scholarly journals Effects of the Des-F(6)-Quinolone Garenoxacin (BMS-284756), in Comparison to Those of Ciprofloxacin and Ofloxacin, on Joint Cartilage in Immature Rats

2002 ◽  
Vol 46 (10) ◽  
pp. 3320-3322 ◽  
Author(s):  
Eva Maria Kappel ◽  
Mehdi Shakibaei ◽  
Akintunde Bello ◽  
Ralf Stahlmann
Keyword(s):  
Body Weight ◽  
Peak Plasma ◽  
Joint Cartilage ◽  
Once Daily ◽  
Cartilage Lesions ◽  
Human Risk ◽  
Immature Rats ◽  
Pediatric Use

ABSTRACT We did not observe signs of chondrotoxicity in immature rats treated orally with garenoxacin (BMS-284756) at doses up to five times 600 mg/kg of body weight or with ciprofloxacin, whereas ofloxacin induced typical cartilage lesions. The peak plasma garenoxacin concentration was 25.5 mg/liter after administration of a dose of 600 mg/kg once daily for 5 days. Assuming that this model is predictive of human risk, BMS-284756 and ciprofloxacin should be more suitable for pediatric use than ofloxacin.

scholarly journals Chondrotoxicity and Toxicokinetics of Sparfloxacin in Juvenile Rats

1998 ◽  
Vol 42 (6) ◽  
pp. 1470-1475 ◽  
Author(s):  
Ralf Stahlmann ◽  
Uta Zippel ◽  
Christian Förster ◽  
Rudolf Schwabe ◽  
Mehdi Shakibaei ◽  
...  
Keyword(s):  
Body Weight ◽  
Oral Dose ◽  
Knee Joint ◽  
Species Differences ◽  
Joint Cartilage ◽  
Juvenile Rats ◽  
Cartilage Lesions ◽  
Old Rats ◽  
Immunohistochemical Studies ◽  
Oral Doses

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.

scholarly journals Synergistic Effect of Ofloxacin and Magnesium Deficiency on Joint Cartilage in Immature Rats

2002 ◽  
Vol 46 (6) ◽  
pp. 1755-1759 ◽  
Author(s):  
Edith Lozo ◽  
Kai Riecke ◽  
Rudolf Schwabe ◽  
Jürgen Vormann ◽  
Ralf Stahlmann
Keyword(s):  
Synergistic Effect ◽  
Magnesium Deficiency ◽  
Peak Plasma ◽  
Pediatric Population ◽  
Standard Diet ◽  
Joint Cartilage ◽  
Deficient Diet ◽  
Cartilage Lesions ◽  
Oral Doses ◽  
And Cartilage

ABSTRACT Single high oral doses of fluoroquinolones (e.g., 1,200 mg of ofloxacin/kg of body weight) are chondrotoxic in juvenile rats. Characteristic cartilage lesions are detectable as early as 12 h after treatment. Since this dosing regimen does not reflect the therapeutic situation, we studied the effects of a 5- or 7-day treatment with ofloxacin at lower oral doses (10, 30, and 100 mg/kg twice a day [b.i.d.]) on joint cartilage in 4-week-old rats. We additionally investigated whether the effects of ofloxacin under these conditions are enhanced in animals kept on a magnesium-deficient diet during treatment. Knee joints were examined histologically. The concentrations of ofloxacin and magnesium were determined in plasma and cartilage. The lowest ofloxacin dose at which cartilage lesions occurred in animals on a standard diet was 100 mg/kg b.i.d. for 5 days. Peak plasma ofloxacin levels were approximately 10 mg/liter in these rats and thus were in the same range as the levels in the plasma of humans during therapy with high doses of ofloxacin. Treatment with 30 mg of ofloxacin/kg b.i.d. for 7 days caused no cartilage lesions in rats on a standard diet, but lesions did occur in 10 of 12 rats that were simultaneously fed a magnesium-deficient diet. Magnesium concentrations in bone, plasma, and cartilage from animals on an Mg2+-deficient diet were significantly lower than those in the controls. The concentration in plasma from animals on an Mg2+-deficient diet was 0.27 ± 0.03 mmol/liter, whereas it was 0.88 ± 0.08 mmol/liter in plasma from rats on a standard diet (means ± standard deviations). Ofloxacin treatment did not change the total magnesium concentrations in tissues, as determined with ashed samples. The incidence of ofloxacin-induced lesions was higher in the magnesium-deficient animals, suggesting a synergistic effect. These results must be taken into account for a benefit-risk evaluation if ofloxacin is considered for use in the pediatric population.

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

2007 ◽  
Vol 51 (3) ◽  
pp. 1022-1027 ◽  
Author(s):  
Kerstin Pfister ◽  
Dago Mazur ◽  
Jürgen Vormann ◽  
Ralf Stahlmann
Keyword(s):  
Vitamin E ◽  
Wistar Rats ◽  
Diet Group ◽  
Standard Diet ◽  
Joint Cartilage ◽  
Cartilage Lesions ◽  
Immature Rats ◽  
Group A ◽  
Group B ◽  
Group D

ABSTRACT 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.

Single and repeated testing of growth hormone secretory capacity in hypopituitarism using growth hormone releasing factor

1986 ◽  
Vol 113 (4_Suppl) ◽  
pp. S118-S122 ◽  
Author(s):  
O. BUTENANDT ◽  
M. EMMLINGER ◽  
H. DOERR
Keyword(s):  
Growth Hormone ◽  
Body Weight ◽  
Pituitary Gland ◽  
Bolus Injection ◽  
Hormone Deficiency ◽  
Test Results ◽  
Repeated Testing ◽  
Plasma Growth Hormone ◽  
Once Daily ◽  
Secretory Capacity

Abstract 38 patients with proven growth hormone deficiency (GHD) and 19 children with familial short stature received an iv GRF-bolus injection of 1 ug/kg body weight. Whereas in all control children plasma growth hormone rose significantly (mean of maximal values 36 ng/ml), only 7 out of 38 patients with GHD reached peak values of 8 ng/ml or more. GRF-priming by 1 ug GRF/kg BW given once daily s.c. for 5 days in 19 patients improved the response of the pituitary gland in 11. Thus, following the first GRF test, only 21 % of patients demonstrated function of the pituitary gland whereas 45 % did so when all test results are combined. To evaluate the pituitary function in patients with GHD correctly, GRF tests following a GRF priming period seems to be necessary to reactivate atrophic somatotropic cells of the pituitary gland.

scholarly journals Effect of Oral Gavage Dosing Regimens in Female Tg rasH2 Transgenic Mice

2004 ◽  
Vol 32 (4) ◽  
pp. 413-417 ◽  
Author(s):  
Daniel Morton ◽  
Rani S. Sellers ◽  
Sylvia M. Furst ◽  
Kristen D. Hawley ◽  
Jeffrey R. May
Keyword(s):  
Body Weight ◽  
Incidental Finding ◽  
Sodium Dodecyl ◽  
Control Group ◽  
Oral Gavage ◽  
Once Daily ◽  
Dosing Regimens ◽  
Rash2 Mice ◽  
Daily Water ◽  
Cortical Architecture

Female Tg rasH2 (CB6F1/Jic-TgrasH2@Tac) mice were administered water once daily, water twice daily with 8 or 12 hours between doses, 1% sodium dodecyl sulfate in water (1% SDS) once daily, or 1% SDS twice daily with 12 hours between doses by oral gavage at volumes of 10 ml/kg/day for 28 or 29 consecutive days. A control group of mice received no treatment and no sham manipulation. There were no significant differences in body weight or food consumption between treated groups and untreated control mice. Mean weights of spleens, livers, and thymuses were lower than control values in most groups of mice subjected to gavage. Focal or multifocal loss of thymic cortical architecture was observed in 13 of 50 mice distributed among all groups (including naïve controls), however only in one instance was this finding suggestive of a precursor to neoplasia. This study demonstrated that Tg rasH2 mice can tolerate once or twice daily gavage dosing with water or vehicle containing 1% SDS. Loss of thymic cortical architecture was a common incidental finding in female Tg rasH2 mice.

scholarly journals Lack of Neuropathological Changes in Rats Administered Tedizolid Phosphate for Nine Months

2014 ◽  
Vol 59 (1) ◽  
pp. 475-481 ◽  
Author(s):  
Michael J. Schlosser ◽  
Hiromi Hosako ◽  
Ann Radovsky ◽  
Mark T. Butt ◽  
Dragomir Draganov ◽  
...  
Keyword(s):  
Body Weight ◽  
Optic Nerve ◽  
Body Weight Gain ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Once Daily ◽  
Clinical Observations ◽  
Activity Measures ◽  
Dose Levels ◽  
Neurobehavioral Effects

ABSTRACTTedizolid, a novel oxazolidinone antibacterial, was administered to Long Evans rats by oral gavage once daily for up to 9 months at doses near the maximum tolerated dose (MTD) to evaluate for potential neurotoxicity. Mean plasma exposures of tedizolid at the low-, medium-, and high-dose levels (7.5, 15, and 30 mg/kg of body weight/day for males; 2.5, 5, and 10 mg/kg/day for females) were similar between males and females and were 1.8-, 3.9-, and 8.0-fold greater than exposures in patients at the therapeutic dose (200 mg once daily). Evaluated endpoints included survival, clinical observations, body weight, and food consumption. At 1, 3, 6, and 9 months, ophthalmic examinations, functional observational batteries, and locomotor activity measures were conducted, brain weights/sizes were recorded, and perfusion-fixed tissues were collected from 12 rats/sex/group/time point. A detailed morphological assessment was conducted on brain, eyes, optic nerve/tract, spinal cord, peripheral nerves (includes sciatic, sural, tibial, peroneal, trigeminal), and skeletal muscle. At the end of 9 months, less body weight gain was seen in high-dose males (−6.7%) and females (−5.8%) compared with that seen in controls. There were no tedizolid-related adverse neurobehavioral effects or tedizolid-related histopathologic changes in the central/peripheral nervous systems, including the optic nerve. Results of this study indicate that tedizolid was not neurotoxic when administered long term to pigmented rats at doses near the MTD, which were up to 8-fold higher than the human therapeutic exposure.

Effects of feeding level, season of calving and body weight on performance and carcass traits of Friesian x native calves

1993 ◽  
Vol 1993 ◽  
pp. 213-213
Author(s):  
S T M Fahmy ◽  
H A Hassan ◽  
F M el-Feel ◽  
N H A Morsy
Keyword(s):  
Body Weight ◽  
Rice Straw ◽  
Cotton Seed ◽  
The Body ◽  
Trifolium Alexandrinum ◽  
Once Daily ◽  
Feeding Level ◽  
Concentrate Mixture ◽  
Department Faculty ◽  
Lime Stone

Forty-two weaned calves( Friesian X Native) of 100 Kg body weight were used in this study to estimate the most appropriate feeding level for calves reared under the upper Egypt conditions. The experimental farm of Animal production department, Faculty of Agriculture, El-Minia University, Egypt, was the farm where this work was conducted. Calves (21 males and 21 females) were randomly alloted into three equal groups fed on concentrate mixture (44% wheat bran, 19% yellow maize, 12.5% cotton seed meal, 12.5% cotton seed hulls, 5% extracted rice bran, 4% molasses, 2% lime stone and 1% sodium chloride) and rice straw in quantities that meet 80 , 100 and 120% of the averaged feed standerds (Kellner, 1926; Morrison,1957; T'ommi,19S3; ARC, 1979 and NEC, 1984). Barseem (Trifolium Alexandrinum),the popular green clover was included in the diet to represent 50% of the roughage portion(1 % of the body weigi when it was available. The concentrate mixture was offered twice dail at 10 a.m. and 4 p.m. while rice straw was introduced once daily at 8 a.m. . Water was freely available. The feeding period was extended til the males achieved 400 Kg body weight and slaughtered, while females were kept for breeding.

scholarly journals Once-daily aminoglycoside therapy: potential ototoxicity.

1996 ◽  
Vol 40 (9) ◽  
pp. 2209-2211 ◽  
Author(s):  
C Singer ◽  
C Smith ◽  
D Krieff
Keyword(s):  
Body Weight ◽  
Current Data ◽  
Once Daily ◽  
Aminoglycoside Therapy

Current data indicate that once-daily aminoglycoside therapy is as efficacious as traditional multiple daily dosing and equally or less toxic. Our experience with once-daily gentamicin, 6 mg/kg of body weight led to a 10% (3 of 33 patients) occurrence of documented ototoxicity after prolonged aminoglycoside exposure.

scholarly journals Pharmacokinetics of Stavudine and Didanosine Coadministered with Nelfinavir in Human Immunodeficiency Virus-Exposed Neonates

2001 ◽  
Vol 45 (12) ◽  
pp. 3585-3590 ◽  
Author(s):  
Chokechai Rongkavilit ◽  
Pimolrat Thaithumyanon ◽  
Theshinee Chuenyam ◽  
Bharat D. Damle ◽  
Sompop Limpongsanurak ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Once Daily ◽  
Concentration Time ◽  
Pediatric Dose ◽  
Immunodeficiency Virus ◽  
To Receive

ABSTRACT We evaluated the pharmacokinetics of stavudine (d4T) and didanosine (ddI) in neonates. Eight neonates born to human immunodeficiency virus-infected mothers were enrolled to receive 1 mg of d4T per kg of body weight twice daily and 100 mg of ddI per m2 once daily in combination with nelfinavir for 4 weeks after birth. Pharmacokinetic evaluations were performed at 14 and 28 days of age. For d4T, on days 14 and 28, the median areas under the concentration-time curves from 0 to 12 h (AUC0–12s) were 1,866 and 1,603, ng · h/ml, respectively, and the median peak concentrations (C maxs) were 463 and 507 ng/ml, respectively. For ddI, on days 14 and 28, the median AUC0–10s were 1,573 and 1,562 h · ng/ml, respectively, and the median C maxs were 627 and 687 ng/ml, respectively. Systemic levels of exposure to d4T were comparable to those seen in children, suggesting that the pediatric dose of 1 mg/kg twice daily is appropriate for neonates at 2 to 4 weeks of age. Levels of exposure to ddI were modestly higher than those seen in children. Whether this observation warrants a reduction of the ddI dose in neonates is unclear.

EFFECT OF BOVINE GROWTH HORMONE AND A PARTIALLY PURE PREPARATION OF SOMATOMEDIN ON VARIOUS GROWTH PARAMETERS IN HYPOPITUITARY DWARF MICE

1981 ◽  
Vol 89 (2) ◽  
pp. 275-282 ◽  
Author(s):  
A. T. HOLDER ◽  
E. M. SPENCER ◽  
M. A. PREECE
Keyword(s):  
Body Weight ◽  
Growth Parameters ◽  
Costal Cartilage ◽  
Regression Line ◽  
Tail Length ◽  
Once Daily ◽  
Organ Weights ◽  
Dwarf Mice ◽  
Weight Velocity

The growth-promoting effects of a partially purified preparation of somatomedin (12·7 units/mg) were compared with those of various doses of bovine GH (5, 20 and 80 μg/day) when injected into hypopituitary dwarf mice. Growth parameters studied were body-weight and tail-length velocities (calculated as the slope of a regression line fitted to daily measurements against time), uptake of 35SO2−4 into costal cartilage in vivo and organ weights (heart, liver and kidney). In the first experiment somatomedin (6·4 units/day), bovine GH and 0·9% NaCl were injected once daily in a volume of 0·1 ml for 10 days. Treatment with bovine GH promoted a significant dose-dependent increase in body-weight and tail-length velocities and 35SO2−4 uptake into costal cartilage in vivo. Somatomedin also promoted a significant increase in body-weight velocity and 35SO2−4 uptake, both responses were between that observed with the lowest dose of bovine GH and control values. Somatomedin did not promote increase in tail-length velocity. Organ weights did not differ significantly between any of the treatment groups when expressed as mg/g body weight. In the second experiment somatomedin (a daily total of 21·6 units/day) and 0·9% NaCl were injected three times per day in a volume of 0·033 ml, bovine GH was again injected once daily in a volume of 0·1 ml, and the treatment period was 12 days. As in the first experiment all doses of bovine GH and somatomedin promoted a significant increase in body-weight velocity. These results are consistent with the somatomedin hypothesis.

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