Arthropathy induced by antibacterial fused N-alkyl-4-pyridone-3-carboxylic acids

Ingham, Brian; Brentnall, D. W.; Dale, Eugenie A.; McFadzean, James A.

doi:10.1016/0378-4274(77)90016-9

Cited by 130 publications

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“…Several other possible mechanisms for quinolone-induced arthropathy have been postulated since the first description of this unusual toxic effect approximately 15 years ago (13,31). Some investigators have favored the idea that chondrocytes are the primary site of quinolone toxicity, possibly by interference of the drugs with mammalian DNA (15,30).…”

Section: Discussionmentioning

confidence: 99%

Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy

Stahlmann

Förster

Shakibaei

et al. 1995

Antimicrob Agents Chemother

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Quinolones accumulate in cartilage, and because they form chelate complexes with divalent cations, they possess the potential to induce a deficiency of functionally available magnesium. To test the hypothesis that quinolone-induced arthropathy is caused (or aggravated) by magnesium deficiency in cartilage, we induced magnesium deficiency by feeding juvenile rats a magnesium-deficient diet for 9 days and treated the rats with single oral doses of ofloxacin (0, 100, 300, 600, or 1,200 mg/kg of body weight) during this period. Additional groups of juvenile rats on a normal diet were treated with ofloxacin correspondingly. Typical cartilage lesions (e.g., swollen matrix, cleft formation) were found in knee joints of all magnesium-deficient rats, including those without ofloxacin treatment. Lesions in these groups were not distinguishable from lesions induced by a single dose of 600 mg of ofloxacin per kg of body weight or higher in rats on a normal diet. Ofloxacin levels in plasma after 600 mg/kg of body weight were approximately 10-fold higher than those in humans during therapy with this quinolone. Lesions in rats treated with ofloxacin plus magnesium deficiency were more pronounced than those in rats with normal magnesium concentrations. After intake of a magnesium-deficient diet for 9 days, the magnesium concentration in serum (mean ؎ standard deviation) was 0.18 ؎ 0.05 mmol/liter (control on normal diet, 0.82 ؎ 0.10 mmol/liter). Magnesium concentrations in bone (femur) and cartilage (processus xiphoideus) samples were 64.7 ؎ 10.5 and 14.3 ؎ 3.9 mmol/kg of dry weight, respectively, which corresponded to approximately 50% of the concentrations measured in controls on a normal diet. It was concluded that quinolone-induced arthropathy is probably caused by a deficit of available magnesium in joint cartilage due to the formation of quinolone-magnesium chelate complexes. If juvenile patients must be treated with quinolones for serious infections, it seems prudent to ensure that these patients do not have a disturbed magnesium balance.Quinolone-induced arthropathy is an unusual toxic effect observed with all known quinolones. Cartilage lesions are inducible in juvenile animals of multiple species, such as dogs (3,4,31), rats (14, 29), nonhuman primates (29), and others (9). The chondrotoxic potential of quinolones in humans under therapeutic conditions is low. Most juvenile patients have shown no signs of arthropathy after treatment with these drugs (1, 26). On the other hand, symptoms of arthropathy in juvenile and even adult patients have been described in a considerable number of case reports (e.g., references 5 and 24). Since most of these patients had cystic fibrosis-a disease which itself can be associated with arthropathy-the causal relationship in these observations and the indications for quinolone therapy in pediatrics remain matters for discussion (6,25,28).Recently, we hypothesized that quinolones might affect magnesium-dependent integrins of the ␤ 1 subfamily in articular cartilage as the primary event of...

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Section: Discussionmentioning

confidence: 99%

Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy

Stahlmann

Förster

Shakibaei

et al. 1995

Antimicrob Agents Chemother

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“…However, quinolones have been reported to induce arthropathy in juvenile animals such as mice [12], rats [4,9,10], rabbits [11], dogs [3,5,8,20], nonhuman primates [17] and others [1,2] as a class effect of these derivatives. Among these species, the juvenile dog is thought to be most susceptible to articular cartilage lesions [6,19,20].…”

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confidence: 99%

A Non-Arthropathic Dose and Its Disposition Following Repeated Oral Administration of Ofloxacin, a New Quinolone Antimicrobial Agent, to Juvenile Dogs.

Yabe

Murakami

Nishida

et al. 2001

The Journal of Veterinary Medical Science

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ABSTRACT. A non-arthropathic dose and disposition of ofloxacin, a potent new quinolone antimicrobial agent, were assessed in male juvenile (3-month-old) dogs, when administered orally at 5, 10 and 20 mg/kg/day once daily for 8 consecutive days. Ofloxacin concentrations in sera and articular cartilages were analyzed by high-performance liquid chromatography (HPLC). Macroscopically, arthropathy characterized by fluid-filled vesicles in articular surface of the humerus and femur was observed in animals receiving 10 and 20 mg/kg/day of ofloxacin, but not in those given 5 mg/kg/day. At 20 mg/kg/day, arthropathy of comparable severity also occurred on day 2. Microscopically, the cavity formation in the middle zone of the articular cartilage was first identified and then necrotic chondrocytes were found numerous around the cavity, followed by appearance of chondrocyte clusters. In pharmacokinetics, peak serum concentration (C max ) and area under the concentrations (AUC 0-24 ) were increased in a dose-dependent manner. However, no remarkable differences in these two parameters were noted between a single and repeated treatments, suggesting no accumulation of the drug. The articular ofloxacin concentration 2 hr after treatment was approximately 1.8 (day 2) to 2.0 times (day 8) higher than the serum concentration. Based on these results, a non-arthropathic dose of ofloxacin in male juvenile dogs following an 8-day treatment is considered to be 5 mg/kg/ day, and its C max , AUC 0-24 and articular cartilage concentrations 2 hr after treatment were 3.4 µg/ml, 35.1 µg⋅hr/ml and 7.0 µg/g, respectively, under these experimental conditions. Thus, arthropathy due to ofloxacin may be predicted by monitoring serum drug concentration. KEY WORDS: arthropathy, juvenile dog, non-arthropathic dose, ofloxacin, pharmacokinetics.J. Vet. Med. Sci. 63(8): 867-872, 2001 New quinolone antimicrobial agents (quinolones) are widely used in clinical fields because of their broad spectra and bactericidal activity. However, quinolones have been reported to induce arthropathy in juvenile animals such as mice [12], rats [4, 9, 10], rabbits [11], dogs [3, 5, 8, 20], nonhuman primates [17] and others [1, 2] as a class effect of these derivatives. Among these species, the juvenile dog is thought to be most susceptible to articular cartilage lesions [6,19,20].In our previous report [23], the arthropathic lesion due to ofloxacin was observed only in juvenile dogs, despite the fact that the drug concentration in the synovial fluid and articular cartilage of immature dogs (3-month-old) was equal to or lower than those in mature dogs (18-month-old). Kato and coworkers [10] have indicated that metabolically active immature chondrocytes are more sensitive to the effects of a quinolone, compared with inactive mature cells in the ex vivo study using 3 H-thymidine. Moreover, they have demonstrated that the initial target of the drug for the induction of arthropathy is the DNA synthesis of chondrocytes. Supporting this hypothesis, several DNA synthesis inhibito...

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“…1,2 The drug administered in an oral way is well absorbed by the gastrointestinal tract and is effective at a single dose of 300 mg. 3 However, the utility of resoxacin was limited by its unacceptable toxicity, mainly gastrointestinal and central nervous-system toxicity, crystalluria with high doses, and cartilage toxicity (seen in some experimental animals). [4][5][6] Because of cartilage toxicity, the quinolones are not recommended for its use in children or in pregnant women. These favorable characteristics and adverse effects are important factors to continue a detailed study of the chemical structure and chemical reactivity of each commercial quinolone.…”

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“…In this paper we describe the crystalline structure of rosoxacin. 5 An X-ray diffraction study has established that the asymmetric unit comprises two independent molecules. Both molecules are similar in terms of their bond lengths and angles, within the experimental error.…”

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Crystal Structure of 1-Ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinoline Carboxylic Acid (Rosoxacin)

1998

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Arthropathy induced by antibacterial fused N-alkyl-4-pyridone-3-carboxylic acids

Cited by 130 publications

References 0 publications

Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy

Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy

A Non-Arthropathic Dose and Its Disposition Following Repeated Oral Administration of Ofloxacin, a New Quinolone Antimicrobial Agent, to Juvenile Dogs.

Crystal Structure of 1-Ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinoline Carboxylic Acid (Rosoxacin)

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