Effects of ciprofloxacin on joint cartilage in immature dogs immediately after dosing and after a 5-month treatment-free period

Keutz, Eckhard von; Rühl-Fehlert, Christine; Drommer, W.; Martin, Rachel W.

doi:10.1007/s00204-004-0551-6

Cited by 29 publications

(20 citation statements)

References 12 publications

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“…Experiments with ciprofloxacin-exposed beagle pups documented evidence of erosions of the weight-bearing articular joint surface as long as 5 months after therapy, despite resolution of joint symptoms that occurred at the time of dosing in these animals. 16 These gross anatomic and histologic data concerning articular cartilage, as well as histologic data documenting abnormalities of the epiphyseal cartilage at the highest doses of trovafloxacin and ofloxacin tolerated in rats, 17 prompted concerns that a better understanding of risk associated with fluoroquinolone use in children would require evaluation of children well beyond the period of exposure. Although animal data strongly supported that fluoroquinolone-related damage to cartilage would be evident during or immediately after drug exposure, it was reasoned in designing the levofloxacin pediatric program that clinically apparent, drug-related injury to joint cartilage or to the epiphyseal plate in children could take months to manifest.…”

Section: Figurementioning

confidence: 99%

Assessment of Musculoskeletal Toxicity 5 Years After Therapy With Levofloxacin

et al. 2014

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BACKGROUND: Safety concerns for fluoroquinolones exist from animal studies demonstrating cartilage injury in weight-bearing joints, dependent on dose and duration of therapy. For children treated with levofloxacin or comparator in randomized, prospective, comparative studies for acute otitis media and community-acquired pneumonia, this 5-year follow-up safety study was designed to assess the presence/absence of cartilage injury. METHODS: Children enrolled in treatment studies were also enrolled in a 1-year follow-up safety study, which; focused on musculoskeletal adverse events (MSAE). Those with persisting MSAEs, protocol-defined musculoskeletal disorders, or of concern to the Data Safety and Monitoring Committee were requested to enroll in four additional years of follow-up, the subject of this report. RESULTS: Of the 2233 subjects participating in the 12-month follow-up study, 124 of 1340 (9%) of the levofloxacin subjects, and 83 of 893 (9%) of the comparator subjects were continued for 5-year posttreatment assessment. From children identified with an MSAE during years 2 through 5 posttreatment, the number that were “possibly related” to drug therapy was equal for both arms: 1 of 1340 for levofloxacin and 1 of 893 for comparator. Of all cases of MSAE assessed by the Data Safety and Monitoring Committee at 5 years’ posttreatment, no case was assessed as “likely related” to study drug. CONCLUSIONS: With no clinically detectable difference between levofloxacin- and comparator-treated children in MSAEs presenting between 1 and 5 years in these safety studies, risks of cartilage injury with levofloxacin appear to be uncommon, are clinically undetectable during 5 years, or are reversible.

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Section: Figurementioning

confidence: 99%

Assessment of Musculoskeletal Toxicity 5 Years After Therapy With Levofloxacin

et al. 2014

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“…In 1977, Ingham et al reported on arthropathy of weight-bearing joints in juvenile animals after postnatal exposure to narrow-spectrum quinolones (5). This effect has also been observed in animal experiments with newer fluoroquinolones (6,7). Therefore, they are generally avoided during pregnancy although studies have not shown any significant risk of cartilage damage in children (8).…”

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confidence: 97%

Observational Cohort Study of Pregnancy Outcome after First-Trimester Exposure to Fluoroquinolones

Padberg

Wacker

Meister

et al. 2014

Antimicrob Agents Chemother

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bFluoroquinolones are avoided during pregnancy due to developmental toxicity in animals. The aim of this study was to assess the fetal risk after intrauterine fluoroquinolone exposure. We performed an observational study of a prospectively ascertained cohort of pregnant women exposed to a fluoroquinolone during the first trimester. Pregnancy outcomes were compared to those of a cohort exposed to neither fluoroquinolones nor teratogenic or fetotoxic drugs. The outcomes evaluated were major birth defects (structural abnormalities of medical, surgical, or cosmetic relevance), spontaneous abortion, and elective termination of pregnancy. Pregnancy outcomes of 949 women with fluoroquinolone treatment were compared with those of 3,796 nonexposed controls. Neither the rate of major birth defects (2.4%; adjusted odds ratio [OR adj ], 0.91; 95% confidence interval [CI], 0.6 to 1.5) nor the risk of spontaneous abortion (adjusted hazard ratio [HR adj ], 1.01; 95% CI, 0.8 to 1.3) was increased. However, there was a nonsignificant increase in major birth defects after exposure to moxifloxacin (6/93, 6.5%; crude odds ratio [OR crude ], 2.40; 95% CI, 0.8 to 5.6). Neither a critical exposure time window within the first trimester nor a specific pattern of birth defects was demonstrated for any of the fluoroquinolones. The rate of electively terminated pregnancies was increased among the fluoroquinolone-exposed women (HR adj , 1.32; 95% CI, 1.03 to 1.7). The gestational ages at delivery and birth weights did not differ between groups. Our study did not detect an increased risk of spontaneous abortion or major birth defects. These reassuring findings support the recommendation to allow fluoroquinolone use in early pregnancy in selected cases. After the use of moxifloxacin, a detailed fetal ultrasound examination should be considered.

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“…However, they are contraindicated for children and adolescents and during pregnancy and nursing due to the potential for joint cartilage lesions as found in immature animals (22,23). Quinolone-induced chondrotoxicity in juvenile animals of multiple species has been demonstrated and shown to be irreversible under experimental conditions (5,24), dose dependent (19), and developmental phase (age) specific (22,23,26). The relevance of those observations for humans is still unclear (3).…”

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confidence: 99%

Diminished Ciprofloxacin-Induced Chondrotoxicity by Supplementation with Magnesium and Vitamin E in Immature Rats

Pfister

Mazur

Vormann³

et al. 2007

Antimicrob Agents Chemother

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Quinolone-induced chondrotoxicity in juvenile rats and multiple other species has been demonstrated previously. Identical damages can be induced in immature rats by feeding them a magnesium-deficient diet. The objective of the present study was to investigate whether, in reverse, oral supplementation with magnesium, vitamin E, or both can diminish the typical quinolone-induced arthropathy in juvenile Wistar rats. Four groups of 12 (6 male, 6 female) 24-day-old Wistar rats were each fed either normal feed (group A), a vitamin E-enriched diet (group B), a magnesium-enriched diet (group C), or a diet enriched with both vitamin E and magnesium (group D) for 10 days. All rats received two subcutaneous ciprofloxacin doses of 600 mg/kg of body weight on postnatal day 32. Two days later, the rats were sacrificed and cartilage samples from knee joints were examined under a light microscope for the presence of typical quinolone-induced joint cartilage lesions. In addition, magnesium, calcium, and vitamin E concentrations in cartilage and plasma were determined. In the samples from rats fed a normal diet (group A), 17 quinolone-induced joint cartilage lesions were observed. In groups fed an enriched diet, the incidence of specific lesions (n) was significantly lower: group B, n ‫؍‬ 10 (41% reduction compared to the incidence for group A; P < 0.05); group C, n ‫؍‬ 6 (65% reduction; P < 0.01); and group D, n ‫؍‬ 3 (82% reduction; P < 0.01). In comparison to the standard diet, diets with magnesium and vitamin E supplementation resulted in significantly higher magnesium and vitamin E concentrations in plasma and articular cartilage. Supplementation with magnesium and vitamin E alone or in combination may relevantly diminish joint cartilage lesions induced by quinolones in immature rats, with an additive effect of combined supplementation. The data further support the proposed pathomechanism of quinolone-induced arthropathy and the crucial role of magnesium in immature joint cartilage.

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Effects of ciprofloxacin on joint cartilage in immature dogs immediately after dosing and after a 5-month treatment-free period

Cited by 29 publications

References 12 publications

Assessment of Musculoskeletal Toxicity 5 Years After Therapy With Levofloxacin

Assessment of Musculoskeletal Toxicity 5 Years After Therapy With Levofloxacin

Observational Cohort Study of Pregnancy Outcome after First-Trimester Exposure to Fluoroquinolones

Diminished Ciprofloxacin-Induced Chondrotoxicity by Supplementation with Magnesium and Vitamin E in Immature Rats

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