Post by Deleted on May 30, 2012 3:51:22 GMT -5
FQs and the connection with elements of the NO ONOO cycle
Part 1
Please keep in your mind that I am only a layman and that English is not my mother language.
Two main mechanisms by which the quinolones cause damage can be distinguished. The first ones are very specific and typical for the drugs of this class.
The second ones are more “general” and in this article I want to focus on the connection of quinolones with the mechanisms like the production of different free radicals, NMDA activation and the vicious cycle of NO ONOO.
You may ask yourself, why this is so important. There are several reasons:
1) There is a lot of scientific literature available supporting the different aspects of the NO ONOO cycle and the symptoms / damage caused by it, which are similar to our symptoms.
Look at Table 1-1 at thetenthparadigm.org/
There are explanations for symptoms like pain, depressions, anxiety, cognitive-learning and memory dysfunction, sleep disturbance, irritable bowel syndrome etc.
2) It gives an explanation why we are so badly damaged at many parts of the body and why it keeps on going
3) The NO ONOO cycle is based on the work of Prof. Pall. He made a list of supplements, which are able to down regulate the cycle. Take it mainly as a guide and not as a “rule” and look, what may be helpful for your personal situation.
In order to understand better, what I am speaking about, please visit Prof. Pall’s homepage at
thetenthparadigm.org/mcs09.htm and take a look at the figures
In fig.1 “Pesticide and Organic Solvent Action in MCS” you can see that very different chemicals like pesticides or solvents are able to activate the NMDA (N-methyl-d-aspartate) receptor through different pathways. I contacted Prof. Pall and he agreed that the quinolones fit into this scheme, too.
Let us look into the literature, what we can find:
There are some articles, where it is mentioned that the quinolones activate the NMDA receptor (agonist) and inhibit the GABA receptor (antagonist).
For example:
You can compare the GABA receptor with the brake in a car. The NMDA receptor is like the gas pedal. So the action of the quinolones is as if you drive down a hill with the brakes no longer working and your foot hits the whole time the gas pedal.
In medicine the result is called excitotoxicity. Under normal conditions the activation of the NMDA receptor is only for a brief amount of time (milliseconds), but if the activation becomes excessive or prolonged, high levels of calcium ions enter the cell. It causes the generation of harmful chemicals like nitric oxide (NO), reactive oxygen species (ROS) and calcium-dependent enzymes such as calpain, endonucleases, ATPases, and phospholipases.
As the cell's membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell. Nitric oxide is able to reduce in the mitochondria (power plant of the cell) the production of energy.
After the mitochondria breaks down, toxins and apoptotic factors are released into the cell. The apoptosis cascade is initiated, causing the cell to "commit suicide."
If the cell dies through necrosis, it releases glutamate and toxic chemicals into the environment around it. Toxins poison nearby neurons, and glutamate can overexcite them.
Necrosis is the premature death of cells in living.
To see the reactions taking place, please visit the fig. at: www.nature.com/nature/journal/v430/n7000/fig_tab/nature02621_F2.html
At www.neurographics.org/2/2/1/4.shtml
you can see the different steps which leads to neuronal cell death under hypoxic conditions.
Below I post now only small parts of an article written by E. Yazar and B. Tras. As you can see there are the same elements of the NO-ONOO cycle, which play a role in regard to the quinolones like nitric oxide NO itself and ROS (reactive oxygen species)
The problem is that these mechanisms of protections are inhibited or decreased through the quinolones as it is shown in the abstract by Li et al.
The following quotes will show you that the fluoroquinolones are able to cause damage in different areas through ROS, NO and related mechanisms/substances:
Achilles Tendons (Kashida, Kato 1997 ) through NO and 5 –lipoxigenase products
Tendons (Kashida, Kato 1997) through NO
Chondrocytes (Li et al 2010) through lipid peroxidation (cause damage to cell membrane), damage to DNA and production of ROS. This results in reduction of glutathion peroxide (GPx), catalase, SOD. (This means the protection against ROS etc is extremely limited!!!)
(Yazar et al 2001) – ROS production, which leads to phototoxicity and cartilage damage
Cerebral and hepatic (Gürbay et al. 2004) – through oxidative stress
Myocardiotoxicity (Savacglu et al. 2009) – through oxidative stress and NO
Lymphocytes (Riesbeck et al.1998) – through increased cytokine production, which is most likely related to stress response
Phototoxicity (Wagai N, Tawara K 1997)
---------------------------------------------------------------------------------
References:
G. S. TILLOTSON
Quinolones: structure-activity relationships and
future predictions
J. Med. Microbiol. - Vol. 44 (1996), 320-324
jmm.sgmjournals.org/cgi/reprint/44/5/320.pdf
Telgt DS, van der Ven AJ, Schimmer B, Droogleever-Fortuyn HA, Sauerwein RW.
Serious psychiatric symptoms after chloroquine treatment following
experimental malaria infection.
Ann Pharmacother. 2005 Mar;39(3):551-4.
www.ncbi.nlm.nih.gov/pubmed/15728331
Ball P, Mandell L, Niki Y, Tillotson G.
Comparative tolerability of the newer fluoroquinolone antibacterials
Drug Saf. 1999 Nov;21(5):407-21.
www.ncbi.nlm.nih.gov/pubmed/10554054
E. YAZAR and ° B. TRAS
Effects of fluoroquinolone antibiotics on hepatic superoxide dismutase and glutathione
peroxidase activities in healthy and experimentally induced peritonitis mice
Revue Méd. Vét., 2001, 152, 3, 235-238
www.revmedvet.com/2001/RMV152_235_238.pdf
Li Q, Peng S, Sheng Z, Wang Y.
Ofloxacin induces oxidative damage to joint chondrocytes of juvenile rabbits: excessive production of reactive oxygen species, lipid peroxidation and DNA damage.
Eur J Pharmacol. 2010 Jan 25;626(2-3):146-53. Epub 2009 Oct 7.
www.ncbi.nlm.nih.gov/pubmed/19818344
Kashida Y, Kato M
Characterization of Fluoroquinolone-Induced Achilles Tendon Toxicity
in Rats: Comparison of Toxicities of 10 Fluoroquinolones
and Effects of Anti-Inflammatory Compounds
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Vol. 41, No. 11 Nov. 1997, p. 2389–2393
aac.asm.org/cgi/reprint/41/11/2389.pdf
Kashida Y, Kato M;
Possible involvement of nitric oxide in the quinolones-induced tendon lesions in rats
Drugs Exp Clin Res 1997; 23:139-43. www.ophsource.org/periodicals/ophtha/medline/record/MDLN.9403275
GÜRBAY Aylin (1) ; HINCAL Filiz (1)
Ciprofloxacin-induced glutathione redox status alterations in rat tissues
Drug and chemical toxicology 2004, vol. 27, no3, pp. 233-242
cat.inist.fr/?aModele=afficheN&cpsidt=16108181
Saraçoğlu A, Temel HE, Ergun B, Colak O.
Oxidative stress-mediated myocardiotoxicity of ciprofloxacin and ofloxacin in juvenile rats.
Drug Chem Toxicol. 2009;32(3):238-42.
www.ncbi.nlm.nih.gov/pubmed/19538020
Kristian Riesbeck,* Arne Forsgren, Agnethe Henriksson, and Anders Bredberg
Ciprofloxacin Induces an Immunomodulatory Stress Response in Human T Lymphocytes
Antimicrobial Agents and Chemotherapy, August 1998, p. 1923-1930, Vol. 42, No. 8
0066-4804/98/$04.00+0
aac.asm.org/cgi/content/full/42/8/1923
Wagai N, Tawara K.
Possible reasons for differences in phototoxic potential of a 5 quinolone antibacterial agents: generation of toxic oxygen.
Free Radic Res Commun. 1992;17(6):387-98.
www.ncbi.nlm.nih.gov/pubmed/1337537
Part 1
Please keep in your mind that I am only a layman and that English is not my mother language.
Two main mechanisms by which the quinolones cause damage can be distinguished. The first ones are very specific and typical for the drugs of this class.
The second ones are more “general” and in this article I want to focus on the connection of quinolones with the mechanisms like the production of different free radicals, NMDA activation and the vicious cycle of NO ONOO.
You may ask yourself, why this is so important. There are several reasons:
1) There is a lot of scientific literature available supporting the different aspects of the NO ONOO cycle and the symptoms / damage caused by it, which are similar to our symptoms.
Look at Table 1-1 at thetenthparadigm.org/
There are explanations for symptoms like pain, depressions, anxiety, cognitive-learning and memory dysfunction, sleep disturbance, irritable bowel syndrome etc.
2) It gives an explanation why we are so badly damaged at many parts of the body and why it keeps on going
3) The NO ONOO cycle is based on the work of Prof. Pall. He made a list of supplements, which are able to down regulate the cycle. Take it mainly as a guide and not as a “rule” and look, what may be helpful for your personal situation.
In order to understand better, what I am speaking about, please visit Prof. Pall’s homepage at
thetenthparadigm.org/mcs09.htm and take a look at the figures
In fig.1 “Pesticide and Organic Solvent Action in MCS” you can see that very different chemicals like pesticides or solvents are able to activate the NMDA (N-methyl-d-aspartate) receptor through different pathways. I contacted Prof. Pall and he agreed that the quinolones fit into this scheme, too.
Let us look into the literature, what we can find:
There are some articles, where it is mentioned that the quinolones activate the NMDA receptor (agonist) and inhibit the GABA receptor (antagonist).
For example:
“These effects correlate with the quinolone binding to the receptors for y-aminobutyric acid (GABA) in the brain, thereby preventing normal binding of GABA and heightening CNS stimulation.” (G. S. Tillotson 1996)
“As quinolines, the antimalarials may have the same pathologic activity as
the fluoroquinolone antibiotics in acting as N-methyl-d-aspartate agonists
and gamma-aminobutyric acid antagonists.” (DS Telgt et al. 2005)
…“Fluoroquinolones differ in their pro-convulsive activity, relating to their
differing potential as gamma-aminobutyric acid antagonists and binding to
the N-methyl-D-aspartate receptor…” (P. Ball et al. 1999)
You can compare the GABA receptor with the brake in a car. The NMDA receptor is like the gas pedal. So the action of the quinolones is as if you drive down a hill with the brakes no longer working and your foot hits the whole time the gas pedal.
In medicine the result is called excitotoxicity. Under normal conditions the activation of the NMDA receptor is only for a brief amount of time (milliseconds), but if the activation becomes excessive or prolonged, high levels of calcium ions enter the cell. It causes the generation of harmful chemicals like nitric oxide (NO), reactive oxygen species (ROS) and calcium-dependent enzymes such as calpain, endonucleases, ATPases, and phospholipases.
As the cell's membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell. Nitric oxide is able to reduce in the mitochondria (power plant of the cell) the production of energy.
After the mitochondria breaks down, toxins and apoptotic factors are released into the cell. The apoptosis cascade is initiated, causing the cell to "commit suicide."
If the cell dies through necrosis, it releases glutamate and toxic chemicals into the environment around it. Toxins poison nearby neurons, and glutamate can overexcite them.
Necrosis is the premature death of cells in living.
To see the reactions taking place, please visit the fig. at: www.nature.com/nature/journal/v430/n7000/fig_tab/nature02621_F2.html
At www.neurographics.org/2/2/1/4.shtml
you can see the different steps which leads to neuronal cell death under hypoxic conditions.
Below I post now only small parts of an article written by E. Yazar and B. Tras. As you can see there are the same elements of the NO-ONOO cycle, which play a role in regard to the quinolones like nitric oxide NO itself and ROS (reactive oxygen species)
“…It is stated that fluoroquinolones produce reactive oxygen species (ROS) (singlet oxygen ; 1O, superoxide radical ; O2-, hydroxyl radical ; -OH and hydrogen peroxide ; H2O2) in phagocytic cells [6, 13, 19, 21], also, side effects of these drugs such as phototoxicity [3, 30, 31] and cartilage damage[35] may related to producing of ROS…”
“…Cells are protected from ROS damage by a chemical and superoxide dismutase (SOD), glutathione peroxidise (GPX) and catalase enzymes called antioxidant enzymes [27, 28]. SOD catalyzes the dismutation of two superoxide radicals to O2 and H2O2 [33]. GPX detoxifies H2O2 to H2O andO2, and converts lipid hydroperoxides to nontoxic alcohols.”
The problem is that these mechanisms of protections are inhibited or decreased through the quinolones as it is shown in the abstract by Li et al.
Ofloxacin induces oxidative damage to joint chondrocytes of juvenile rabbits: excessive production of reactive oxygen species, lipid peroxidation and DNA damage.
http://www.ncbi.nlm.nih.gov/pubmed/19818344
“This study was undertaken to investigate the role of oxidative damage in ofloxacin (one typical quinolones)-induced arthropathy …. 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… 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.
The following quotes will show you that the fluoroquinolones are able to cause damage in different areas through ROS, NO and related mechanisms/substances:
Achilles Tendons (Kashida, Kato 1997 ) through NO and 5 –lipoxigenase products
“These results suggest that nitric oxide and 5-lipoxigenase
products partly mediate fluoroquinolone-induced tendon lesions…”
“…the lesions induced by fluoroquinolones
included the dilation of blood vessels in the edematous
area, which may also suggest the involvement of NO.
Furthermore, the interactions between NO and arachidonic
acid products have been reported to be very complex (14, 34,
39). NO itself is not thought to mediate hyperpermeability, but
it may participate in fluoroquinolone-induced Achilles tendon
lesions in combination with some other mediators. A number
of mediators are involved in hyperpermeability of blood vessels:
prostaglandin I2 prostaglandin E2, leukotrienes, histamine, serotonin, bradykinin, platelet activating factor, interleukin-1, and tumor necrosis factor…”
Tendons (Kashida, Kato 1997) through NO
“…These results suggest that NO is involved in the induction of Achilles tendon lesions in juvenile rats by pefloxacin (PFLX) and may be similar to the tendon disorder of humans receiving quinolones…”
Chondrocytes (Li et al 2010) through lipid peroxidation (cause damage to cell membrane), damage to DNA and production of ROS. This results in reduction of glutathion peroxide (GPx), catalase, SOD. (This means the protection against ROS etc is extremely limited!!!)
“…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 addition, SOD decline and reactive oxygen species production were strongly inhibited, and the loss in cell viability was partly abated by additional glutathione (GSH), N-acetylcysteine (NAC) and dithiothreitol (DTT). In conclusion, these results clearly demonstrated that ofloxacin could induce oxidative stress, lipid peroxidation and DNA oxidative damage to chondrocytes….”
(Yazar et al 2001) – ROS production, which leads to phototoxicity and cartilage damage
“… It is stated that fluoroquinolones produce reactive oxygen
species (ROS) (singlet oxygen ; 1O, superoxide radical ; O2
-,
hydroxyl radical ; -OH and hydrogen peroxide ; H2O2) in
phagocytic cells [6, 13, 19, 21], also, side effects of these
drugs such as phototoxicity [3, 30, 31] and cartilage damage
[35] may related to producing of ROS….
… However, it was reported that
fluoroquinolones could enhance ROS production in phagocytic
cells [13, 24] such as enoxacin, norfloxacin, fleroxacin,
levofloxacin, ofloxacin and enrofloxacin [6, 12, 19, 21]…”
Cerebral and hepatic (Gürbay et al. 2004) – through oxidative stress
“…The possible oxidative stress inducing effect of a fluoroquinolone (FQ) antibiotic, ciprofloxacin (CPFX), was investigated in rats measuring glutathione redox status.
… Our results, thus, indicate that CPFX treatment introduces an oxidative stress in cerebral and hepatic tissues of rat.
Myocardiotoxicity (Savacglu et al. 2009) – through oxidative stress and NO
“…Ciprofloxacin and ofloxacin may cause myocardiotoxicity by inducing the oxidative stress in the heart, and nitric oxide is partly responsible for this toxicity…”
Lymphocytes (Riesbeck et al.1998) – through increased cytokine production, which is most likely related to stress response
“…In conclusion, an association between stress response and cytokine superinduction triggered by ciprofloxacin has been described in the present communication. Several gene transcripts included in the c-Fos and c-Jun families in addition to most T-cell cytokines (30) were augmented in primary lymphocytes exposed to ciprofloxacin. Moreover, AP-1 binding activity was increased in ciprofloxacin-treated PBLs, which is a commonly described phenomenon during mammalian stress…”
Phototoxicity (Wagai N, Tawara K 1997)
“…These results showed that the phototoxic potentials of the 5 quinolones were probably related to the amounts of toxic oxygens generated in the target cells during irradiation…”
---------------------------------------------------------------------------------
References:
G. S. TILLOTSON
Quinolones: structure-activity relationships and
future predictions
J. Med. Microbiol. - Vol. 44 (1996), 320-324
jmm.sgmjournals.org/cgi/reprint/44/5/320.pdf
Telgt DS, van der Ven AJ, Schimmer B, Droogleever-Fortuyn HA, Sauerwein RW.
Serious psychiatric symptoms after chloroquine treatment following
experimental malaria infection.
Ann Pharmacother. 2005 Mar;39(3):551-4.
www.ncbi.nlm.nih.gov/pubmed/15728331
Ball P, Mandell L, Niki Y, Tillotson G.
Comparative tolerability of the newer fluoroquinolone antibacterials
Drug Saf. 1999 Nov;21(5):407-21.
www.ncbi.nlm.nih.gov/pubmed/10554054
E. YAZAR and ° B. TRAS
Effects of fluoroquinolone antibiotics on hepatic superoxide dismutase and glutathione
peroxidase activities in healthy and experimentally induced peritonitis mice
Revue Méd. Vét., 2001, 152, 3, 235-238
www.revmedvet.com/2001/RMV152_235_238.pdf
Li Q, Peng S, Sheng Z, Wang Y.
Ofloxacin induces oxidative damage to joint chondrocytes of juvenile rabbits: excessive production of reactive oxygen species, lipid peroxidation and DNA damage.
Eur J Pharmacol. 2010 Jan 25;626(2-3):146-53. Epub 2009 Oct 7.
www.ncbi.nlm.nih.gov/pubmed/19818344
Kashida Y, Kato M
Characterization of Fluoroquinolone-Induced Achilles Tendon Toxicity
in Rats: Comparison of Toxicities of 10 Fluoroquinolones
and Effects of Anti-Inflammatory Compounds
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Vol. 41, No. 11 Nov. 1997, p. 2389–2393
aac.asm.org/cgi/reprint/41/11/2389.pdf
Kashida Y, Kato M;
Possible involvement of nitric oxide in the quinolones-induced tendon lesions in rats
Drugs Exp Clin Res 1997; 23:139-43. www.ophsource.org/periodicals/ophtha/medline/record/MDLN.9403275
GÜRBAY Aylin (1) ; HINCAL Filiz (1)
Ciprofloxacin-induced glutathione redox status alterations in rat tissues
Drug and chemical toxicology 2004, vol. 27, no3, pp. 233-242
cat.inist.fr/?aModele=afficheN&cpsidt=16108181
Saraçoğlu A, Temel HE, Ergun B, Colak O.
Oxidative stress-mediated myocardiotoxicity of ciprofloxacin and ofloxacin in juvenile rats.
Drug Chem Toxicol. 2009;32(3):238-42.
www.ncbi.nlm.nih.gov/pubmed/19538020
Kristian Riesbeck,* Arne Forsgren, Agnethe Henriksson, and Anders Bredberg
Ciprofloxacin Induces an Immunomodulatory Stress Response in Human T Lymphocytes
Antimicrobial Agents and Chemotherapy, August 1998, p. 1923-1930, Vol. 42, No. 8
0066-4804/98/$04.00+0
aac.asm.org/cgi/content/full/42/8/1923
Wagai N, Tawara K.
Possible reasons for differences in phototoxic potential of a 5 quinolone antibacterial agents: generation of toxic oxygen.
Free Radic Res Commun. 1992;17(6):387-98.
www.ncbi.nlm.nih.gov/pubmed/1337537