of saliva stimulation.”

Immunomodulatory effects of quinolones.    “We review data on the in-vitro, ex-vivo, in-vivo, and clinical effects of fluoroquinolones on the synthesis of cytokines and their mechanisms of immunomodulation. In general, most fluoroquinolone derivatives superinduce in-vitro interleukin 2 synthesis but inhibit synthesis of interleukin 1 and tumour necrosis factor (TNF); α furthermore, they enhance significantly the synthesis of colony-stimulating factors (CSF). Fluoroquinolones affect in-vivo cellular and humoral immunity by attenuating cytokine responses. Interleukins 10 and 12 have an important role in the functional differentiation of immunocompetent cells and trigger the initiation of the acquired immune response. In addition, certain fluoroquinolones were seen to enhance haematopoiesis by increasing the concentrations of CSF in the lung as well as in the bone marrow and shaft. Those fluoroquinolones exerting significant effects on haematopoiesis were those with a cyclopropyl moiety at position N1 of their quinolone core structure. Mechanisms that could explain the various immunomodulatory effects of fluoroquinolones include: (1) an effect on intracellular cyclic adenosine-3,5-monophosphate and phosphodiesterases; (2) an effect on transcription factors such as nuclear factor (NF) κB, activator protein 1, NF-interleukin-6 and nuclear factor of activated T cells; and (3) a triggering effect on the eukaryotic equivalent of bacterial SOS response with its ensuing intracellular events. Further studies are required, especially in the clinical setting to exploit fully the potential of the immunomodulatory effect of fluoroquinolones during, for example, immunosuppression, chronic airway inflammatory diseases, and sinusitis.”

Modulation of the Production of Cytokines in Titanium-Stimulated Human Peripheral Blood Monocytes by Pharmacological Agents. The Role of cAMP-Mediated Signaling Mechanisms.      “Phosphodiesterase inhibitors, such as isobutyryl methylxanthine and pentoxifylline, which increase intracellular levels of cAMP, caused a decrease in the production of tumor necrosis factor-α and an increase in the production of interleukin-6.   In contrast, the fluoroquinolone antibiotic ciprofloxacin, which is also a phosphodiesterase inhibitor, caused a dose-dependent inhibition of the synthesis of both tumor necrosis factor-α and interleukin-6 by titanium-stimulated monocytes, suggesting that ciprofloxacin suppresses the synthesis of interleukin-6 through a mechanism that is independent of cAMP.”

Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.    “Other mechanisms for regulating the immune system by FQs are known. Cyclic AMP, protein kinase A and Phosphodiesterases (PDE), signal molecules or enzymes associated with a series of intracellular protein phosphorylation or transcription factor activation/suppression, are known to be regulated by FQs. The inhibitory effect on TNF-α production triggered by CPFX is mediated by PDE, leading to the accumulation of cAMP. Therefore, other inhibitory effects of FQs may exist in the inflammatory response under conditions of an influenza virus infection.”

Patent:   Quinolones and their therapeutic use US 5753666 A “The present invention relates to the therapeutic use of quinolone derivatives, and to certain novel such compounds.  Quinolone compounds are known primarily as antibacterial agents or antiviral agents but also as inhibitors of 5-lipoxygenase cardiotonics and vasodilators and 5-HT3 antagonists for the treatment of peripheral disorders associated with pain. None of these publications discloses utility as PDE IV inhibitors. (phosphodiesterase inhibitors). . . . The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.  This invention relates to compounds, many of which are novel, which can be used to treat disease states, for example disease states associated with proteins that mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV . . . PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet’s disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn’s disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer’s disease), memory impairment associated with Parkinson’s disease, depression and multi-infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE IV inhibitors could have utility as gastroprotectants. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma. . . . The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex. . . . This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (MIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.  The compounds of this invention may also be used in association with the veterinary treatment of animals, other than humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.  The compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis.”

Patent:  Treatment of myasthenia gravis by cyclic nucleotide phosphodiesterase inhibition US 6413968 B1    “I have discovered that the use of a cyclic nucleotide phosphodiesterase inhibitor causes more normal muscle function, especially in the extraocular muscle of myasthenic patients. Moreover, the use of a cyclic nucleotide phosphodiesterase inhibitor potentiates the effects of acetylcholinesterase inhibitors for skeletal muscle treatment in myasthenic gravis.   There are at least seven different types of cyclic nucleotide phosphodiesterase (PDE). Their primary substrates vary (e.g., cGMP vs. cAMP) and their concentrations vary by tissue type. Inhibitors of each type can have a crossover inhibition of other types. For example, cGMP-specific PDE5 inhibitors in the penis can block PDE6 activity in photoreceptors. The present invention teaches the use of inhibitors of phosphodiesterase that have sufficient cGMP specificity in muscle tissue to effect a beneficial increase in cGMP and, hence, in muscle function. FIG. 1 shows the acetylcholine released from the nerve cell membrane (1), traverses the extracellular space to attach to acetylcholine receptors on the muscle cell membrane (2). Here, acetylcholinesterase acts to remove acetylcholine. Acetylcholine receptor activity results in stimulation of cGMP levels, probably through guanylate cyclase activity. cGMP is then metabolized by a cyclic nucleotide phosphodiesterase to 51-GMP. In the present invention, a cyclic nucleotide phosphodiesterase is used to increase cGMP levels independently of acetylcholinesterase inhibition.”

 

 

 

Immunomodulatory / Kinase Inhibitors: Target for Studies / Unintentional Targets / Adverse Effects

The immune system is beyond complex, and it seems the more we mess with it, the more problems we end up with in the long run.   I won’t be surprised if all the “immune modulation” drugs of today, become part of tomorrow’s “autoimmune epidemic”.   The statistics are astounding for the percentage of people already suffering from some kind of autoimmune disorder, and the numbers only continue to grow.   It appears to be yet another huge health epidemic on the horizon.

FQT/FQAD symptoms can appear to be very “autoimmune” in nature.   It’s easy for mainstream docs to automatically throw us into this category.   I was offered Pred and other autoimmune drugs initially during the acute stage of my reaction, despite being seronegative for everything they tested for, and all the common mainstream inflammatory markers were within normal limits too.   (The one set of tests they didn’t run were the anti-thyroid antibodies at that time; I had to test and discover that for myself at Month 16 post).    With all the severe sensitivities to foods, drugs, and supplements that can develop in some of us, these, too can look very “autoimmune” in nature.   On this webpage and throughout this website, I have tried to offer other ideas that could contribute to all these sensitivities, and not simply label everything “autoimmune” or even “inflammatory”.   This is because I think that 1) there are other possibilities for our symptoms, and 2) it’s dangerous to label our symptoms as being autoimmune in nature, and even more dangerous to treat with autoimmune drugs, all with their own long lists of horrific potential side effects, when there is no objective proof that we have an autoimmune condition in the first place.   To this day, I remain seronegative for everything but the anti-thyroid antibodies, and well within normal limits or low for all inflammatory markers tested as well.

“Autoimmunity” cannot be ruled out, however.  And that facts are, I do now have one autoimmune disease already, possibly as a result of the FQ, and it’s generally accepted that if a person has one autoimmune disease, they are susceptible to developing others as well.    If autoimmunity is the one common underlying mechanism for all of my symptoms, then I have become “allergic to life”:   increasingly, I can’t tolerate almost all foods, drugs, supplements, sunlight, exercise, even extreme emotions due to the neurotransmitter fluctuations.   That’s pretty serious, and an incredibly high price to pay for taking a “simple” antibiotic to clear up a simple UTI.    If I really thought an “autoimmune drug” was going to solve all my problems, I might try it, although with all my drug sensitivities, it would be a fairly terrifying trial at this point in time.    What I would much prefer to do, however, is something like plasmapheresis as a trial, in an effort to at least see if that would make a difference in my symptoms (and I wish that had been offered to me during my acute phase).    I suspect it might, as even removing a few tubes of blood for blood testing makes me feel better within a couple hours.   Whether that’s due to antibody removal, or removal of toxic metabolites, I can’t say; I only know I feel better for a day or two.  In my own case, since I have Hashi’s, there is an autoimmune component going on with me, and I think it’s probably exacerbating my FQT/FQAD symptoms as well.   However, plenty of severe FQT/FQAD victims who don’t have any anti-thyroid antibodies or any other autoimmune antibody markers as measured in serum are as bad off or worse than I am.   This suggests that either these symptoms are not autoimmune based, or, if they are, it’s an as of yet unidentified autoimmune reaction without a measurable biomarker yet.

Just in this section alone, I’ve provided a long list of unintentional targets of FQs, and “autoimmunity” could develop with any of them.  FQ-protein and FQ-DNA adducts can form, which are then seen as antigenic, initiating “autoimmunity” to exogenous proteins or endogenous metabolites.  There was a long list of less common antibody testing I would have liked to have done, but I didn’t have the access or the finances, or they could only be done in a research setting.   There are clinical syndromes with autoimmune markers to CYP1A2, or T4 and T3 directly, for example, and of course a long list of antibody testing for all the “neuro-autoimmune” syndromes exists.   “Autoimmunity” alone still doesn’t answer the question of why only some people in the population develop it.  It’s probably multifactorial in nature, but it could still go back to or include the “Overdose Hypothesis” and unique genetic polymorphisms promoting increased drug-protein or drug-DNA interactions.

A significant number of people diagnosed with Sjogren’s Syndrome, an autoimmune condition, say they “feel better” when they get a cold (forum for SJS here).   They attribute this to “the antibodies are so busy fighting the virus, they’re not fighting me”.   This may or may not be true (it’s as good a hypothesis as any right now).   But I tend to think of it more as an “increase” in something needed to fight a virus, such as endogenous cortisol production (which can increase greater than 100 fold to combat a cold), or an increase in some other “inflammatory substance” (cytokines) that the body needs to increase to fight a virus.   I, too, feel better when I catch a bug, at least the day before all the other symptoms hit.   I know when I’ve caught a cold, because the day before, my body’s immune system is “ramping up” something that I need to fight the virus.   And whatever that “something is”, I need that to feel “normal” as well.  That day before the cold fully hits me, my muscles feel better, I feel more energized, my head clears up, my mood clears up, my eyes and sinuses are less dry, and for a few blessed hours, I almost feel normal.  The following day, when I get hit full force with the stuffiness and sneezing and sinus congestion is no fun.  But I still continue to clear my colds within a day or two (as I always did), and then, as the “something” declines again, I have another day or two where I feel better “on the way down”.    And then that “something” drops to below the normal, constitutive level that I need, and all my FQT/FQAD symptoms come back again, and I’m back to feeling miserable again.   I do tend to think of this cycle as an “increase” in something I need, but it’s also true than a “decrease” in something “too high” could be occurring during this process.  However, FQ mechanisms of action are to “inhibit”, “shut down”, and “turn off” so many processes necessary for cell survival (which is why they make such great cancer drugs, see Part 1 on previous page).   And it feels like that “shut down” has occurred permanently in me (if there are any “increases” anywhere, I’m guessing they are a compensatory response of collateral routes).   Every “inflammatory” marker I have tested for has been extremely low; for example, my TNFa is plastered at the very bottom of the range.  I can’t help but wonder if what I really need is a little more TNFa, or at least, better regulation of it.

When I get a cold, it shows me that my body IS still able to “turn on” this inflammatory substance or cascade, but only under circumstances of stress, in this case, viral stress.   Another example of this is “stressing” myself by eating certain foods.   It does seem to stimulate “something” in me, which could be attributed as an “autoimmune” or “innate immune” response.    Sometimes I try to utilize this to my advantage.  Instead of waiting until I get a cold, I can try a food that I’m now highly sensitive to, and take a very small, controlled amount, in an attempt to “control” the reaction and make myself feel better for a day or two.   But it’s a dangerous strategy, because my “immune system” (if that’s what the problem is) is so sensitive now, I tend to have very “on/off” reactions.   Mast Cell Activation Syndrome and Cytokine Storm was on my list for those horrific flares I was having, and although I tested negative for markers related to MCA, it can’t be ruled out entirely.  This is another case where I would have liked to have multiple, serial blood testing done, every few hours if necessary, tracking all kinds of “inflammatory/immune” markers as I went through these cycles, either virally or food induced.   I never had any food allergies or any other allergies prior to taking the FQ, and these food sensitivities, whatever is causing them, pretty much contribute to destroying any quality of life.  At this point in time, one teaspoon of butter, jam, a nut, a few beans, or half an egg can lead to anaphylactic-like reactions within hours, with horrific CNS symptoms in particular (feels like ‘A-fib in my head’, as if something is bouncing around in there, and of course that plunge into feelings of impending doom, along with the tachycardia, chest pain, sweating, etc.), and then continue on with a worsening of all my symptoms for days after.  Just the thought of eating my favorite meal pre-flox:  3 egg veggie omelet loaded with cheese, English muffin with jam, a side of pancakes, and at least a quart of milk — I honestly think it would actually kill me now.

If a person has a serious diagnosed autoimmune condition, I’m not against trying “autoimmune drugs” to try and solve it, if that’s the only route available.    However, I AM very much against throwing immune modulating drugs such as the FQs around so callously and nonchalantly, which may very well be CONTRIBUTING to or CREATING those autoimmune disorders in the first place.

Take it from someone who now has at least one diagnosed autoimmune disorder (Hashi’s), and possibly additional as of yet unknown autoimmune issues as well:   they are hell, and you don’t want one.   If you have cancer, or are on your death bed due to sepsis nothing else will get, you might want to consider an FQ.   But for anything and everyone else — why take the risk?

Two fluoroquinolones and their combinations with hyaluronan: comparison of effects on canine chondrocyte culture.     “Fluoroquinolones (FQs) are frequently used for septic arthritis. Increased antibacterial activity has been associated with mammalian cell cytotoxicity that may increase the risk of developing osteoarthritis . . . Enro regulated IL-1β-stimulated cells to overexpress IL-1β, TNF, and MMP3, whereas Mar induced upregulation of PTGS2 and NFKB1 and enhanced the expression of ECM component genes HAS1, COL2A1, and ACAN as well as TIMP1 and MMP9.”

Effect of trovafloxacin on production of cytokines by human monocytes.   “We examined the effect of the broad-spectrum fluoroquinoline antibiotic trovafloxacin on cytokine synthesis by monocytes obtained from healthy human volunteers . . . Trovafloxacin levels achievable in humans suppressed in vitro synthesis of each of the cytokines analyzed, viz., interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-10, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha . . . These results reveal that trovafloxacin possesses significant immunomodulatory activity in vitro and suggest that suppression of acute-phase inflammatory responses may occur in vivo, elicited through trovafloxacin’s effect on cytokine synthesis by human monocytes.”

Immunomodulatory effects of quinolones.    “We review data on the in-vitro, ex-vivo, in-vivo, and clinical effects of fluoroquinolones on the synthesis of cytokines and their mechanisms of immunomodulation. In general, most fluoroquinolone derivatives superinduce in-vitro interleukin 2 synthesis but inhibit synthesis of interleukin 1 and tumour necrosis factor (TNF); α furthermore, they enhance significantly the synthesis of colony-stimulating factors (CSF). Fluoroquinolones affect in-vivo cellular and humoral immunity by attenuating cytokine responses. Interleukins 10 and 12 have an important role in the functional differentiation of immunocompetent cells and trigger the initiation of the acquired immune response. In addition, certain fluoroquinolones were seen to enhance haematopoiesis by increasing the concentrations of CSF in the lung as well as in the bone marrow and shaft. Those fluoroquinolones exerting significant effects on haematopoiesis were those with a cyclopropyl moiety at position N1 of their quinolone core structure. Mechanisms that could explain the various immunomodulatory effects of fluoroquinolones include: (1) an effect on intracellular cyclic adenosine-3,5-monophosphate and phosphodiesterases; (2) an effect on transcription factors such as nuclear factor (NF) κB, activator protein 1, NF-interleukin-6 and nuclear factor of activated T cells; and (3) a triggering effect on the eukaryotic equivalent of bacterial SOS response with its ensuing intracellular events. Further studies are required, especially in the clinical setting to exploit fully the potential of the immunomodulatory effect of fluoroquinolones during, for example, immunosuppression, chronic airway inflammatory diseases, and sinusitis.”

Several gene programs are induced in ciprofloxacin-treated human lymphocytes as revealed by microarray analysis.   “Fluoroquinolones have immunomodulatory properties and interfere with cytokine production . . . The increased mRNAs were distributed between major gene programs, including interleukins (36.5%), signal-transduction molecules (13.5%), adhesion molecules (10.6%), tumor necrosis factor and transforming growth factor-β superfamilies (10.6%), cell-cycle regulators (9.6%), and apoptosis-related molecules (8.7%) . . . We conclude that the fluoroquinolone ciprofloxacin at high concentrations interferes with several gene programs, which is in accordance with a mammalian stress response.”

Quinolone-Induced Upregulation of Osteopontin Gene Promoter Activity in Human Lung Epithelial Cell Line A549.    “A number of reports have described the inhibitory effect of FQs on cytokine production.   Gatifloxacin (GAT) reduced interleukin-8 (IL-8) release from unstimulated cells of the prostatic cancer cell line PC-3 as well as peptidoglycan-, Mycoplasma hominis-, phorbol ester (phorbol myristate acetate [PMA])-, and tumor necrosis factor alpha (TNF-α)-stimulated PC-3 cells but did not significantly reduce the basal level of TNF-α and IL-6 (34). Moxifloxacin (MFX) inhibited IL-8, TNF-α, and IL-1β production in THP-1 cells and in monocytes when preincubated with MFX and stimulated with lipopolysaccharide (LPS) (38). Another report suggested that ciprofloxacin (CIP) may have an immunomodulatory effect on septic patients by attenuating the proinflammatory response, thus decreasing TNF-α, IL-6, IL-1β, and IL-8 levels in patients’ serum (15). Levofloxacin at concentrations of 100 μg/ml and higher was found to dose dependently reduce the IL-6 and IL-8 levels in TNF-α-stimulated NL20 human bronchial epithelial cells, but lower concentrations did not alter the studied cytokines (35). Elevated levels of IL-1β, IL-6, and TNF-α in patients with nonbacterial prostatitis became undetectable after treatment with sparfloxacin (SPX). . . . Several studies attempted to elucidate the signaling pathways and transcription factors that regulate the quinolone-induced cytokine modulation . . . In conclusion, we found that quinolones enhance OPN synthesis by activation of the OPN gene promoter. The antiapoptotic effects of quinolones do not appear to be associated with OPN elevation. Our study supports the idea that quinolones have immunomodulatory properties.”

Non-Antibiotic Effects of Fluroquinolones in Mammalian Cells.   “FQs Inhibit JNK1 Activity—It has been suggested that c-Jun N-terminal kinases (JNK) play a role in VHL-independent degradation of HIF proteins (68, 69). Gong et al. (68) found that some quinolone-derived drugs bound strongly to the ATP binding pocket of JNK1.”

Discovery of a novel series of 4-quinolone JNK inhibitors.     “A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.”

Moxifloxacin inhibits cytokine-induced MAP kinase and NF-κB activation as well as nitric oxide synthesis in a human respiratory epithelial cell line.   “Stimulation with the cytokines interleukin-1β(IL-1β)/interferon-γ (IFN-γ) increased NO up to 3.3-fold and moxifloxacin inhibited this up to 68% (P < 0.05).   Similarly, the increase in iNOS levels was inhibited in cells pre-treated with moxifloxacin by up to 62%.   IL-1β stimulated a rapid increase in the activities of early intracellular signalling molecules, ERK1/2 and JNK.    Moxifloxacin inhibited ERK1/2 by up to 100% and p-JNK activation by 100%.    NF-κB, as measured by electrophoretic mobility shift assay, was inhibited up to 72% by moxifloxacin.   Western-blot analysis revealed that IL-1β enhanced NF-κB p65 and p50 proteins by 1.7- and 3.6-fold, respectively, whereas moxifloxacin inhibited the proteins by up to 60%.   Moxifloxacin inhibits intracellular signalling, iNOS expression and NO secretion in a lung epithelial cell line. Future studies may uncover a primary site of quinolone immunomodulation, either upstream or at the cell membrane.   Eventually, this quinolone might become an important therapy for inflammatory lung diseases.”

Inhibition of DPP IV is a suggested mechanism of the immunomodulatory effects of sparfloxacin.   “Fluoroquinolones could modulate both cellular and humoral immunity. The results of this study showed that Sparfloxacin could significantly suppress the proliferation of both stimulated Balb/c splenocytes and stimulated murine macrophages. Moreover, the release of the IL-6 from these cells was also suppressed. Interestingly, Sparfloxacin inhibits dipeptidyl peptidase IV enzyme (DPP IV) in a dose dependent manner with an IC50 of 29.6 μM. These findings suggest that DPP IV inhibition by Sparfloxacin could be one of the mechanisms by which Sparfloxacin exerts its immune-modulatory activities. . . . FQs were found to affect both cellular and humoral immunity. Some FQs, like ciprofloxacin, were found to inhibit in vitro as well as in vivo the synthesis of TNF-α, Il-1, Il-6, and Il-12. The kinetics of the inhibitory effect on TNF-α production triggered by ciprofloxacin occurred at a very early step of TNF-α synthesis. The basic mechanisms underlying FQs immunomodulatory activity have not been elucidated in a comprehensive and satisfying manner. The precise cascade of intracellular processes leading to stimulatory or inhibitory effects on cytokines, chemokines and other components of the immune system needs to be elucidated . . . Several reports, however, have tried to explain the various immunomodulating effects of FQs in eukaryotic cells, this includes the effects of FQs on intracellular cyclic AMP (cAMP) and phosphodiesterases, the effects of certain members of this group on critical transcription factors such as NF-kappaB, AP-1, NF-Il-6. Recent reports have demonstrated the inhibitory potential of Gemfloxacin, FQ member, on two enzymes Glycogen Synthase Kinase-3β (GSK-3β) and Dipeptidyl peptidase IV (DPP IV). The inhibition of these targets could justify, at least partly, the reported immunomodulatory effects of this drug . . . During the last years, posttranslational modification by proteolysis has been recognized as one of the mechanisms involved in regulating the biological activities of many chemokines. As suggested by recently published findings, the protease dipeptidyl peptidase IV (DPP IV), a highly specific and unique aminopeptidase, may be of special importance in modulating chemokine activity. . . . Many reports concluded that quinolones exert their effects on the synthesis of various cytokines and chemokines through modulation of key cellular transcription factors. Recent reports have demonstrated the inhibitory potential of Gemfloxacin, FQ member, on DPP IV. The inhibition of these targets could justify, at least partly, the reported immunomodulatory effects of this drug. Moreover, many synthetic competitive DPP IV inhibitors significantly suppress production of IL-2, IL-1and IFN-γ in PWM-stimulated T cells. Under the same conditions, the inhibitors are capable of inducing the secretion of the latent form of the ‘immunoinhibitory’ cytokine transforming growth factor- β1, (TGF- β1). It has been shown, however, that high levels of IL-6 could induce the release of TGF- β1. IL-6 is a multi-functional protein with roles in host defense, acute phase reactions, inflammation and immunity. It can be regulated by a number of transcription factors, apparently depending upon the cell type and stimulus. DPP IV inhibitors, generally, suppress antigen induced proliferation and Il-6 production in immune cell lines. Here, in our study, we demonstrate that sparfloxacin which showed an effective DPP IV inhibition, could suppress cellular proliferation and IL-6 production in both Con A stimulated splenocytes and LPS-Raw macrophages. This sparfloxacin immunomodulatory effect could be attributed, at least in part, to DPP IV inhibitory activities . . . Intriguingly, a major noncardiac side effect of sparfloxacin is the pronounced hypoglycemia which could also be a side effect of most FQs. This side effect can be also correlated to its DPP IV inhibitory potential. Incretins: glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotopic polypeptide (GIP) are well known DPP VI substrates. Incretins stimulates insulin biosynthesis and secretion and reduces glucagons release. These peptides (incretins) have very short half-lives because of their rapid degradation by DPP IV (approximately two minutes). Therefore, inhibiting DPP IV should promote the hypoglycemic effects of GLP-1 and GIP. Therefore, the reported hypoglycemic effect of Spar and other floroquinolones could be attributed at least partly to DPP IV inhibition.”

 

Cytotoxicity and Oxidative Stress Related:   Unintentional Targets / Adverse Effects

https://www.ncbi.nlm.nih.gov/pubmed/19818344   Ofloxacin induces oxidative damage to joint chondrocytes of juvenile rabbits: excessive production of reactive oxygen species, lipid peroxidation and DNA damage.   “Quinolones are widely used in infection therapy due to their good antimicrobial characteristics. However, their potential joint chondrotoxicity on immature animals has stood in the way of the therapeutic application of these agents, the exact mechanism of which is still unclear. This study was undertaken to investigate the role of oxidative damage in ofloxacin (one typical quinolone)-induced arthropathy . . . The extent of oxidative damage was assessed by measuring the reactive oxygen species level, activities of antioxidant enzymes, and oxidative damage to some macromolecules. It was observed that ofloxacin induced a concentration-dependent increase in intracellular reactive oxygen species production, which may be an early mediator of ofloxacin cytotoxicity. Similarly, ofloxacin resulted in a significant lipid peroxidation, revealed by a concentration-dependent increase in the level of thiobarbituric acid reactive substances. At the same time, ofloxacin induced DNA damage in a concentration-dependent manner for 24h measured by comet assay, which may be a cause for overproduction of reactive oxygen species. Furthermore, antioxidant enzyme activities, such as glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD), were rapidly decreased after treatment with ofloxacin . . . In conclusion, these results clearly demonstrated that ofloxacin could induce oxidative stress, lipid peroxidation and DNA oxidative damage to chondrocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/17191880   Photophysical and phototoxic properties of the antibacterial fluoroquinolones levofloxacin and moxifloxacin.   “Two antibacterial fluoroquinolones, levofloxacin and moxifloxacin, were investigated to evaluate their photophysical properties and to explore the mechanism of their phototoxicity . . . Cellular phototoxicity was inhibited by the addition of superoxide dismutase, catalase, and free radical and hydroxyl radical scavengers (BHA, GSH, mannitol, and DMTU), indicating the involvement of superoxide anion and/or a radical mechanism in their cytotoxicity. A good correlation was observed between lipid peroxidation, protein photodamage, and cellular phototoxicity, indicating that test compounds exert their toxic effects mainly in the cellular membrane.”

https://www.ncbi.nlm.nih.gov/pubmed/17098346   Cytotoxic effect of ciprofloxacin in primary culture of rat astrocytes and protection by Vitamin E.   “The aim of this study was to investigate the possible cytotoxic and oxidative stress inducing effects of ciprofloxacin (CPFX) on primary cultures of rat astrocytes . . . The data obtained in this study suggest that, in accordance with our previous results with fibroblast cells, CPFX-induced cytotoxicity is related to oxidative stress.”

https://www.ncbi.nlm.nih.gov/pubmed/16112836   Inhibition of cell differentiation by quinolones in micromass cultures of rat embryonic limb bud and midbrain cells.   “Micromass cultures (MMC) of rat embryonic limb bud (LB) and midbrain (CNS) cells were applied to compare the developmental toxicity of three quinolone antimicrobials: norfloxacin (Nor), enrofloxacin (Enr) and ciprofloxacin (Cip) . . . In LB cultures all three drugs were cytotoxic . . . Ciprofloxacin was the most toxic and CNS cells were more sensitive than LB.”

https://www.ncbi.nlm.nih.gov/pubmed/14569066   In vitro discrimination of fluoroquinolones toxicity on tendon cells: involvement of oxidative stress. “Tendinopathy are classic side effects observed with fluoroquinolones antibiotics. A previously validated model based on a spontaneously immortalized rabbit tendon cell line (Teno cell line) was used to evaluate cellular responses to the fluoroquinolones pefloxacin (PEF), ofloxacin (OFX), levofloxacin (LVX), and ciprofloxacin (CIP), in various concentrations. Cell viability, redox status changes, reduced glutathione content, and reactive oxygen species production were assessed . . . All fluoroquinolones showed moderate cytotoxicity after 24 h and more severe, significant toxicity after 72 h on tendon cells . . . Our model supports a role for early oxidative stress in the development of fluoroquinolone-induced tendinopathy.”

https://www.ncbi.nlm.nih.gov/pubmed/12540033   Cytotoxicity in ciprofloxacin-treated human fibroblast cells and protection by vitamin E.   “Quinolones (Qs) were shown to have cytotoxic effects in various cell lines including human carcinoma cells; however, mechanism of these effects was not fully understood. To investigate the possibility of the involvement of an oxidative stress induction in this mechanism of action, we examined viability of human fibroblast cells exposed to a Q antibiotic, ciprofloxacin (CPFX), and measured lipid peroxidation and total glutathione (GSH) levels, and activities of catalase (Cat), superoxide dismutases (SODs), glutathione peroxidase (GPx) . . . These results suggested that CPFX-induced cytotoxicity on human fibroblast cell cultures is related to oxidative stress, and vitamin E pretreatment can afford a protection.”

https://www.ncbi.nlm.nih.gov/pubmed/20334059   Genotoxic and cytotoxic effects of antibacterial drug, ciprofloxacin, on human lymphocytes in vitro.   “These are the indications of both cytotoxicity and genotoxicity of Ciprofloxacin on human lymphocyte culture in vitro. All the parameters obtained from the experimental group were statistically significant when compared to that of control.”

https://www.ncbi.nlm.nih.gov/pubmed/18157922   Intrinsic cytotoxic effects of fluoroquinolones on human corneal keratocytes and endothelial cells.   “To determine the intrinsic cytotoxicity of five fluoroquinolones (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin) on human corneal keratocytes (HCK) and human corneal endothelial cells (HCE) . . . In this assay, fluoroquinolones displayed the potential to be cytotoxic to human corneal keratocytes and endothelial cells, depending on drug concentration and duration of exposure. The potential for cytotoxicity may differ among fluoroquinolones.”

https://www.ncbi.nlm.nih.gov/pubmed/20021053   Ciprofloxacin-Induced Cytotoxicity and Apoptosis in HeLa Cells.   “These data confirmed our previous studies obtained with normal human fibroblast cell cultures and indicated that CPFX induces cytotoxicity and apoptosis in HeLa cells.”

https://www.ncbi.nlm.nih.gov/pubmed/11698174   In vitro method for prediction of the phototoxic potentials of fluoroquinolones.   “The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation.”

https://www.ncbi.nlm.nih.gov/pubmed/11117292   Inhibitory effects of the quinolone antibiotics trovafloxacin, ciprofloxacin, and levofloxacin on osteoblastic cells in vitro.   “We studied the inhibitory effects of the fluoroquinolones levofloxacin, ciprofloxacin, and trovafloxacin on growth and extracellular matrix mineralization in MC3T3-E1 osteoblast-like cell cultures. Levofloxacin had the least inhibitory effect on cell growth, with a 50% inhibitory concentration of approximately 80 microg/ml at 48 and 72 hours. Ciprofloxacin had an intermediate degree of inhibition, with a 50% inhibitory concentration of 40 microg/ml at 48 and 72 hours. Trovafloxacin exerted a profound inhibitory effect on cell growth, with a 50% inhibitory concentration of 0.5 microg/ml, lower than clinically achievable serum levels . . . The quinolones evaluated also inhibited extracellular matrix mineralization by MC3T3-E1 cells. Treatment of confluent cultures with trovafloxacin, ciprofloxacin, or levofloxacin resulted in strong inhibition of calcium deposition.”

https://www.ncbi.nlm.nih.gov/pubmed/8045610   In vitro short-term and long-term cytotoxicity of fluoroquinolones on murine cell lines.   “Short-term and long-term cytotoxicity of four fluoroquinolones (ciprofloxacin, rufloxacin, ofloxacin, lomefloxacin) on 7 established murine cell lines . . . The results confirm toxic activity of quinolones on mammalian cells evidencing that the sensitivity to quinolones, in short-term cytotoxic test, correlates with the doubling time of cell population. The results further suggest that long-term cytotoxic tests measure better the antiproliferating activity of quinolones providing a more powerful assay to investigate their in vitro toxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/2808191   Cytotoxicity and uptake of pefloxacin, ciprofloxacin, and ofloxacin in primary cultures of rat hepatocytes.   “The cytotoxicity and the uptake of three 4-quinolones–pefloxacin, ciprofloxacin, and ofloxacin–were investigated in primary cultures of rat hepatocytes. As assessed by intracellular enzyme release in culture media, pefloxacin at concentration 400 mg/l and ciprofloxacin at 200 mg/l were found to be hepatotoxins.”

https://www.ncbi.nlm.nih.gov/pubmed/25653759   The effect of ciprofloxacin on sperm DNA damage, fertility potential and early embryonic development in NMRI mice.   “In conclusion CPFX was able to induce DNA damage and chromatin abnormalities of sperm cells which could be contributed in the observed low fertilization rate and retarded embryonic development.”

https://www.ncbi.nlm.nih.gov/pubmed/12966282   Levofloxacin and trovafloxacin inhibition of experimental fracture-healing.   “We previously have shown that experimental fractures exposed to ciprofloxacin have diminished fracture healing. The purpose of this study was to assess the effect of levofloxacin and trovafloxacin on experimental fracture healing to test the hypothesis that diminished fracture healing is a quinolone class effect. . . . These data suggest that experimental fractures systemically exposed to levofloxacin or trovafloxacin have diminished healing during the early stages of fracture repair. The administration of quinolones during early fracture repair may compromise fracture healing in humans.”

 

Cardiac:   Unintentional Target / Adverse Effects

I had never felt a heart palp in my life until I took an FQ.   Since then, I’ve experienced plenty of heart pounding, tachycardia (fast heart beat), bradycardia (slow heart beat), arrhythmias (heart palps, A-fib, and what feels like supra-ventricular tachycardia), and some rapid “machine gun firing” rates for several seconds at a time (thankfully, no longer than that for those, as I would not survive it).   I’ve experienced the severe chest pain, tightness, heart pounding and sweating as if I’m having a heart attack – but apparently that wasn’t what it was; it only felt that way.   Which is no small comfort when you feel like you’re having a “heart attack” several times a day, every day, for weeks or months on end.   In my case, my “cardiac” issues appear to be very TH related, and for the most part, keeping control of my TH helps my cardiac issues immensely (I discussed this in “Cardiac Arrhythmias: Palpitations, Tachycardia, Chest Pain”).  I tend to think of my “cardiac issues” as mostly being “receptor / transporter issues”, the same receptors / transporters that feel like they’re problematic in a lot of other parts of my body.  But there’s no doubt my cardiac tissue is pretty sensitive overall now to whatever my major problems are, and I pretty much feel like I’m a heart attack or stroke waiting to happen.

Many FQT/FQAD victims experience cardiac arrhythmias and pounding such as I have described.   Some people have had more serious cardiac issues, including heart attacks.   As of this writing (December 2016), there is a cardiac research study initiated looking for FQT/FQAD people with cardiac issues. The FQT/FQAD author of this website has suffered two heart attacks post FQ.

Fluoroquinolone Cardiac Research:    If you took a fluoroquinolone antibiotic and developed a cardiac condition that you believe was due to the fluoroquinolones, please consider checking out this study.

If you have cancer, or are on your death bed due to sepsis nothing else will get, you might want to consider an FQ. But for anything and everyone else — why take the risk?

 

Aldehyde Dehydrogenases:   Unintentional Target / Adverse Effects

I could find very little information linking an “Aldehyde Toxicity” directly to FQs.    But this is another case where, if I had any money to bet, I’d bet that “Aldehyde Toxicity” is occurring in some of us with FQT/FQAD.   From a symptoms approach alone, I often felt like I could be experiencing a “Disulfiram” -like  reaction, which was my first clue.    Subsequent research on the Aldehyde Dehydrogenase family of enzymes provided links to a huge number of connections and associations, including to thyroid hormone and retinoic acid (see “Additional Mechanisms to Consider” , “Steroid Super Family Receptors/ HRE’s”), where I included a few lines about this.   Importantly for our purposes, note that the drug Accutane has a fairly horrific ADR profile, which can include tendon ruptures.   I do appear to be sensitive to polyunsaturated fats, and lipid peroxidation results in end product reactive aldehydes (although my lipid peroxides TBARS test was well within range and low).

I really think “Aldehyde Toxicity” is a track worth studying for FQT/FQAD, and I hope that research is initiated on this.   FQs appear to target (the long list of) oxidoreductase enzymes, which includes dehydrogenases such as the Aldehyde Dehydrogenase family.   As always, those of us with FQT/FQAD may have unique ALDH genetic polymorphisms which left us susceptible to these drugs, or, due to the “Overdose Hypothesis”, de novo mutations or epigenetic suppression of one or more aldehyde dehydrogenases might occur post antibiotic.   I haven’t gone through my 23andMe data for all the genes on ALDH yet.  There’s a lot of them, so using an automated program like Enlis is the way to go.

Here are the few published references I could find, but I could not track down the original data on quinolone interaction or inhibition of ALDH1A1.   I also included a couple studies of quinoLINES.   Although there appear to be many similarities between the quinolines and quinolones, it’s important to remember that these are different drugs.   Still, their molecular structure and ADR profile is quite similar in some ways, which is why I wanted to include these references.

Ciprofloxacin decreases the rate of ethanol elimination in humans.

Identification and Characterization of Small Molecule Inhibitors of Aldehyde Dehydrogenase 1A1.   “As a binding protein, ALDH1A1 functions as an androgen-, thyroid hormone-, and cholesterol-binding protein and is also capable of interacting with such drugs as quinolone, daunorubicin, and flavopiridol.”

 ALDH1A1: From Lens and Corneal Crystallin to Stem Cell Marker     “Aside from its metabolic properties, ALDH1A1 has been shown to be capable of non-catalytic interactions with chemically-diverse compounds, including endobiotics (androgen, thyroid hormone and cholesterol) and xenobiotics (flavopiridol, daunorubicin and quinolone).”

Mefloquine use, psychosis, and violence: A retinoid toxicity hypothesis.    Mefloquine, a quinoline, has a similar CNS adverse effect profile to the quinlones; an interesting hypothesis relating a retinoid (Vitamin A) toxicity to quinoline toxicity is presented here.   Please note that in this paper, the word quinolone is a typo, and they should all be replaced with the word quinoline; I confirmed this with the author.

Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome     An interesting study I would love to see repeated with quinolones is this one here.   “The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear.   In this study, we used a functional proteomics approach that exploited the structural similarities between the quinoline compounds and the purine ring of ATP to identify quinoline-binding proteins.   Several quinoline drugs were screened by displacement affinity chromatography against the purine binding proteome captured with γ-phosphate-linked ATP-Sepharose.   Screening of the human red blood cell purine binding proteome identified two human proteins, aldehyde dehydrogenase 1 (ALDH1) and quinone reductase 2 (QR2) . . . Our results show that ALDH1 and QR2 are selective targets of the quinolines and may provide new insights into the mechanism of action of these drugs.”

Xenopus Cytosolic Thyroid Hormone-binding Protein (xCTBP) Is Aldehyde Dehydrogenase Catalyzing the Formation of Retinoic Acid.   “Our results demonstrate that xCTBP is identical to ALDH1 and suggest that this protein might modulate RA synthesis and intracellular level of free T3.”

Effect of coenzymes and thyroid hormones on the dual activities of Xenopus cytosolic thyroid-hormone-binding protein (xCTBP) with aldehyde dehydrogenase activity.   “Hydrophobic molecules that signal via nuclear receptors, such as thyroid and steroid hormones, retinoic acid and vitamin D3, predominantly exist within plasma and within intracellular compartments bound to specific proteins. The kinetics and the nature of the cellular responses to these signaling molecules are determined by these specific binding proteins. This has been well documented for cytosolic retinoic acid and retinol binding proteins where it has been suggested that these binding proteins may act, not only as buffers or reservoirs of intracellular retinoids to maintain significant levels of free retinoids, but also as modulators transporting retinoids to their target sites, the retinoid responsive genes within the nucleus and the metabolic enzymes within the cytoplasm [1–3]. Although similar functions have been assumed for cytosolic thyroid-hormone-binding proteins (CTBPs), a unified view regarding their function is yet to be decided due to their divergent molecular and hormone-binding characteristics [4–8]. . . . In this report, we examine the effects of coenzymes and several hydrophobic signaling molecules on T3-binding and ALDH activities of xCTBP/xALDH1. We demonstrate that NAD+, NADH and two steroids inhibit the T3-binding activity of this protein, whereas NADH, NADPH and iodothyronines inhibit the ALDH activity. Detailed studies revealed that NAD+ and T3 each act as a noncompetitive inhibitor on the T3-binding and enzyme activities of the protein, respectively.”

 

Viral DNA/RNA and proteins:   Target for Anti-viral / Adverse Effects

FQs are being studied for their anti-viral potential.   Rather than thinking what “wonder drugs” they are because they seem to get “everything”, this should be a red flag.   FQs target DNA directly.  They seem to target bacterial DNA, fungal DNA, viral DNA/RNA, plant DNA, and under the right conditions, our DNA too.  The fact that FQs target DNA directly, and not only proteins, is what makes them so scary.   If they were “only” binding up proteins, we wouldn’t have to worry about the over 6 billion places within our genetic code that these drugs could be targeting, and ultimately, changing as well.   At least with CRISPR technology, people are at least thinking about the ethical issues involved, and working hard at knowing exactly when and where gene editing will occur so “mistakes” aren’t made (1, 2).     No such luck, or introspection, with the FQs.   With the FQs, this same “editing” may be occurring more often than we realize – except no one knows where, or when, or why, or in who it will happen in.   With the FQs, “gene editing” has potentially been going on a long time, showing up in the form of all manner of illnesses, and no one really seems bothered by that fact at all.

It’s also why I think looking at Whole Genome Sequencing within the FQT/FQAD population, rather than just Exome Sequencing, is ultimately what will have to happen.  I’m in the camp that happens to believe the non-coding regions will eventually prove to be highly significant, in regulatory, or other unknown functions as of yet.  Quinolones intercalate themselves between DNA strands (1), and that could be anywhere, including within the non-coding region.   Not to mention, recent research has revealed that as much as 8-9 percent of the human genome consists of viruses that inserted themselves into our DNA, and in some cases, these viral codes may be playing supportive, protective, or even necessary roles for our survival (1, 2).    Is it possible FQs are targeting some of these endogenous retroviruses that are playing a protective or supportive role in our health?   The answer, of course, is “No one knows”.    And that’s a problem.

Post FQ-Syndrome can look an awful lot like Post-Viral Syndromes, as discussed in “Is it Lyme’s Disease, Sjogren’s Syndrome, Mitochondrial Disease, Chronic Fatigue Syndrome, Fibromyalgia, Fluoroquinolone Toxicity Syndrome, or . . . The Commonalities of Post-Viral, Post-Bacterial, and Post Fluoroquinolone Syndromes”.   Viruses can hijack host DNA under the right circumstances, probably at specific site locations, and FQs can target host DNA under the right circumstances, also probably at specific site locations.    Surely there is something to be learned from this.

If you have cancer, or are on your death bed due to sepsis nothing else will get, you might want to consider an FQ. But for anything and everyone else — why take the risk?

Antiviral properties of quinolone-based drugs.   “Quinolones inhibit prokaryotic type II topoisomerases, namely DNA gyrase and, in a few cases, topoisomerase IV, through direct binding to the bacterial chromosome.  Based on the hypothesis that these drugs could also bind to the viral nucleic acids or nucleoprotein-complexes, several quinolone derivatives were tested for their antiviral activity.  Indeed, antibacterial fluoroquinolones were shown to be effective against vaccinia virus and papovaviruses; these preliminary results prompted the synthesis of modified quinolones to optimize antiviral action and improve selectivity index.”

Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells.   “Reactivation of human polyomavirus BK (BKV) may cause polyomavirus-associated nephropathy or polyomavirus-associated hemorrhagic cystitis in renal- or bone marrow-transplant patients, respectively.  Lack of treatment options has led to exploration of fluoroquinolones that inhibit topoisomerase II and IV in prokaryotes and possibly large T-antigen (LT-ag) helicase activity in polyomavirus.”

Synthesis and Antiviral Studies of Novel N-Sulphonamidomethyl piperazinyl Fluoroquinolones.   “A series of novel N-Sulphonamidomethyl piperzinyl fluoroquinolones were synthesized and screened antiviral activity . . . Synthesized compounds were screened for antiviral activity against influenza A (H1N1, H3N2, H5N1) and influenza B viruses in MDCK cell culture . . . Compound CF-SD and CF-SDM inhibits the influenza A (H1N1) and compound GF-SDM inhibit the replication of influenza A (H5N1) and B in MDCK cells.”

Inhibition of the RNA-dependent transactivation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37.   “We recently reported that fluoroquinoline derivatives inhibited HIV-1 replication most likely by blocking viral transcription . . . K-37 and its derivative compounds are considered to be feasible candidates for a novel AIDS therapy.”

Broad-spectrum antiviral activity and mechanism of antiviral action of the fluoroquinolone derivative K-12.   “The fluoroquinolone derivatives have been shown to inhibit human immunodeficiency virus (HIV) replication at the transcriptional level . . . Also, K-12 proved inhibitory to herpes virus saimiri, human cytomegalovirus, varicella-zoster virus and herpes simplex virus types 1 and 2 (in order of decreasing sensitivity), but was not inhibitory (at subtoxic concentrations) to human herpesvirus type 8 (as evaluated in BCBL-1 cells), vaccinia virus, Sindbis virus, vesicular stomatitis virus, respiratory syncytial virus, Coxsackie virus, Punta Toro virus, parainfluenza virus or reovirus.   Time-of-addition experiments and quantitative transactivation bioassays indicated that K-12 inhibits the Tat-mediated transactivation process in HIV-infected cells.”

 

Fungal DNA and proteins:   Target for Anti-fungal / Adverse Effects

The data on using FQs as antifungal agents is mixed.  On the one hand, use of all antibiotics, including FQs, has been shown to increase the potential for fungal infections such as Candida.   On the other hand, here, studies are ongoing in using FQs as potential anti-fungal agents too.   So far, it looks like “at therapeutic concentrations”, FQs should not cause, nor effectively treat, fungal infections.   However, at increasing concentrations, the anti-fungal activity of FQs may increase as well.   If you’ve read the rest of this page, there are too many reasons to count to do your best to never get a “supra-therapeutic dose” of an FQ, and in fact, to do your best to stay away from this class of drug all together.  So I certainly would never consider an FQ as an option to treat a fungal infection.

If you have cancer, or are on your death bed due to sepsis nothing else will get, you might want to consider an FQ. But for anything and everyone else — why take the risk?

 

Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action?   “This review summarizes evidence that commercially available fluoroquinolones used for the treatment of bacterial infections are active against other non-bacterial infectious agents as well.   Any of these fluoroquinolones exerts, in parallel to its antibacterial action, antiviral, antifungal, and antiparasitic actions at clinically achievable concentrations.   This broad range of anti-infective activities is due to one common mode of action, i.e., the inhibition of type II topoisomerases or inhibition of viral helicases, thus maintaining the selective toxicity of fluoroquinolones inhibiting microbial topoisomerases at low concentrations but mammalian topoisomerases at much higher concentrations.   Evidence suggests that standard doses of the fluoroquinolones studied are clinically effective against viral and parasitic infections, whereas higher doses administered topically were active against Candida spp. causing ophthalmological infections.   Well-designed clinical studies should be performed to substantiate these findings.”

Antifungal effect of Gatifloxacin and copper ions combination.   “Outcomes of the research concluded that gatifloxacin 100 μg ml(-1) can be used by 0.20% of copper ions to prevent growth of some fungal strains (Candida albicans and Aspergillus niger), which causes skin infections with more potency.”

In vitro antifungal activity of the fourth generation fluoroquinolones against Candida isolates from human ocular infections.   “Both drugs undiluted inhibited greater than 95% of growth at 24 hrs . . . Current commercial topical preparations of moxifloxacin and gatifloxacin demonstrated a definite in vitro antifungal activity against ocular Candida species.”

Inhibition of Candida albicans virulence factors by novel levofloxacin derivatives.     “The aim of the present study was to investigate the antibiofilm properties of novel levofloxacin derivatives on C. albicans biofilms.  The levofloxacin derivatives at their Biofilm Inhibitory Concentrations (BIC) were able to inhibit the biofilms of C. albicans, the yeast-to-hyphal transition and were also able to disrupt their mature biofilms.   Furthermore, Real-time PCR analysis showed that the expression of ergosterol biosynthesis pathway gene (ERG11) and the efflux pump-encoding genes (CDR1 and MDR1) was decreased upon treatment with the levofloxacin derivatives.  The total ergosterol content quantified using UV spectrophotomer showed decrease in ergosterol in the presence of levofloxacin derivatives.   Overall, levofloxacin derivatives (6a, 6c and 7d) are capable of inhibiting C. albicans virulence factors.  Therefore, these compounds with potential therapeutic implications can be used as new strategy to treat biofilm-related candidal infections.”

Fungal keratitis responsive to moxifloxacin monotherapy.

Clinical response of contact lens-associated fungal keratitis to topical fluoroquinolone therapy.

Effects of levofloxacin, moxifloxacin and prulifloxacin on murine gut colonization by Candida albicans.    “Fluoroquinolones are broad-spectrum antibiotics increasingly utilized as empirical or prophylactic therapy in the management of cancer patients.   We evaluated the effects of newer generation fluoroquinolones on the level of gastrointestinal (GI) colonization by Candida albicans in a previously established mouse model. . . . In conclusion, we have shown that all fluoroquinolones tested induced substantial increases in the murine intestinal concentration of C. albicans.”

Influence of fluoroquinolones on phagocytosis and killing of Candida albicans by human polymorphonuclear neutrophils.   “Candida albicans infections often occur during or shortly after antibacterial treatment . . . When used at therapeutic concentrations, the FQ tested did not influence to a clinically significant degree the phagocytosis or the killing of C. albicans by human PMN and also not their activation.  However, at high concentrations those FQ with cyclopropyl-moiety at position N1 showed increase in CD11b expression and diminished phagocytosis and oxidative burst.”

In vitro synergistic effect of moxifloxacin and amphotericin B combination against Candida strains.   “Contradictory results such as synergy or indifferent effect, have been reported about the interactions between quinolones and antifungal drugs in different studies.  The aim of this study was to investigate the in vitro susceptibilities of Candida spp. to moxifloxacin (MOX) alone and MOX + amphotericin B (AmB) combination. . . . It was concluded that these preliminary results should be confirmed by large-scaled in vitro and in vivo studies to evaluate MOX + AmB combination as a therapeutic option for the treatment of Candida infections.”

Levofloxacin and moxifloxacin increase human gut colonization by Candida species.     “Among them, the newer fluoroquinolones levofloxacin and moxifloxacin have enhanced activity against respiratory and anaerobic pathogens.   No studies have examined the role of these two antimicrobial agents on the gut colonization of humans by Candida species. T  herefore, we evaluated the effect of levofloxacin and moxifloxacin on the human gastrointestinal tract colonization by Candida species in 30 patients who received levofloxacin or moxifloxacin for 8 to 10 days as monotherapy for the treatment of a variety of infections . . . Both antibiotics increased intestinal colonization by the yeast. . . . In conclusion, we showed that levofloxacin and moxifloxacin can significantly increase the concentration of Candida species in the human gut.   Hence, these agents should be used with caution in patients at risk for systemic fungal infections.”

Ciprofloxacin shows synergism with classical antifungals against Histoplasma capsulatum var. capsulatum and Coccidioides posadasii.   “This study brings potential alternatives for the treatment of histoplasmosis and coccidioidomycosis, raising the possibility of using CIP as an adjuvant antifungal therapy, providing perspectives to delineate in vivo studies.”

 

Plant DNA:   Target for Herbicide / Adverse Effects

It seems to me, that it should go without saying that using an FQ, or an FQ derivative, as an herbicide to spray all over the environment, would be a really, really bad idea.  I guess that’s about all I can say about that.   See the next section to see how FQs are already environmental pollutants.

DNA Gyrase Is the Target for the Quinolone Drug Ciprofloxacin in Arabidopsis thaliana.     “Plant gyrase is targeted to organelles (chloroplasts and mitochondria); given their prokaryotic origins, this provides a rationale for the presence of gyrase in plants.    However, the exact role of gyrase in plant physiology and its specific function in organelles remain to be established, although it is likely to have a role in supporting organellar replication.   The presence and apparent essentiality of gyrase in plants present opportunities for herbicide targeting; indeed it has been shown that Arabidopsis thaliana is sensitive to both the quinolone and the aminocoumarin antibiotics, implying that a functional gyrase is essential for A. thaliana development . . . . The confirmation that A. thaliana gyrase is indeed the target for quinolone antibacterials raises the possibility of developing compounds specifically targeted to this enzyme that could be developed as herbicides.”

New target found in search for new, more effective herbicide.

Commonly Used Antibiotic Could Be the Basis of a New Herbicide.

Common Antibiotic Inspires Hunt For New Herbicide.

 

Environmental pollution:   Resistance / Adverse Effects

They’re everywhere, in all kinds of places they’re not supposed to be.    ‘Nuff said.

Who Is Responsible for Antibiotic Resistance?    “We commonly blame physicians for overprescribing antibiotics, patients for demanding them and, increasingly, agribusiness for squandering antibiotics as growth promoters.   All of those are major problems.   One less-often mentioned factor is a side effect of the manufacturing process itself, where pharmaceutical companies dump huge quantities of antibiotics into wastewater—which then goes into rivers, or is used in irrigation. . . . They found a number of drugs contaminating the water, some in concentrations higher in the water than in patients’ blood. The worst was pollutant was ciprofloxacin, with concentrations up to 31 mg/L and in only one day totaling “44 kg, which is equivalent to Sweden’s entire consumption over 5 days⁠, or, expressed in another manner, sufficient to treat everyone in a city with 44,000 inhabitants.”

Pollution from drug manufacturing:  review and perspectives.   “The concentration of ciprofloxacin, which is a broad-spectrum antibiotic, was as high as 31 mg/L, which is approximately one million times greater than the levels that are regularly found in treated municipal sewage effluents and toxic to a range of organisms.   The estimated total release of ciprofloxacin for 1 day was 44 kg, which is equivalent to Sweden’s entire consumption over 5 days, or, expressed in another manner, sufficient to treat everyone in a city with 44,000 inhabitants.  These discharges have led to pollution of river sediment, surface, ground and drinking water to unprecedented levels, and a recent report also demonstrated contamination of irrigated soils.”

Occurrence of antibiotics in hospital, residential, and dairy effluent, municipal wastewater, and the Rio Grande in New Mexico “The relatively high concentrations (up to 35,500 ng/L) of ofloxacin found in hospital and residential effluent may be of concern due to potential genotoxic effects and development of antibiotic resistance.”

Occurrence of Antibiotics in Drinking Water “Overall, fluoroquinolones were the most frequently detected antibiotics in source waters . . . Most of the antibiotics detected in source water are not detected in finished water or are present at a much lower levels if detected, indicating their partial removal during conventional treatment processes or chemical transformation during disinfection. The incomplete removal of some antibiotics, such as ciprofloxacin, is of concern due to their unknown health effects if they do persist in finished waters even at ng/L levels. Future research will be focused on how these compounds persist and transform during drinking water treatment processes.”

Persistence of the Fluoroquinolone Antibiotic Difloxacin in Soil and Lacking Effects on Nitrogen Turnover.    

Determination of fluoroquinolone antibiotics in wastewater effluents by liquid chromatography-mass spectrometry and fluorescence detection.

Determination of 25 quinolones in cosmetics by liquid chromatography-tandem mass spectrometry

Screening method for the determination of tetracyclines and fluoroquinolones in animal drinking water by liquid chromatography with diode array detector.

Do antibiotics have environmental side-effects? Impact of synthetic antibiotics on biogeochemical processes.

Parameters influencing ciprofloxacin, ofloxacin, amoxicillin and sulfamethoxazole retention by natural and converted calcium phosphates.

Quantitation of fluoroquinolones in honey using tandem mass spectrometry (LC-MS/MS): nested validation with two mass spectrometers

Rapid determination of fluoroquinolone residues in honey by a microbiological screening method and liquid chromatography.

Quantitation and validation of fluoroquinolones in eggs using liquid chromatography/tandem mass spectrometry

Multiresidue determination of quinolone and fluoroquinolone antibiotics in fish and shrimp by liquid chromatography/tandem mass spectrometry

Determination of ofloxacin, norfloxacin, and ciprofloxacin in sewage by selective solid-phase extraction, liquid chromatography with fluorescence detection, and liquid chromatography–tandem mass spectrometry

Do antibiotics have environmental side-effects? Impact of synthetic antibiotics on biogeochemical processes.

Evaluating the vulnerability of surface waters to antibiotic contamination from varying wastewater treatment plant discharges.

Heterogeneous photo-Fenton treatment for the reduction of pharmaceutical contamination in Madrid rivers and ecotoxicological evaluation by a miniaturized fern spores bioassay.

 

 

 

 

 

 

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