Abstract
Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 ± 1.8, 9.2 ± 1.7, 9.6 ± 2.7, 13.0 ± 1.8, 12.3 ± 1.6, 3.4 ± 0.4, and 0.30 ± 0.20 mg/liter, respectively (mean ± standard deviation [SD]; n = 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 ± 1.5, 15.9 ± 1.6, 19.1 ± 1.7, 14.9 ± 3.1, 4.1 ± 0.6, and 0.46 ± 0.37 mg/liter, respectively (mean ± SD; n = 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 ± 80, 99.4 ± 31.5, 84.9 ± 16.8, 44.4 ± 13.9, and 14.2 ± 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 ± 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.
Compared to other available fluoroquinolones, sparfloxacin exhibits improved activity against gram-positive pathogens. For example, pneumococci, which are becoming increasingly resistant to β-lactams, show a favorable susceptibility to this fluoroquinolone (2). Infections caused by such pathogens also play an important role in pediatrics. However, sparfloxacin is not approved for use in children and adolescents because all fluoroquinolones known so far have the potential to induce lesions of joint cartilage in immature animals (for reviews, see references 6 and 18).
A reasonable extrapolation of the toxicological data obtained from studies of quinolones in immature animals is still limited by the fact that the results of very few toxicokinetic studies have been published. However, from the available data it is clear that due to significant differences in the kinetics of the drugs in rodents and humans, it makes no sense to compare the doses applied in toxicological experiments with rats to those used therapeutically; instead, concentrations achieved in plasma or the target tissue represent a much better basis for such a comparison. We have shown earlier that with 600 mg of ofloxacin/kg of body weight in juvenile rats, which corresponds approximately to a dose 100-fold the dose used therapeutically, the concentrations in plasma are only approximately 10-fold higher than the concentrations in plasma during therapy (12, 17). The best basis for a reasonable comparison between the therapeutic situation and the conditions of a toxicological experiment would be a comparison of the concentrations achieved in joint cartilage. Therefore, we performed detailed studies of the kinetics of sparfloxacin in plasma and joint cartilage from immature rats and investigated knee joint cartilage by histology and immunohistochemistry.
(The data presented here are part of the doctoral thesis of Uta Zippel, to be submitted to the Fachbereich Humanmedizin, Freie Universität Berlin.)
MATERIALS AND METHODS
Sparfloxacin treatment and histology.
Wistar rats were kept in Macrolon cages at a room temperature of 23 ± 1°C, a relative humidity of 50% ± 5%, and a constant light-dark schedule (light from 0700 to 1900 h).
For treatment with sparfloxacin, commercially available tablets (ZAGAM) containing 200 mg of the drug were suspended in a 2% starch suspension. The freshly prepared suspension was administered via a gastric tube at a volume of 10 ml per kg of body weight. A total of 40 rats were treated for histological examination. In addition, another 40 rats were treated for the toxicokinetic study.
Three days after treatment most rats were killed and cartilage was studied by histological techniques; 10 rats, however, were studied 7 months after treatment with daily doses of 600 mg of sparfloxacin/kg of body weight for 4 days. For histological examination, knee joints were prepared and fixed in formalin (10%), decalcified in an EDTA solution (10%; pH 7.4), dehydrated in an alcohol series, and embedded in paraffin. Series of 40 to 50 slices (thickness, 6 μm) were prepared from the predilection sites of one knee joint of each animal and stained with an aqueous 1% solution of toluidine blue (Merck, Darmstadt, Germany).
Immunohistochemistry.
Contralateral knee joints were embedded in Tissue TEK (Miles Diagnostics, Elkhardt, Ind.) without fixation or decalcification and were frozen with liquid nitrogen. Cryosections (thickness, 7 μm) were prepared from the knee joints and were mounted on poly-l-lysine-coated glass slides. The sections were stained with a primary antibody against fibronectin which had been prepared at our institute (1) or against the α5β1-integrin (CD49eCD29) on chondrocytes (purchased from Biomol, Hamburg, Germany). Slices were incubated at 4°C overnight, washed three times in phosphate-buffered saline (Ca2+ and Mg2+ free), stained with a secondary fluorescein isothiocyanate (FITC)-labelled antibody for 30 min at room temperature, and inspected under a fluorescence microscope. The secondary antibody was FITC-labelled goat anti-rabbit immunoglobulin G (gar-FITC) purchased from Nordic, Tiburg, The Netherlands.
Sparfloxacin kinetics in juvenile rats.
Groups of three to six juvenile rats (age, 5 weeks) were treated with 600 or 1,800 mg of sparfloxacin/kg as described above. Animals were decapitated after 0.25 (low dose only), 0.75, 1.5, 3, 6, 12 (low dose only), 24, and 48 (high dose only) h, and blood samples were obtained with hematocrit capillaries coated with sodium heparinate. The differences in the times that the animals receiving the two doses were studied were based on results from preliminary experiments. Blood was centrifuged and plasma was stored at −20°C until analysis. Also, bone (femur) and joint cartilage (femoral head) samples were collected from the rats that had been treated with the high dose.
HPLC analysis.
Plasma samples were deproteinized with acetonitrile and were analyzed by high-pressure liquid chromatography (HPLC). Bone and cartilage samples were extracted twice with a 10-fold volume (wt/vol) of 0.1 M phosphoric acid for 24 h at 4°C. The extraction efficacies were 90.2% for bone and 76.5 and 82.4% for cartilage for a duplicate extraction and five repeat extractions, respectively. Recovery from plasma was 94.8%. All samples were analyzed by HPLC by a previously published method (3). Briefly, separation was performed on a cation-exchange column (Nucleosil-100 5 SA; 125 by 4 mm; mean particle size, 5 μm). The main column was protected by a guard column filled with Perisorb RP18 (30 by 4 mm; particle size, 30 to 40 μm). The mobile phase (pH 3.8) consisted of 750 ml of acetonitrile and 250 ml of 0.1 M phosphoric acid to which sodium hydroxide had been added to a final concentration of 23 mmol of sodium per liter. The flow rate of the mobile phase was 1.5 ml/min. Sparfloxacin was determined by spectrofluorometry (excitation wavelength, 295 nm; emission wavelength, 525 nm). Detection limits were calculated with SQS software (Perkin-Elmer). Detection limits were 0.09 mg/liter for serum and 0.23 mg/liter for bone and cartilage. The linear ranges of the calibration line were 0.17 to 10.0 mg/liter for serum and 0.83 to 25.0 mg/liter for bone and cartilage. The within-series precision (coefficient of variation) was 3.5% for plasma. For bone and cartilage, the within-series precision was estimated from duplicate analyses, and it amounted to 14.0% for bone and 9.8 to 10.4% for cartilage.
Data analysis.
Pharmacokinetic analysis of the sparfloxacin concentrations in plasma, cartilage, and bone was performed by using the TOPFIT program (8).
RESULTS
We did not observe any cartilage alterations in 32 rats treated once or multiple times with 600 mg of sparfloxacin/kg of body weight (Table 1). However, after treatment with the threefold dose we observed typical lesions such as matrix swelling, loss of chondrocytes, and reduced stainability with toluidine blue in five of eight animals. Figure 1 shows an example of such a lesion in the knee joint cartilage of a 5-week-old rat. Knee joint cartilage was studied 3 days after dosing for most of the animals. A group of 10 rats was studied 7 months after treatment to ascertain whether subchondrotoxic doses, which do not lead to histological alterations immediately after dosing, might induce lesions with increasing age of the animals. However, no alterations to the joint cartilage in these adult rats were found by the techniques used in this study (data not shown).
TABLE 1.
Effects of sparfloxacin on joint cartilage in juvenile ratsa
| Dose (mg/kg) | No. of doses per day | Duration of treatment (days) | Incidence of lesions in knee joint cartilageb |
|---|---|---|---|
| 600 | 1 | 1 | 0/6 |
| 600 | 1 | 4 | 0/10c |
| 600 | 1 | 8 | 0/10 |
| 600 | 2 | 1 | 0/6 |
| 1,800 | 1 | 1 | 5/8d |
All doses were administered orally. The rats were investigated 3 days after administration of the last dose.
Values are number of rats with lesions in knee joint cartilage/number of rats studied.
Rats from this group were studied 7 months after dosing.
All cartilage lesions were located in the femoral part of the knee joint (ventral).
FIG. 1.
Knee joint cartilage from a juvenile rat (age, 5 weeks) stained with toluidine blue. A cartilage lesion (white arrows) in the middle layer of the rather thick immature articular-epiphyseal cartilage complex (left and central parts of the figure, respectively) induced by treatment with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight can be seen. The normal cartilage layer is at the right part of the picture. Arrowheads mark the joint surface; stars mark bone. Magnification, ×10.
Immunohistochemistry confirmed these findings. It is of particular interest that by using a monoclonal antibody against fibronectin, increased staining in the vicinity of the lesions was demonstrable. Increased staining with this antibody was also detectable in areas of the joint cartilage where no gross structural alterations were visible (Fig. 2). Immunohistochemistry with an antibody against the α5β1-integrin on chondrocytes showed no significant alterations compared with the chondrocytes of the controls (Fig. 3).
FIG. 2.
Knee joint cartilage from juvenile rats (age, 5 weeks), with immunohistochemical detection of fibronectin in the cartilage matrix. (A) Untreated control, showing the characteristic distribution of small amounts of fibronectin in the cartilage matrix mainly located at the cartilage surface (arrowheads). Stars mark bone. Magnification, ×10. (B) Rats treated with 1,800 mg of sparfloxacin/kg. A cleft is present within the middle zone of cartilage, and increased amounts of fibronectin are present along the margin of the lesion (arrows). Arrowheads mark the joint surface; stars mark bone. Magnification, ×10.
FIG. 3.
Knee joint cartilage from juvenile rats (age, 5 weeks), with immunohistochemical detection of α5β1-integrin (fibronectin receptor) on chondrocytes from juvenile rats. Arrowheads mark the joint surface; stars mark bone. (A) Untreated control, showing regular staining of chondrocytes. Magnification, ×10. (B) Rats treated with 1,800 mg of sparfloxacin/kg. A cleft is present within the middle zone of cartilage (arrows). Cells in the vicinity of the cleft are slightly less intensely stained. Magnification, ×10.
Sparfloxacin was rapidly absorbed from the gastrointestinal tract. As early as 15 min after the administration of 600 mg/kg via a gastric tube, concentrations of 6.3 ± 1.8 mg/liter (mean ± standard deviation [SD]) were measured in plasma. Peak concentrations (Cmax) were determined 3 h after dosing (13.0 ± 1.8 mg/liter); concentrations declined to 3.4 ± 0.4 mg/liter at 12 h after dosing. By using the TOPFIT program and mean values, a Cmax of 12.4 mg/liter at 115 min after dosing was calculated. The area under the concentration-time curve (AUC) was 228 mg · h/liter.
After treatment with the low dose, cartilage and bone samples were analyzed only at 12 h after dosing. The concentrations were 20.9 ± 3.9 and 15.7 ± 2.5 mg of sparfloxacin/kg, respectively. The mean concentrations were 6.1 and 4.6 times higher than the corresponding mean concentrations in plasma, respectively.
The concentrations in plasma measured after administration of the threefold dose did not increase proportionally, and Cmaxs (19.1 ± 1.7 mg/liter) were only approximately 50% higher. Mean concentrations of the drug in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg of body weight were 10.9 ± 1.5, 15.9 ± 1.6, 19.1 ± 1.7, 14.9 ± 3.1, 4.1 ± 0.6, and 0.46 ± 0.37 mg/liter, respectively (mean ± SD). By using the TOPFIT program and mean values, a Cmax of 18.4 mg/liter at 167 min after dosing was calculated. The AUC was 293 mg · h/liter.
The concentrations of sparfloxacin in joint cartilage after treatment with 1,800 mg of sparfloxacin/kg were significantly higher than those in plasma at all time points studied (114.8 ± 80, 99.4 ± 31.5, 84.9 ± 16.8, 44.4 ± 13.9, and 14.2 ± 4.8 mg of sparfloxacin/kg after 1.5, 3, 6, 24, and 48 h, respectively). Ratios of the concentrations in cartilage to the concentrations in plasma were 7.2, 5.2, 5.7, 10.8, and 30.9 at 1.5, 3, 6, 24, and 48 h after treatment, respectively. The range of concentrations in bone were similar to those in cartilage (67.0 ± 21.0, 115.1 ± 12.1, 86.2 ± 5.6, 31.5 ± 9.3, and 9.0 ± 2.8 mg/kg, respectively). AUCs for the concentrations of sparfloxacin in cartilage were 2,066 mg · h/liter, and those for the concentrations in bone were 1,950 mg · h/liter.
Figure 4 presents the concentrations in plasma, joint cartilage, and bone (means ± SDs) after treatment with 1,800 mg of sparfloxacin/kg of body weight.
FIG. 4.
Concentrations of sparfloxacin in plasma, joint cartilage, and bone after oral treatment with a single dose of 1,800 mg of sparfloxacin/kg of body weight (values are means ± SDs). Note the differences in the y axes for the concentrations in plasma, cartilage, and bone. Slanted lines on the x axes indicate interruption of linearity.
DISCUSSION
For most xenobiotic compounds, kinetics in animals and humans differ considerably. Therefore, data from toxicological studies can be interpreted only on the basis of the kinetics of the compound in the species studied. Here we present data combining information on the chondrotoxic effect of sparfloxacin as well as the kinetics of the drug in the plasma and target tissue of juvenile rats.
We investigated knee joint cartilage from juvenile rats after the administration of single and multiple doses of sparfloxacin. Lesions were detectable only after oral treatment with 1,800 mg of sparfloxacin/kg of body weight. After the administration of single or multiple doses of 600 mg/kg, no lesions were observed. Treatment with other fluoroquinolones, such as ofloxacin or fleroxacin, proved to be chondrotoxic at this dose under otherwise identical conditions (5, 15, 17, 19).
It is of major importance that we found unexpectedly low Cmaxs in plasma (13.0 ± 1.8 and 19.1 ± 1.7 mg/liter) after the administration of oral doses as high as 600 or 1,800 mg/kg of body weight. Mean peak levels in the plasma of human volunteers after the administration of a single oral dose of 400 mg (approximately 6 mg/kg) were measured 4 to 5 h after dosing and ranged from 1.2 to 1.4 mg/liter (16). Thus, although we used a dose that was up to 300-fold the therapeutic dose for our experiments, concentrations in the plasma of juvenile rats were only approximately 15 times higher than those under therapeutic conditions. In a previous experiment we had found a similar discrepancy with ofloxacin (17).
Only a few data on the sparfloxacin concentrations in plasma, cartilage, and bone of experimental animals after oral administration have been published so far. If the concentrations in plasma published by other investigators are compared with our data, it must be considered that the data were generated under different experimental conditions (dose, vehicle, mode of administration, and age and strain of animals, etc.). For example, a mean concentration in plasma of approximately 12 mg of sparfloxacin/liter in adult Wistar rats was measured after oral treatment with a single dose of 200 mg/kg of body weight (9).
Cremieux and coworkers (4) described an autoradiographic pattern of the sparfloxacin distribution in rabbits 60 min after the intravenous infusion of 250 μCi of [14C]sparfloxacin. High levels of radioactivity were measured in tibial epiphyseal disk cartilage (the levels were approximately 15-fold higher than the levels in blood), femoral cartilage, and articular ligaments.
More detailed data on the concentrations of other quinolones in joint cartilage from rats, rabbits, and dogs have been published. The concentrations of norfloxacin and nalidixic acid in the plasma and cartilage of various experimental animals as well as the chondrotoxic effects of these drugs have been investigated by Machida and coworkers (13). Juvenile rats were least susceptible to norfloxacin-induced arthropathy, with concentrations in cartilage of 20.6 ± 4.6 μg/g after the administration of the lowest arthropathogenic dose. In juvenile rabbits, this threshold concentration was lower (9.4 ± 2.8 μg/g of tissue). In dogs, the concentration of norfloxacin in cartilage after the administration of the lowest arthropathogenic dose was 6.9 μg/g of tissue (single value). A corresponding rank order for the susceptibilities of the three animal species was seen with nalidixic acid. The concentrations in cartilage after the administration of the minimum arthropathogenic dose were 34.1 ± 3.4, 21.5 ± 10.4, and 4.6 (single value) μg/g in rats, rabbits, and dogs, respectively.
Kato and coworkers (10) measured the concentrations of levofloxacin in articular cartilage from young rabbits after the administration of single oral doses of 30 or 100 mg/kg of body weight. Cmaxs in cartilage were 4.9 ± 2.3 and 12.2 ± 5.8 mg/kg 30 min after the administration of the low and high doses, respectively. The rate of elimination of the fluoroquinolone from cartilage was considerably lower than that from plasma. Cartilage lesions were observed only after treatment with 100 mg/kg of body weight.
The mean concentration of pefloxacin in the cartilage of juvenile rabbits increased from 17.5 ± 4.3 μg/g of tissue after 1 day to 81.5 ± 8.2 μg/g after 7 days of daily treatment with two doses of 150 mg/kg of body weight. Using flow cytometric techniques, the investigators could demonstrate a significant increase in the respiratory burst in chondrocytes from both groups. A corresponding effect was observed with ofloxacin at concentrations of 7.3 ± 2.8 μg/g of cartilage (7).
Only very limited data on the concentrations in the cartilage of humans under therapeutic conditions are available. To our knowledge, ofloxacin is the only drug that has been studied so far. Cartilage ofloxacin concentrations have been investigated in patients undergoing hip replacement for osteoarthritis. In these patients the maximum concentration of 2.2 ± 0.5 mg/liter (assuming an average cartilage density of 1 kg/liter) was measured 13 h after the administration of a single intravenous dose of 200 mg of ofloxacin (14).
From the limited available information it might be concluded that fluoroquinolones such as norfloxacin or nalidixic acid induce lesions in the joint cartilage of juvenile rats at lower concentrations than those at which sparfloxacin induces lesions. This could be related to the fact that sparfloxacin seems to have a rather low affinity for magnesium (11). We have shown before that the chelating properties of fluoroquinolones are likely the primary reason for their chondrotoxicities (19).
Taken together, two main results of our study seem to be especially noteworthy. First, the concentrations of sparfloxacin in the plasma of juvenile rats after oral administration are significantly lower than might be expected from the dose administered. Second, the minimal chondrotoxic concentrations of sparfloxacin, which has a low affinity for magnesium, are higher than those of other quinolones in joint cartilage from juvenile rats. From a toxicological point of view a fluoroquinolone which has a low affinity for magnesium and which reaches comparatively low concentrations in cartilage might be the least chondrotoxic one and thus may be the most suitable for the treatment of infections in pediatric patients. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.
ACKNOWLEDGMENTS
We are indebted to Irmela Baumann-Wilschke, Ursula Kastner, and Hildegard Hartwig for skillful technical assistance. Our thanks also go to Ursula Schwikowski and Ingrid Wolff for photographic assistance and Barbara Steyn for help in preparing the manuscript.
The study was supported by a grant from the Deutsche Forschungsgemeinschaft.
Footnotes
Dedicated to Hartmut Lode, Chest and Infectious Disease Department, City Hospital Zehlendorf, Berlin, Germany.
REFERENCES
- 1.Barrach H J, Grundmann K, Hinz N, Felies A. Comparison of the differentiation of muscle and connective tissue of mouse limb-buds in culture and in vivo: a morphological study by indirect immunofluorescence. In: Neubert D, Merker H J, editors. Culture techniques. Berlin, Germany: Walter de Gruyter Verlag; 1981. pp. 135–159. [Google Scholar]
- 2.Barry A L, Fuchs P C, Brown S D. In vitro activities of five fluoroquinolone compounds against strains of Streptococcus pneumoniae with resistance to other antimicrobial agents. Antimicrob Agents Chemother. 1996;40:2431–2433. doi: 10.1128/aac.40.10.2431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Borner K, Borner E, Lode H. Determination of sparfloxacin in serum and urine by high-performance liquid chromatography. J Chromatogr. 1992;579:285–289. doi: 10.1016/0378-4347(92)80393-5. [DOI] [PubMed] [Google Scholar]
- 4.Cremieux A C, Mghir A S, Bleton R, Manteau M, Belmatoug N, Massias L, Garry L, Sales N, Maziere B, Carbon C. Efficacy of [14C]sparfloxacin in experimental Staphylococcus aureus joint prosthesis infection. Antimicrob Agents Chemother. 1996;40:2111–2116. doi: 10.1128/aac.40.9.2111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Förster C, Kociok K, Shakibaei M, Merker H J, Vormann J, Günther T, Stahlmann R. Integrins on joint cartilage chondrocytes and alterations by ofloxacin or magnesium deficiency in immature rats. Arch Toxicol. 1996;70:261–270. doi: 10.1007/s002040050272. [DOI] [PubMed] [Google Scholar]
- 6.Gough A W, Kasali O B, Sigler R E, Baragi V. Quinolone arthropathy—acute toxicity to immature cartilage. Toxicol Pathol. 1992;20:436–450. doi: 10.1177/019262339202000313. [DOI] [PubMed] [Google Scholar]
- 7.Hayem G, Petit P X, Levacher M, Gaudin C, Kahn M F, Pocidalo J J. Cytofluorometric analysis of chondrotoxicity of fluoroquinolone antimicrobial agents. Antimicrob Agents Chemother. 1994;38:243–247. doi: 10.1128/aac.38.2.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Heinzel G, Woloszczak R, Thomann P. TopFit 2.0. Pharmacokinetic and pharmacodynamic data analysis system for the PC. Stuttgart, Germany: Gustav Fischer; 1993. [Google Scholar]
- 9.Inokuchi K, Miki I, Fujita K. Interaction between sparfloxacin and 4-biphenylacetic acid. Oyo Yakuri. 1995;49:515–518. [Google Scholar]
- 10.Kato M, Takada S, Ogawara S, Takayama S. Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions in vivo. Antimicrob Agents Chemother. 1995;39:1979–1983. doi: 10.1128/aac.39.9.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lecomte S, Baron M H, Chenon M T, Coupry C, Moreau M J. Effect of magnesium complexation by fluoroquinolones on their antibacterial properties. Antimicrob Agents Chemother. 1994;38:2810–2816. doi: 10.1128/aac.38.12.2810. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lode H, Höffken G, Olschewski P, Sievers B, Kirch A, Borner K, Koeppe P. Pharmacokinetics of ofloxacin after parenteral and oral administration. Antimicrob Agents Chemother. 1987;31:1338–1342. doi: 10.1128/aac.31.9.1338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Machida M, Kusajima H, Aijima H, Maeda A, Ishida R, Uchida H. Toxicokinetic study of norfloxacin-induced arthropathy in juvenile animals. Toxicol Appl Pharmacol. 1990;105:403–412. doi: 10.1016/0041-008x(90)90144-j. [DOI] [PubMed] [Google Scholar]
- 14.Meissner, A., K. Borner, and P. Koeppe. 1990. Concentrations of ofloxacin in human bone and cartilage. J. Antimicrob. Chemother. 26(Suppl. D):69–74. [DOI] [PubMed]
- 15.Schwabe, R., U. Zippel, C. Förster, I. Baumann-Wilschke, and R. Stahlmann. 1996. Plasma concentrations and chondrotoxicity of three fluoroquinolones in juvenile rats. Naunyn-Schmiedebergs Arch. Pharmacol. 354(Suppl. 1):R28. (Abstract 110.)
- 16.Shimada J, Nogita T, Ishibashi Y. Clinical pharmacokinetics of sparfloxacin. Clin Pharmacokinet. 1993;25:358–369. doi: 10.2165/00003088-199325050-00002. [DOI] [PubMed] [Google Scholar]
- 17.Stahlmann R, Merker H-J, Hinz N, Webb J, Heger W, Neubert D. Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations. Arch Toxicol. 1990;64:193–204. doi: 10.1007/BF02010725. [DOI] [PubMed] [Google Scholar]
- 18.Stahlmann R, Förster C, van Sickle D. Quinolones in children: are concerns over arthropathy justified? Drug Safety. 1993;9:397–403. doi: 10.2165/00002018-199309060-00002. [DOI] [PubMed] [Google Scholar]
- 19.Stahlmann R, Förster C, Shakibaei M, Vormann J, Günther T, Merker H-J. Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy. Antimicrob Agents Chemother. 1995;39:2013–2018. doi: 10.1128/aac.39.9.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]