Abstract
Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of N-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen.
Highlights
Fluoroquinolones are widely used in clinical practice because of their excellent antibacterial activity, wide spectrum of activity, and high degree of bioavailability
As an oxidative event was observed in cartilage [11, 33], we considered the attractive hypothesis that the pathophysiological effects due to pefloxacin administration result from the same effects on both articular cartilage and tendon
Fluoroquinolone derivatives are characterized by good tissue penetration, a broad antibacterial spectrum, and a relatively low incidence of serious side effects
Summary
Fluoroquinolones are widely used in clinical practice because of their excellent antibacterial activity, wide spectrum of activity, and high degree of bioavailability. Since 1992, tendinopathy has been described as another side effect in patients treated with fluoroquinolones, with the tendinopathy sometimes resulting in the rupture of the tendon The cause of this rare (Յ1%) [7] but severe complication remains unexplained [13, 14, 28]. The Achilles tendon and articular cartilage are characterized by a low level of or no blood perfusion, respectively, resulting in a low O2 pressure [18]. These conditions render them more susceptible to oxidative stress resulting from an incomplete reduction of oxygen in the mitochondria and the formation of superoxide. The results obtained provide new insights into the mechanism of fluoroquinolone-induced tendinopathies
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