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An approach to minimization of toxicity of a new compound is to elucidate the mechanisms of toxicity of analogous compounds and to clarify their structure-toxicity relationships. A problem with this approach, however, is that such elucidation remains difficult. For quinolones, some improvements in this mechanistic approach have been achieved in the central nervous system (CNS), particularly with regard to their interaction with non-steroidal anti-inflammatory drugs (NSAIDs), and in genotoxicity and phototoxicity studies, particularly in comparison with other toxicities, such as to the cardiovascular, gastrointestinal, bone, reproductive, and developmental systems. This review concentrates on a description of the known effects of quinolones on various organ systems in experimental animals and humans. Given the logarithmic increase in the synthesis of new quinolones, it is questionable whether these drugs share similar safety and efficacy. Nevertheless, this mechanistic approach to the investigation and minimization of toxicity has produced satisfactory results to date and deserves to be continued.

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We investigated the toxic effect of levofloxacin (LVFX), a quinolone antibacterial agent, on cartilage by examining aspects of its in vivo toxicokinetics and effect on the function of cultured chondrocytes of the femoral articular cartilage from juvenile New Zealand White rabbits. Repeated administration of LVFX (100 mg/kg) orally for 7 days induced focal necrosis and superficial erosion in the articular cartilage of the femoral condyle, but 30 mg/kg did not. Concentrations of LVFX in the cartilage were highest at the first sampling point (30 min) after a single administration, being 4.93 and 12.2 g/g in the 30-and 100-mg/kg groups, respectively. The arthropathic concentration of LVFX in the cartilage was then shown to be 12.2 g/g or more. For an in vitro study, chondrocytes were separated from the articular cartilage of the rabbit femoral condyle and cultured for 7 days until confluence. 35SO 4 uptake by cultured chondrocyte sheets was most susceptible to LVFX, decreasing at drug concentrations of 5 g/ml or more in 24-and 48-h cultures but not in a 72-h culture. Furthermore, 3 H-thymidine uptake was decreased at concentrations of 10 g/ml or more in a 48-h culture but not in 24-and 72-h cultures. Rhodamine 123 accumulation was susceptible to inhibition in cultured chondrocytes at an LVFX concentration of 10 g/ml or more. These results suggest that LVFX inhibits glycosaminoglycan synthesis initially and DNA synthesis and mitochondrial function secondarily at actual arthropathic concentrations in cultured rabbit chondrocytes but that these changes are reversible and not enough to kill the cells.Adverse effects of quinolone antibacterial drugs, including arthralgia, joint swelling, arthropathy, and arthritis, have been reported at incidences of less than 0.5% in healthy volunteers and juvenile and adult patients (17). Quinolones are well known to induce cavitation in the articular cartilage of juvenile rats, rabbits, guinea pigs, dogs, marmosets, and crab-eating monkeys but not in that of adults; of these species, dogs are thought to be most susceptible to this chondrotoxicity (4,5,11,12,15,16,24,25,27,29,31). However, the relationship between the adverse clinical effects of these drugs and their toxic lesions in laboratory animals has not been clarified.The initial changes in quinolone-induced toxicity in the articular cartilage of juvenile animals are thought to occur in chondrocytes (6,8,19) or in the matrix (4). In our previous ex vivo study, ofloxacin (OFLX) inhibited the uptake of 3 H-thymidine and 35 SO 4 by the articular cartilage of juvenile rats 12 h after oral administration of a single large dose (20). Considering the inhibitory effect of the drug on topoisomerase II of mammalian cells, we then speculated that the initial target of OFLX in its induction of cartilage damage was the DNA synthesis of chondrocytes. Histopathological examinations by Stahlmann et al. (29) and Burkhardt et al. (6,8) after administration of OFLX and difloxacin revealed mitochondrial swelling and distention of the rough endopla...

The phototoxic effects of quinolone antimicrobial agents on mouse auricular skin and retina were examined histologically. Sparfloxacin at 50 or 100 mg/kg, which alone causes no histologic change, was orally administered to albino Balb/c mice, which were irradiated with ultraviolet A for 4 hr immediately after administration. In the auricle, degeneration of basal epidermal cells was sporadically observed at 2 hr (during the irradiation). Foci of slight edema with degenerated fibroblasts were seen in the dermis at 4 hr. Edema and neutrophil infiltration in the dermis became severe up to 96 hr. Initial changes in the retina were observed at 2 hr. Vacuolation of the photoreceptor segments (particularly the inner segment) was occasionally associated with swelling of retinal pigment epithelial cells. The segments became disorganized with time, and the outer nuclear layer showed reduced cellularity. The segments and layer were partially thinned and lost 96 hr later. Enoxacin at 400 and 800 mg/kg induced similar lesions to those of sparfloxacin. Levofloxacin caused similar lesions in the auricle but no change in the retina. The combination of oral administration of quinolone and ultraviolet A irradiation, which never caused apparent morphological changes alone, was shown to be able to induce phototoxic lesions in albino mice. Therefore, this method is thought to be useful to examine morphological changes caused by quinolone phototoxicity.

We studied the effects of 'y-aminobutyric acid (GABA)-benzodiazepine receptor agonists and glutamate receptor antagonists on levofloxacin (LVFX)-and ciprofloxacin (CPFX)-induced convulsions using intrathecal (i.t.) injections in mice. We also studied the effects of these agonists and antagonists on exacerbated convulsions induced by coadministration of the quinolone with 4-biphenylacetic acid (BPAA). The agonists or antagonists were injected i.t. 5 min and BPAA was administered orally 30 min before a single i.t. injection of the quinolone (10 pl per animal). The animals were observed for clonic convulsion and death, and latency times to the appearance of convulsion were determined. Among the agonists, baclofen showed marked inhibition of both LVFX-and CPFX-induced convulsions, while other compounds such as GABA, muscimol, diazepam, and 3-aminopropylphosphonic acid had slight effects. Among the antagonists, kynurenic acid showed the strongest inhibition of convulsions caused by all doses of LVFX and CPFX and prolonged latency times; 'y-glutamylaminomethylsulfonic acid (GAMS) also markedly inhibited convulsions. The antagonists D-AP-5, AP-7, and 6,7-dinitroquinoxaline-2,3-dione (DNQX) had slight effects. Additionally, GAMS, DNQX, and MK-801 significantly lowered the incidence of death in the groups treated with CPFX. The enhanced convulsive activities of LVFX or CPFX by pretreatment with BPAA were clearly blocked by baclofen, kynurenic acid, GAMS, and DNQX. D-AP-5 and AP-7 also showed clear effects on the activity of LVFX. These results suggest that LVFX has fewer effects on the brain than CPFX and that convulsions induced by these quinolones alone and by these quinolones administered with BPAA may be mediated largely through glutamate and GABAB rather than GABAA receptors in mice.Because of their excellent activities, quinolone antibacterial agents have been widely adopted for use in clinical practice. Although recently developed quinolones are less toxic than earlier compounds, they still produce very few incidences of various adverse effects on the central nervous system. Among these, convulsions remain a serious problem; enoxacin (ENX) (29), norfloxacin (NFLX) (2, 39), and ciprofloxacin (CPFX) (3) have been reported to induce convulsions in humans. Furthermore, these convulsions have been reported to be enhanced by coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) (2,3,29,31). The mechanisms underlying these convulsions have therefore been investigated in animal models.It (1, 6, 14, 26-28, 33, 40). Moreover, their enhanced convulsive activity in the presence of NSAIDs is thought to be mediated through the augmentation of interactions between quinolones and GABAA by NSAIDs, as evidenced by electrophysiological studies (10, 18) and binding assays (7). In contrast, other studies have reported the failure of GABA-benzodiazepinergic drugs to inhibit completely convulsions caused by coadministration of a quinolone and an NSAID (11,20,30,31), the lack of any clear correlation between the activitie...

Based on a localized crystal electric field model for the U 4+ in the (5f) 2-configuration, we analyze the resonant x-ray scattering spectra around U MIV and MV edges in URu2Si2, taking full Coulomb and spin-orbit interactions into account. We consider two level schemes, a singlet model of Santini and Amoretti and a doublet model of Ohkawa and Shimizu, and assume the antiferroquadrupolar order and the antiferromagnetic order as candidates for the ambient pressure phase and the high pressure phase. It is found that the spectral shapes as a function of photon energy are independent of the assumed level scheme, but are quite different between the antiferroquadrupole and antiferromagnetic phases, This may be useful to determine the character of the ordered phase. KEYWORDS: resonant x-ray scattering, URu2Si2, singlet scheme, doublet scheme 1. Introduction The ternary intermetallic compound URu 2 Si 2 has been attracting much attentions since the discovery of the coexistence of antiferromagnetic (AFM) ordering below T 0 = 17.5 K and superconductivity below T C = 1.2 K. 1 The ordering pattern of the AFM order is type-I structure with the propagation vector Q = (001) along the c-axis (Fig. 1). The phase transition at T 0 is characterized by bulk anomalies such as specific heat, 2 linear susceptibility, 2 non-linear susceptibility, 3, 4 thermal expansion 5 and electrical resistivity, 6 strongly indicating that the transition is of second order. The observed magnetic moment is unusually tiny (µ ord ∼ (0.03 ± 0.01)µ B per U ion at saturation). 7-9 It is too small to account for the observed bulk anomalies. The magnetic excitation spectra shows energy gap below T 0 according to neutron scattering experiments. 10 Under the magnetic field, the magnetic moment and the magnetic excitation gap exhibit the different field dependencies. 11 Based upon these observations, it is widely believed that, the AFM order below T 0 is merely a secondary order and there exists some unknown primary order, so-called "hidden order (HO)". 12 As for the true nature of the HO phase, various competing theoretical possibilities have been demonstrated. For instance, the antiferroquadrupole (AFQ) order, 13-17 the multispin correlation , 18 the unconventional spin density wave, 19 inho-mogeneous orbital current, 20-22 Jahn-Teller distortions 23 and so on were proposed. However, it is safe to say that the microscopic mechanism governing the whole phenomena is still in a matter of controversy. Recently, neutron scattering and 29 Si NMR experiments were performed under pressure. 24-29 The measurements are interpreted that not the magnitude of the AFM moment but the volume fraction of the AFM phase is tiny below T 0. The volume fraction of the AFM phase is estimated about 1 % at ambient pressure while the magnitude of the moment is 0.25 µ B per U ion. Another discovery of importance is the presence of the phase tran