Quinolones
Antibiotics

Ascorbic Acid and ROS production

Divicine

Divicine can transfer electrons from ascorbic acid to O2 producing Hydrogen Peroxide (H2O2)

Effect of divicine and isouramil on red cell metabolism in normal and G6PD-deficient (Mediterranean variant) subjects. Possible role in the genesis of favism. 1981

Fava beans contain high amounts (up to 6.7 g/100 g dry weight) vicine and convicine. Their active aglycones divicine and isouramil have equivalent metabolic effects. They rapidly oxidize GSH to GSSG in normal and G6PD-deficient red cells. No regeneration of GSH occurs in deficient cells. The stoichiometry of the divicine oxidation of GSH is 1:1. Ascorbic acid is quickly oxidized by isouramil in both normal and deficient cells but regenerates only in normal cells. Isouramil oxidizes NADH at a much lesser extent than NADPH. Glycolysis is activated at the glyceraldehyde 3-phosphate dehydrogenase step. Divicine strongly stimulates hexone monophosphate shunt only in normal red cells. Divicine alone or associated with ascorbic acid has almost no effect in deficient red cells. Malonyl dialdehyde production is slight and virtually the same in normal and deficient cells treated with 5 mM isouramil. Large polypeptide aggregates are formed after 12 and 24 hours incubation with 1 mM divicine in deficient cells only. Divicine (0.25 mM) markedly decreases the filterability of deficient cells. The results are consistent with a causal role of divicine/isouramil in the genesis of the hemolytic crisis occurring in G6PD-deficient subjects after fava bean ingestion.

Quinolones

Aminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death. 2011

Taken together, our results show that ascorbate enhances quinone redox-cycling and leads to ROS formation that inhibits cell proliferation and provokes caspase-independent cell death.

An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities. 2010 Fulltext

A first group, which caused a severe decrease in the intracellular ATP content, is represented by the dimethylhydrazonofuryl-bearing naph- toquinones 1 and 2 which decreased ATP by 70% and 82%, respectively. A second group, composed of the benzoqui- nones 3 and 6, decreased ATP by nearly 40%. Finally, within the formylfuryl-bearing naphtoquinone group, a minor effect on ATP was observed: 5 decreased ATP by only 32%, while 4 had no effect on ATP content. For the second selected metabolic marker, namely the level of GSH, the situation was rather different to that observed for ATP and more closely resembled the effect observed on membrane cell lysis (Fig. 2). Indeed, almost all the quinone compounds decreased the level of GSH by approximately 30-40%.

NADPH oxidase activation

Activation of phagocytic cell NADPH oxidase by norfloxacin: a potential mechanism to explain its bactericidal action. 2002
El Bekay R1, Alvarez M, Carballo M, Martín-Nieto J, Monteseirín J, Pintado E, Bedoya FJ, Sobrino F.
Author information
* Abstract
The mechanisms underlying the bactericidal power of fluoroquinolones against intracellular parasites in host macrophages remain poorly understood. We have analyzed the effect of norfloxacin, a fluoroquinolone antibiotic, on the production of reactive oxygen intermediates (O(2)(*-) and H(2)O(2)) and NADPH oxidase activity in mouse macrophages. The generation of anion superoxide (O(2)(*-)) was found to be significantly greater in macrophages incubated with norfloxacin than in untreated controls. This enhancing effect of norfloxacin was dose-dependent and reached maximal values within 10 min after its addition. The O(2)(*-) generated was mainly intracellular, as determined by the use of specific dyes, such as lucigenin and luminol, and able to diffuse freely through the cell membrane. Also, the production of H(2)O(2) was increased in macrophages in response to norfloxacin. The positive effect of norfloxacin was associated to an enhanced mobilization of NADPH oxidase subunits p47(phox) and p67(phox) from the cytosol to the plasma membrane in phagocytic cells. The effect of the antibiotic persisted in vivo for several hours. These data support the notion that norfloxacin inhibits mycobacterial growth within phagocytic cells by enhancing intracellular production of O(2)(*-) and other reactive oxygen species.

Impairment of Thyroid Hormones function

Ciprofloxacin interacts with thyroid replacement therapy. 2005

Ciprofloxacin impairs TH uptake by the cells

Quante persone hanno un TSH piu' alto dopo Chinolonici?

In merito alla deplezione muscolare che si verifica in alcuni casi seri di tossicità da fluorochinoloni, sembrerebbe che questo sia causato da piu' cause:

• patologie che coinvolgono il sistema nervoso periferico contribuendo all'atrofia dei muscoli
• la condizione di costante acidosi causata dal malfunzionamento dei mitocondri danneggiati dai FQ con diminuita produzione di CO2 e aumento di acido lattico (misurabile)
  • Diurnal hormone-metabolite profiles in hypothyroidism. 1981
    Fasting blood lactate and pyruvate levels were normal but post-prandial hyperlactataemia and hyperpyruvicaemia were found and mean 12 h values for lactate (hypothyroid 1.80 +/- 0.06 v. control 0.77 +/- 0.03 mmol/l, P less than 0.01) and pyruvate (0.10 +/- 0.01 v. 0.08 +/- 0.003 mmol/l, P less than 0.01) were elevated.

(per il meccanismo che potrebbe essere spiegato dalla prima parte di questo video; che mi sembra dubbio GP)

Discussione di un caso clinico

Maschio sano, anni 28
A causa di una sospetta cistite mi è stato prescritto dal medico curante il Ciproxin. A circa 20 ore dall’assunzione della prima compressa ho iniziato ad avvertire dolore al tendine d’Achille sinistro, poco dopo anche a quello destro. Mi sono recato quindi da uno specialista urologo che in seguito alla mia richiesta di un farmaco meno aggressivo per i tendini e mi ha prescritto il Tavanic (Levofloxacina) con l’aggiunta di un corticosteroide.
Il terzo giorno, dopo quindi due sole compresse, non riuscivo più a camminare a causa del dolore ai tendini d’Achille, talloni e ginocchia.
95% sintomi motori
5% sintomi sensitivi

Nonostante l’assunzione del farmaco sia stata interrotta, l’infiammazione ai tendini si è estesa in una settimana a tutto il corpo. A distanza di tre mesi qualsiasi movimento ripetitivo mi causa dolore e la forza che riesco ad esercitare nei movimenti è scarsissima. Mi è stata diagnosticata inoltre una neuropatia periferica sensitivo-motoria agli arti inferiori, pertanto la atrofia muscolare è stata notevolmente ridotta rendendomi difficili anche i più brevi spostamenti e precludendomi la possibilità di guidare o fare scale.

quinolones toxicity dexamethasone

Synergistic effects of dexamethasone and quinolones on human-derived tendon cells. 2010

Combined exposure to quinolones and dexamethasone led to more pronounced effects in tenocyte cultures at most of the analysed endpoints.

Perche'

Perche' inibiscono l'azione della 1,25(OH)Vit D?

Ipotesi di lavoro

Assumiamo che i Chinolonici danneggino il mitocondrio riducendone la capacita' respiratoria e quindi la sintesi di ATP

• Calcium Signals Are Affected by Ciprofloxacin as a Consequence of Reduction of Mitochondrial DNA Content in Jurkat Cells, 2006
  The effects of ciprofloxacin on mitochondrial DNA (mtDNA) content, oxygen consumption, mitochondrial membrane potential, cellular ATP formation, and capacitative Ca2+ entry into Jurkat cells were investigated. In cells incubated for several days with 25 μg/ml ciprofloxacin, a 60% reduction of mtDNA content, inhibition of the respiratory chain, and a significant decrease in mitochondrial membrane potential were observed. These changes led to a decrease in the calcium buffering capacity of mitochondria which, in turn, resulted in a gradual inhibition of the capacitative Ca2+ entry. On days 4, 7, and 11 of incubation with ciprofloxacin, the initial rates of Ca2+ entry were reduced by 33%, 50%, and 50%, respectively. Ciprofloxacin caused a transient decrease in the cellular capability for ATP formation. In cells incubated for 15 min with glucose, pyruvate, and glutamine as exogenous fuel, ciprofloxacin reduced ATP content by 16% and 35% on days 4 and 7, respectively, of incubation with the drug. However, on day 11 of incubation with ciprofloxacin, a recovery of cellular ATP formation was observed. In conclusion, long-term exposure of Jurkat cells to ciprofloxacin at a concentration of 25 μg/ml seriously affects cellular energy metabolism and calcium homeostasis.

per capire perche' alcuni soggetti presentino sintomi bisogna conoscere tutte i possibili fattori da cui dipende la produzione di ATP a livello mitocondriale.

Lo stesso ragionamento e' gia' stato applicato ai dolori muscolo/articolari

Sintesi di ATP

nutrients

• glucose
  • muscle
    • blood glucose
    • insulin
  • nerve
    • blood glucose
    • serum sodium
• fatty acids
  • muscle
    • adrenaline ??
    • carnitine

oxygen

• anemia
• smoking
• BPCO

mitochondria

• Krebs Cycle
  • B complex vitamins
• Respiratory Chain
  • Cytochrome C
    • Iron deficiency (general)
    • Iron deficiency (local)
      • Varicella-Zoster Virus ( varicella-zoster virus palsy)
      • HSV ( HSV palsy)
    • Lead poisoning
    • Sex hormones deficiency
    • Ipothyroidism
      • Ciprofloxacin and rifampin have opposite effects on levothyroxine absorption. 2013 Case reports have indicated an association between cotreatment with ciprofloxacin or rifampin and hypothyroidism in patients on a stable L-T4 dose.
      • Ciprofloxacin interacts with thyroid replacement therapy. 2005
    • Excess antioxidants
    • Respiration rate (training)
  • Coenzyme Q
    • Thyroid Hormones (Iodine, Na+, Selenium, phenylalanine)
    • Respiration rate (training)
    • Low cholesterol synthesis (genetic)
    • Drugs affecting cholesterol and CoQ synthesis (Rhabdomyolysis due to an uncommon interaction of ciprofloxacin with simvastatin. 2009
      A case report of a ciprofloxacin and simvastatin interaction is presented. The addition of ciprofloxacin to chronic simvastatin therapy led to the development of rhabdomyolysis. As ciprofloxacin is a weak inhibitor of CYP3A4, it is very likely that other mechanisms involving the ATP-binding cassette drug efflux transporter family played a role in this drug interaction. Fulltext
      Hypothyroidism, iron deficiency, drugs burden, statins
• ATP stabilization by Mg
  • Effects of magnesium deficiency on joint cartilage in immature beagle dogs: immunohistochemistry, electron microscopy, and mineral concentrations. 2000 Electron microscopy revealed alterations in chondrocytes from the magnesium-deficient dogs (e.g., swollen mitochondria and enlarged endoplasmic reticulum) which are also seen after treatment with quinolones.
• Miscellaneous Genetic Mitochondrial Defects
  • Charcot-Marie-Tooth (Hereditary Neuropathy Unmasked by Levofloxacin, 2011)

Circulation

Vasodilation

requires:

• Serum Calcium
  • Calcium deficiency
    • low 25(OH)Vit D (its synthesis depends on mitochondrial respiration)
    • low calcium intake
• Acetylcholine
• Arginine
• eNOS (endothelial nitric oxide synthase)

• Calcium deficiency
  • 25(OH)Vit D (its synthesis depends on mitochondrial respiration)

Thrombosis

• Platelets
  • Influence of ciprofloxacin on leukotriene generation from various cells in vitro. 1990 Preincubation of human platelets led to a suppression of the calcium-ionophore induced 12-HETE generation at high concentrations (8 and 4 micrograms/10(8) cells) and to an increased synthesis of 12-HETE at lower concentrations (0.5, 1, and 2 micrograms ciprofloxacin/1 × 10(8) platelets).
  • Thrombocytopenia associated with intravenous ciprofloxacin. 2005 ; On discontinuation of the drug, her platelet counts began to return to normal.

Drugs Affecting Quinolones Pharmacokinetic

CPK aumenta con statine

fluoroquinolone toxicity

quinolones mitochondria

Ofloxacin induces apoptosis in microencapsulated juvenile rabbit chondrocytes by caspase-8-dependent mitochondrial pathway. 2008

• Ofloxacin also stimulated a concentration-dependent translocation of cytochrome c from mitochondria into the cytosol and a decrease of mitochondrial transmembrane potential, which was completely inhibited by zIETD-fmk.

In merito alla sindrome di tossicità da fluorochinoloni, la reazione avversa a questi farmaci, quando si presenta nel modo più grave, sembra avere in comune sempre lo stesso schema: Infiammazione e/o degenerazione tendinea a distanza di pochi giorni dalla prima compressa assunta e danni al sistema nervoso periferico con conseguente atrofia muscolare di carattere esteso e visibile dopo pochi mesi.
Possono manifestarsi anche casi di neurotossicità a carico delle fibre minori con conseguente alterazioni delle sensazioni caldo/freddo, bruciori, pizzicore, scariche elettriche, etc...

Generalmente la sindrome migliora molto lentamente, con una remissione dei sintomi del 70% circa in 2-5 anni.
Purtroppo in alcuni casi i danni a carico del sistema nervoso risultano essere anche permanenti (come riportato anche in questo articolo) e stranamente non risultano essere dose-dipendenti secondo le centinaia di casi discussi fin'ora nei gruppi di discussione.

Osservando gli studi disponibili in letteratura, i meccanismi per cui questa tossicità si presenta sembrano essere i seguenti:

• Deplezione del magnesio con conseguente indebolimento della struttura dei tendini
  • Effects of magnesium deficiency on joint cartilage in immature beagle dogs: immunohistochemistry, electron microscopy, and mineral concentrations. 2000
    Electron microscopy revealed alterations in chondrocytes from the magnesium-deficient dogs (e.g., swollen mitochondria and enlarged endoplasmic reticulum) which are also seen after treatment with quinolones.
• Citotossicità e neurotossicità da parte della struttura molecolare del chinolone e in particolar modo dell'atomo di fluoro che rende possibile una maggior penetrazione della molecola all'interno dei tessuti con conseguente necrosi cellulare più o meno generalizzata e possibile deplezione della mielina.
• Inibizione dei recettori GABA grazie alla loro affinità chimica con la maggior parte delle molecole appartenenti alla famiglia dei fluorochinoloni.
  Deplezione del DNA mitocondriale attraverso l'inibilzione delle topoisomerasi e alterazione della permeabilità delle pareti dei mitocondri.

Tutto questo però non giustifica come mai la reazione avversa si presenti solo in alcuni rari casi (1-5%); si ritiene vi possano essere delle motivazioni dettate dal proprio patrimonio genetico tali da rendere più difficile da metabolizzare il farmaco giustificando quindi la maggiore tossicità individuale.

Influence of ciprofloxacin on leukotriene generation from various cells in vitro. 1990

• The effect of ciprofloxacin on leukotriene generation from human polymorphonuclear leucocytes (PMN) and the respective lymphocyte, monocyte and basophil (LMB) containing cell fraction has been studied. Furthermore, the influence on the LTB4-receptor expression of PMNL, as well as on the synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) from human platelets, was analysed. The antibiotic concentrations ranged from 0.5 to 4 micrograms/10(7) cells. Analysis of the generated leukotrienes was performed by high performance liquid chromatography (HPLC). The calcium-ionophore A23187 induced leukotriene generation from PMNs and LMBs was significantly suppressed by preincubation with ciprofloxacin in a dose-dependent manner. Incubation of PMNs with the same concentrations of ciprofloxacin induced an augmentation of the LTB4-receptor expression. Preincubation of human platelets led to a suppression of the calcium-ionophore induced 12-HETE generation at high concentrations (8 and 4 micrograms/10(8) cells) and* to an increased synthesis of 12-HETE at lower concentrations (0.5, 1, and 2 micrograms ciprofloxacin/1 × 10(8) platelets)*.

Miscellaneous. 2008

Administration with metformin (150 mg / kg, p.o.), a widely used oral hypoglycemic agent, to diabetic animals further reduced circulating thyroid hormones and caused drug-induced hypothyroidism.

quinolones+mitochondria+potential

Role of mitochondria in ciprofloxacin induced apoptosis in bladder cancer cells. 2002

Cyclosporin A, a known inhibitor of the mitochondrial permeability transition pore, protected cells against decreased mitochondrial potential.