No abstract

This review focuses on the most recent research findings on adverse reactions caused by quinolone antibiotics. Reactions of the gastrointestinal tract, the central nervous system (CNS) and the skin are the most often observed adverse effects. Occasionally major events such as phototoxicity, cardiotoxicity, arthropathy and tendinitis occur, leading to significant tolerability problems. Over the years, several structure-activity and side-effect relationships have been developed, in an effort to improve overall antimicrobial efficacy while reducing undesirable side-effects. In this article we review the toxicity of fluoroquinolones, including the newer derivatives such levofloxacin, sparfloxacin, graepafloxacin and the 7-azabicyclo derivatives, trovafloxacin and moxifloxacin. A special attention is given to new data on mechanistic aspects, particularly those regarding CNS effects. In recent years extensive in vivo and in vitro experiments have been performed in an attempt to explain the neurotoxic effects of quinolones sometimes observed under therapeutic conditions. However, the molecular target or receptor for such effects is still not exactly known. Several mechanisms are thought to be responsible. The involvement of gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission and the kinetics of quinolones distribution in brain tissue are discussed. In addition, quinolones may interact with other drugs--theophylline and nonsteroidal antiflammatory drugs (NSAID(s))--in producing CNS effects This article provides information about the different mechanisms responsible of quinolones interaction with NSAID(s), methylxanthines, warfarin and antiacids.

Here, we investigate the effects of renal ischemia/reperfusion (I/R) on the degree of renal injury, dysfunction, and inflammation in interleukin (IL)-6 knockout (IL-6 Ϫ/Ϫ ) mice and mice administered a monoclonal antibody against IL-6. IL-6 Ϫ/Ϫ mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (24 h). At the end of experiments, indicators and markers of renal dysfunction, injury, and inflammation were measured. Kidneys were used for histological evaluation of renal injury. Renal expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and P-selectin, as well as nitration of proteins in the kidney, were determined using immunohistochemistry. In addition, wild-type mice were pretreated (24 and 1 h before ischemia) with an IL-6 antibody to mimic the effects that would be seen in IL-6 Ϫ/Ϫ mice. IL-6 Ϫ/Ϫ mice and wild-type mice administered the IL-6 antibody demonstrated significantly reduced plasma urea and creatinine levels, indicating reduction of renal dysfunction caused by I/R. Neutrophil infiltration was also significantly reduced in IL-6

Recent studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. NO, peroxynitrite (formed from NO and superoxide anion), and poly (ADP-Ribose) synthetase (PARS) have been implicated as mediators of neuronal damage following focal ischemia. In the present study, we have investigated the effects of melatonin treatment in Mongolian gerbils subjected to cerebral ischemia. Treatment of gerbils with melatonin (10 mg kg(-1), 30 min before reperfusion and 1, 2, and 6 hr after reperfusion) reduced the formation of post-ischemic brain edema, evaluated by water content. Melatonin also attenuated the increase in the brain levels malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischemia. Positive staining for nitrotyrosine was found in the hippocampus of Mongolian gerbils subjected to cerebral ischemia. Hippocampus tissue sections, from Mongolian gerbils subjected to cerebral ischemia, also showed positive staining for PARS. The degrees of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received melatonin. Melatonin treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischemia and reperfusion. Histological observations of the pyramidal layer of CA-1 showed a reduction of neuronal loss in animals that received melatonin. These results show that melatonin improves brain injury induced by transient cerebral ischemia.

The epileptogenic activities of several ␤-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various ␤-lactam antibiotics tested, but the epileptogenic patterns were similar. The patterns consisted of an initial phase characterized by wet-dog shakes followed by head tremor, nodding, and clonic convulsions. After the largest doses of ␤-lactam antibiotics injected, clonus of all four limbs and/or the trunk, rearing, jumping, falling down, escape response, transient tonic-clonic seizures, and sometimes generalized seizures were observed, followed by a postictal period with a fatal outcome. At a dose of 0.033 mol per rat, cefazolin was the most powerful epileptogenic compound among the drugs tested. It was approximately three times more potent than benzylpenicillin in generating a response and much more potent than other cephalosporins, such as ceftriaxone, cefoperazone, and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid, cefixime, and ceftizoxime in this model. The more convulsant compounds (i.e., cefazolin and ceftezole) are both characterized by the presence of a tetrazole nucleus at position 7 and show a marked chemical similarity to pentylenetetrazole. Imipenem and meropenem, the two carbapenems tested, also showed epileptogenic properties, but imipenem was more potent than meropenem, with a convulsant potency similar to those of ceftezole and benzylpenicillin. In addition, the monobactam aztreonam possessed convulsant properties more potent than those of cefoperazone and cefamandole. This suggests that the ␤-lactam ring is a possible determinant of production of epileptogenic activity, with likely contributory factors in the substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid that may increase or reduce the epileptogenic properties of the ␤-lactam antibiotics. While the structure-activity relationship was also investigated, there seem to be no convincing correlations among the rank order of lipophilicities and the convulsant potencies of the compounds studied. The lack of marked convulsant properties of cefixime, cefonicid, cefuroxime, and cephradine suggests that these antibiotics may interact with a binding site which is different from that by which the ␤-lactam antibiotics exert their convulsant effects or may demonstrate a reduced affinity for the relevant site(s).