The Fluoroquinolone Toxicity Research Foundation

 
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DISCUSSION: The reported neurotoxic effects of the fluoroquinolones include insomnia, seizures, delirium, and psychosis, best explained by the gamma-aminobutyric acid-antagonistic properties of this class of drugs. (quinolones are known as gaba inhibitors so have the ability to bind to neurorecptor sites).

Several hypotheses have been proposed to explain the development of these cases of tendinopathy: immuno-allergic mechanisms, direct toxicity of the molecule on collagen fibres, cell-mediated oxidative aggression, or tendon necrosis due to In vitro method for prediction of the phototoxic potentials of fluoroquinolones.

Yamamoto T, Tsurumaki Y, Takei M, Hosaka M, Oomori Y.

Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi-Mitarai, Shimotsuga-gun, 329-0114, Tochigi, Japan. fvbb0984@mb.infoweb.ne.jp

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. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without
Fluoroquinolone's effect on growth of human chondrocytes and chondrosarcomas. In vitro and in vivo correlation.

Multhaupt HA, Alvarez JC, Rafferty PA, Warhol MJ, Lackman RD.

Division of Biomedical Sciences, Imperial College of Science Technology and Medicine, Sir Alexander Fleming Building, Exhibition Hall, London SW7 2AZ, England.

Clinical and in vitro studies have demonstrated that fluoroquinolones are toxic to chondrocytes; however, the exact mechanism of fluoroquinolone arthropathy is unknown. We investigated the toxicity of ciprofloxacin on normal cartilage and on cartilaginous tumors. Normal human cartilage, enchondroma, and chondrosarcoma explants were cultured either alone or with the addition of ciprofloxacin at 1, 10, or 20 mg/L of medium. Samples were collected up to twenty-one days after treatment and were processed for electron microscopy and conventional light microscopy. The specimens were characterized morphologically with use of conventional light microscopy, electron microscopy, and immunohistochemistry to identify extracellular matrix, cell proliferation, and apoptosis. Cultures of normal chondrocytes expressed type-II collagen. Electron microscopy revealed a large amount of glycogen in the cells; the presence of fat droplets, rough endoplasmic reticulum, and prominent Golgi apparatus; and a proteoglycan layer surrounding the cells. With prolonged ciprofloxacin treatment and with increased doses, there was an increase in dilated rough endoplasmic reticulum, the appearance of phagosomes, and disintegrated bundles of vimentin filaments. The treated chondrocytes showed a decrease in cell proliferation, but there was no induction of apoptosis or effect on the expression of extracellular matrix proteins. Ciprofloxacin-treated chondrosarcoma cultures and tissue samples showed changes in cartilage matrix composition. Ultrastructural analysis demonstrated clumped glycogen, dilation of endoplasmic reticulum, numerous abnormal lysosomes containing degeneration products, and a decreased proteoglycan deposit surrounding the tumor cells. Treated chondrosarcoma cells and tissue specimens did not proliferate, and apoptosis was induced. In contrast, the in vitro growth of other noncartilaginous malignant tumors like osteosarcoma and liposarcoma was unaffected by ciprofloxacin. Our results indicate that ciprofloxacin is toxic to chondrocytes. In vitro and in vivo treated chondrosarcomas are the most affected.

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Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions.

Pea F, Furlanut M.

Institute of Clinical Pharmacology and Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Italy. federico.pea@med.uniud.it

Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.

Microsomal metabolism of ciprofloxacin generates free radicals.

Gurbay A, Gonthier B, Daveloose D, Favier A, Hincal F.

Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Ankara, Turkey.

Ciprofloxacin (CPFX) is a widely used fluoroquinolone antibiotic with a broad spectrum of activity. However, clinical experience has shown a possible incidence of undesirable adverse effects including gastrointestinal, skin, hepatic, and central nervous system (CNS) functions, and phototoxicity. Several examples in the literature data indicate that free radical formation might play a role in the mechanism of some of these adverse effects, including phototoxicity and cartilage defects. The purpose of this study is to investigate free radical formation during the metabolism of CPFX in hepatic microsomes using electron spin resonance (ESR) spectroscopy and spin trapping technique. We then investigate the effects of a cytochrome P450 inhibitor, SKF 525A, Trolox, and ZnCl2 on CPFX-induced free radical production. Our results show that CPFX induces free radical production in a dose- and time-dependent manner. The generation of 4-POBN/radical adduct is dependent on the presence of NADPH, CPFX, and active microsomes. Furthermore, free radical production is completely inhibited by SKF 525A, Trolox, or ZnCl2.

PMID: 11369501 [PubMed - indexed for MEDLINE]