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1.
The concentration-effect relationships of phenylbutazone, indomethacin, betamethasone, pentosan polysulphate (PPS) and polysulphated glycosaminoglycan (PSGAG), on proteoglycan synthesis by equine cultured chondrocytes grown in monolayers, and articular cartilage explants were measured. The effect of PSGAG on interleukin-1beta induced suppression of proteogycan synthesis was also investigated. Proteoglycan synthesis was measured by scintillation assay of radiolabelled sulphate (35SO4) incorporation. Polysulphated glycosaminoglycan and PPS stimulated proteoglycan synthesis in chondrocyte monolayers in a concentration-related manner with maximal effects being achieved at a concentration of 10 microg/mL. Polysulphated glycosaminoglycan reversed the concentration-related suppression of proteoglycan synthesis induced by interleukin-1beta. Neither PSGAG nor PPS exerted significant effects on radiolabel incorporation in cartilage explants. Betamethasone suppressed proteoglycan synthesis by both chondrocytes and explants at high concentrations (0.1-100 microg/mL), but the effect was not concentration-related. At low concentrations (0.001-0.05 microg/mL) betamethasone neither increased nor decreased proteoglycan synthesis. Phenylbutazone and indomethacin increased radiolabel incorporation in chondrocyte cultures but not in cartilage explants at low (0.1, 1 and 10 microg/mL), but not at high (20 and 100 microg/mL) concentrations. These findings may be relevant to the clinical use of these drugs in the treatment of equine disease.  相似文献   

2.
OBJECTIVE: To evaluate the effects of orally administered phenylbutazone on proteoglycan synthesis and chondrocyte inhibition by IL-1beta in articular cartilage explants of horses. ANIMALS: 11 healthy 1- to 2-year-old horses. PROCEDURE: Horses were randomly assigned to the control (n = 5) or treated group (4.4 mg of phenylbutazone/kg of body weight, p.o., q 12 h; n = 6). Articular cartilage specimens were collected before treatment was initiated (day 0), after 14 days of treatment, and 2 weeks after cessation of treatment (day 30). Proteoglycan synthesis and stromelysin concentration in cartilage extracts were assessed after 72 hours of culture in medium alone or with recombinant human interleukin-1beta (IL-1beta; 0.1 ng/ml). RESULTS: On day 0, proteoglycan synthesis was significantly less in cartilage explants cultured in IL-1beta, compared with medium alone. Mean proteoglycan synthesis in explants collected on days 14 and 30 was significantly less in treated horses, compared with controls. However, incubation of explants from treated horses with IL-1beta did not result in a further decrease in proteoglycan synthesis. Significant differences in stromelysin concentration were not detected between or within groups. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of phenylbutazone for 14 days significantly decreased proteoglycan synthesis in articular culture explants from healthy horses to a degree similar to that induced by in vitro exposure to IL-1beta. Phenylbutazone should be used judiciously in athletic horses with osteoarthritis, because chronic administration may suppress proteoglycan synthesis and potentiate cartilage damage.  相似文献   

3.
OBJECTIVE: To study the effect of polysulfated glycosaminoglycan (PSGAG) on proteoglycan metabolism and DNA content of control and osteoarthritic (OA) cartilage. STUDY DESIGN: An in vitro study comparing the effects of PSGAG on articular cartilage explants from canine stifle joints with and without chronic OA after transection of the left cranial cruciate ligament. SAMPLE POPULATION: Five large cross-breed dogs. METHODS: Cartilage explants (6 to 13 per treatment group) from the medial side of the femoral trochlea and medial femoral condyle from both stifles of each dog were incubated in a defined medium containing 0, 0.05, 0.5, or 5 mg/mL of PSGAG. After 72 hours in culture, explants were pulsed for 6 hours with sodium [35S]sulfate. Aminophenylmercuric acetate (APMA) was used to activate endogenous neutral matrix metalloproteinases (MMPs) and induce proteoglycan degradation in the radiolabeled explants. DNA content and radioactivity were measured in papain-digested explants, and radioactivity was measured in the medium by liquid scintillation counting. Proteoglycan synthesis and degradation were calculated. Cartilage was examined histologically for signs of OA. A mixed model analysis of variance and linear contrasts were used to test for significant (P < .05) effects of OA and treatment with PSGAG. RESULTS: Transection of the cranial cruciate ligament produced OA in operated joints. DNA content and proteoglycan synthesis of OA cartilage were significantly lower than in cartilage from control joints. For both DNA content and proteoglycan synthesis, significant interactions occurred between the concentration of PSGAG and whether the articular cartilage was from OA or control joints. The two lower concentrations of PSGAG (0.05 and 0.5 mg/mL) predominantly increased DNA content in OA cartilage (7 and 18%, respectively, compared with 0 mg/mL PSGAG) while the highest concentration (5 mg/mL) predominantly increased DNA content in control cartilage (30% compared with 0 mg/mL PSGAG). PSGAG at .05 mg/mL predominantly decreased proteoglycan synthesis in OA cartilage (19% reduction compared with 0 mg/mL PSGAG) while PSGAG at .5 and 5 mg/mL predominantly decreased proteoglycan synthesis in control cartilage (17 and 55% reduction, respectively, compared with 0 mg/mL PSGAG). Following activation of MMPs, PSGAG caused a dose-dependent decrease in degradation of radiolabeled proteoglycan in both OA and control cartilage. CONCLUSIONS: OA cartilage was responsive to treatment with PSGAG at 100-fold lower concentration than control cartilage. When treated with PSGAG, articular cartilage explants maintained or increased DNA content at the expense of proteoglycan synthesis. Following MMP activation, proteoglycan degradation was inhibited in OA and control explants in a dose-dependent manner. CLINICAL RELEVANCE: If the results of this study extend to in vivo use, treatment with PSGAG may modify the progression of OA in articular cartilage by maintaining chondrocyte viability or stimulating chondrocyte division as well as protecting against extracellular matrix degradation.  相似文献   

4.
Articular cartilage explants from 3 horses were maintained in tissue culture to test the effects of a polysulfated glycosaminoglycan on proteoglycan biosynthesis. Cultures were exposed to concentrations of 0, 50, or 200 micrograms of the drug/ml for either 2 days or 6 days, and labeled with 35S, before measuring the content of sulfated proteoglycan in the culture media and in extracts of cartilage. In a second experiment, the explants were incubated with the isotope and subsequently exposed to the same concentrations of the polysulfated glycosaminoglycan for 4 days. Subsequently, the amount of remaining labeled proteoglycan was determined. Gel filtration chromatography was used to compare the hydrodynamic size of proteoglycans from the cartilage explants in each experiment. Polysulfated glycosaminoglycan caused a dose-dependent depression of sulfated proteoglycan synthesis, which was statistically significant after 6 days of exposure. Radioactive proteoglycan content in explants was similar in the experiment involving isotopic labeling prior to exposure to the drug. Proteoglycan monomer size was similar in all treatment groups. It was concluded that polysulfated glycosaminoglycan caused a modest depression in proteoglycan synthesis, had little effect on endogenous proteoglycan degradation, and did not influence the size of sulfated proteoglycans synthesized by normal equine chondrocytes in explant culture.  相似文献   

5.
OBJECTIVE: To study in vitro (1) the dose-response relationships between proteoglycan metabolism in normal and corticosteroid-treated articular cartilage; (2) long-term proteoglycan metabolism after treatment of articular cartilage with corticosteroids; and (3) the effect of corticosteroids on proteoglycan metabolism in articular cartilage treated with monocyte-conditioned medium (MCM). STUDY DESIGN: Equine and canine articular cartilage explants were treated with corticosteroids and MCM. Proteoglycan synthesis and degradation were measured by radioactive labeling in short-term culture, and the long-term effect of corticosteroid treatment on proteoglycan metabolism was studied in normal explants. ANIMALS: Two young cross-breed horses and 3 young Labrador retrievers. METHODS: Equine articular cartilage explants were incubated in medium containing methylprednisolone sodium succinate (MPS) at 0, .001, .01, .1, 1, and 10 mg/mL (final concentration) for 1 day and then in fresh medium without MPS. Proteoglycan synthesis was measured by incorporation of sodium [35S]sulfate at 1, 3, 7, 10, and 13 days after initial treatment with MPS. Proteoglycan release was measured from separate explants prelabeled with sodium [35S]sulfate and treated similarly. Equine articular cartilage explants were treated with equine MCM simultaneously with, and 24 hours before MPS, at 0, 0.01, 0.1, 1, or 5 mg/mL for 72 hours. Proteoglycan synthesis and degradation in these explants was compared. Proteoglycan synthesis and degradation were measured similarly in canine articular cartilage explants treated simultaneously with canine MCM and MPS at 0, 0.001, 0.01, 0.1, 1 and 10 mg/mL for 72 hours. Equine articular cartilage explants treated with 0, 0.01, 0.1, 1, and 5 mg/mL of MPS for 72 hours were evaluated histologically. RESULTS: Proteoglycan synthesis in normal equine articular cartilage was severely depressed by 10 mg/mL MPS for 24 hours, and proteoglycan synthesis failed to recover after 13 days of culture in medium without MPS. Cartilage treated with 5 mg/mL MPS had pyknotic chondrocyte nuclei and empty lacunae. Concentrations of 1 and 0.1 mg/mL MPS depressed proteoglycan synthesis in normal equine cartilage explants. For these 2 concentrations, proteoglycan synthesis recovered 2 days after MPS removal and increased significantly (P < .05) 7 days after treatment with MPS compared with controls without MPS. Concentrations of 0.001 and 0.01 mg/mL MPS did not significantly affect proteoglycan synthesis in normal equine cartilage explants. Cumulative proteoglycan loss over 13 days in culture from normal equine explants treated for 24 hours with different concentrations of MPS was not significantly different between treatment groups at any time point. MCM significantly depressed proteoglycan synthesis in both canine and equine articular cartilage explants and significantly increased proteoglycan release. These effects were prevented in the canine explants by simultaneous treatment with MPS at 1 and 0.1 mg/mL, and proteoglycan release induced by MCM in equine articular cartilage was inhibited by 1 mg/mL MPS. CONCLUSIONS: Concentrations of 1.0 and 0.1 mg/mL MPS alleviated articular cartilage degradation in MCM-treated articular cartilage in vitro. These concentrations of MPS in contact with normal cartilage explants for 24 hours are unlikely to be detrimental in the long term to proteoglycan synthesis. The response of articular cartilage to MPS was affected by treatment with MCM so that results of experiments with normal articular cartilage explants may not reflect results obtained with abnormal cartilage. CLINICAL RELEVANCE: It may be possible to find an intraarticular concentration of corticosteroid that protects articular cartilage against cytokine-induced matrix degradation yet not have prolonged or permanent detrimental effects on chondrocyte matrix synthesis.  相似文献   

6.
OBJECTIVE: To compare the inhibitory effects of glucosamine and mannosamine on articular cartilage degradation and the effects on chondrocyte viability in vitro. SAMPLE POPULATION: Bovine articular cartilage explants. PROCEDURES: Explants were cultured in commercial medium for 48 hours. Cartilage was exposed to medium containing 10% fetal bovine serum, 10 microg of lipopolysaccharide/mL, and 0.5, 1.0, 2.5, 5.0, and 10.0 mg of glucosamine or mannosamine/mL for 24 hours. Nitric oxide (NO) production (nitrite concentration) and proteoglycan (PG) release (PG concentration) in media were measured. Cartilage extracts were analyzed via zymography to detect gelatinolytic activity. At the end of the experiment, explants were assessed for chondrocyte viability. RESULTS: Addition of lipopolysaccharide resulted in increased NO production and PG release, but no increase in gelatinolytic activity, compared with controls. Glucosamine and mannosamine at concentrations as low as 0.5 mg/mL inhibited NO production. Glucosamine inhibited PG release at a minimum concentration of 1.0 mg/mL, whereas mannosamine inhibited PG release at a concentration of 0.5 mg/mL. Concentrations of glucosamine < or = 5.0 mg/mL did not adversely affect chondrocyte viability; however, at a concentration of 10.0 mg/mL, cell death was evident. Mannosamine had a toxic effect at a concentration of 5.0 mg/mL and was associated with pronounced chondrocyte death at a concentration of 10.0 mg/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Glucosamine and mannosamine inhibit selected indices of bovine articular cartilage degradation at concentrations that do not affect chondrocyte viability. The potential for cytotoxic effects at higher concentrations underscores the importance of establishing appropriate dosage regimens for these aminomonosaccharides.  相似文献   

7.
Background: Intravenous administration of human immunoglobulin G (hIVIgG) has been suggested to potentiate thromboembolism in dogs, but supportive scientific reports are lacking.
Objectives: To determine if hIVIgG therapy promotes hypercoagulability and inflammation in dogs.
Animals: Twelve healthy Beagle dogs.
Methods: Prospective, experimental trial. An hIVIgG/saline solution was infused IV at 1 g/kg BW over 8 hours to 6 dogs, and physiological saline was infused to the other 6 dogs. Blood samples were drawn before, during, and after infusion for serial measurement of indicators of coagulation and inflammation. Data were analyzed by 2-way repeated measures analysis of variance.
Results: Dogs administered hIVIgG developed mildly decreased blood platelet concentrations without thrombocytopenia (median, 200 × 103/μL; range, 150–302 × 103/μL; P < .01), leukopenia (median, 3.5 × 103/μL; range, 20–62 × 103/μL; P < .001), and mildly increased plasma total protein concentrations (median, 6.3 g/dL; range, 5.6–6.7 g/dL; P < .001). Administration of hIVIgG was also associated with increases in fibrin/fibrinogen degradation products in all dogs (either 5 μg/mL or 10 μg/dL), thrombin-antithrombin III complexes (median, 7.2 ng/mL; range, 4.9–14.2 ng/mL; P < .001), and C-reactive protein concentrations (median, 2.5 mg/dL; range, 0.5–4.3 mg/dL; P < .01).
Conclusion and Clinical Importance: Administration of hIVIgG to dogs promotes hypercoagulability and an inflammatory state. This should be further evaluated and considered when using hIVIgG in dogs with IMHA or other prothrombotic conditions.  相似文献   

8.
OBJECTIVE: To evaluate the effects of dimethyl sulfoxide (DMSO) on equine articular cartilage matrix metabolism. STUDY DESIGN: Using a cartilage explant culture system, proteoglycan (PG) synthesis, PG release, lactate metabolism, chondrocyte viability, and metabolism recovery were determined after cartilage exposure to DMSO. SAMPLE POPULATION: Cartilage harvested from metacarpophalangeal and metatarsophalangeal joints of 12 horses (age range, 1 to 10 years). METHODS: Explants were exposed to concentrations of DMSO (1% to 20%) for variable times (3 to 72 hours). PG synthesis and release were determined by a radiolabel incorporation assay and dimethylmethylene blue (DMMB) dye assay, respectively. Lactate released into culture media was measured, and chondrocyte viability was assessed using the Formizan Conversion Assay and a paravital staining protocol. Metabolism recovery was assessed in explants that were allowed to recover in maintenance media after exposure to DMSO. RESULTS: PG synthesis and lactate metabolism were inhibited in a dose- and time-dependent manner after exposure to DMSO concentrations > or = 5%; there was no significant alteration in PG release. No change in chondrocyte viability was detected after incubation with DMSO. PG synthesis and lactate metabolism returned to baseline rates when allowed a recovery period after exposure to DMSO. CONCLUSIONS: DMSO concentrations > or = 5% suppress equine articular cartilage matrix metabolism. Suppression of PG synthesis and lactate metabolism is reversible and does not appear to be the result of chondrocyte death. CLINICAL RELEVANCE: Equine clinicians adding DMSO to intraarticular lavage solutions should be aware that DMSO may have deleterious effects on equine articular cartilage matrix metabolism.  相似文献   

9.
Cimetidine was administered intravenously and by the intragastric route to six mares at a dose of 4.0 mg/kg of body weight (bw). Specific and sensitive high performance liquid chromatographic methods for the determination of cimetidine in horse plasma and urine and cimetidine sulfoxide in urine are described. Plasma cimetidine concentration vs. time data were analysed by non-linear least squares regression analysis to determine pharmacokinetic parameter estimates. The median (range) plasma clearance (Cl) was 8.20 (4.96–10.2) mL/min.kg of body weight, that of the steady-state volume of distribution (Vdss) was 0.771 (0.521–1.15) L/kg bw, and that of the terminal elimination half-life ( t ½β) was 92.4 (70.6–125) minutes. The median (range) renal clearance of cimetidine was 4.08 (2.19–6.23) mL/min.kg bw or 55.4 (36.3–81.8)% of the corresponding plasma clearance. Cimetidine sulfoxide was excreted in urine and its urinary excretion through 8 h accounted for 12.0 (9.8–16.6)% of the plasma clearance of cimetidine. The median (range) extent of intragastric bioavailability was 14.4 (6.82–21.8)% and the maximum plasma concentration after intragastric administration was 0.31 (0.24–0.50) μg/mL.
Intravenous cimetidine had no effect on the disposition of intravenous phenylbutazone or its metabolites except that the maximum plasma concentration of γ-hydroxyphenylbutazone was less after cimetidine treatment.  相似文献   

10.
OBJECTIVE: To determine whether enrofloxacin has detrimental, dose-dependent effects on equine articular cartilage in vitro. ANIMALS: Cartilage explants were developed from 6 healthy horses between 0 and 96 months old. PROCEDURE: Patellar cartilage explants were incubated in 5 concentrations of enrofloxacin (2 microg/ml, 10 microg/ml, 1,000 microg/ml, 10,000 microg/ml, and 50,000 microg/ml) for 72 hours. Proteoglycan synthesis (Na35SO4 incorporation for 24 hours), proteoglycan degradation (Na35SO4 release for 72 hours), endogenous proteoglycan content (dimethylmethlene blue assay), and total protein content were determined. Cartilage explants were evaluated by use of histomorphologic and histomorphometric techniques (toluidine blue stain) for cytologic and matrix characteristics. Quantitative data were analyzed with a one-way ANOVA to compare results among various enrofloxacin concentration groups and the control group. A general linear model was used to determine whether age had an effect. RESULT: Proteoglycan synthesis was excellent in control specimens and in specimens incubated in low concentrations of enrofloxacin (2 microg/ml and 10 microg/ml). High concentrations of enrofloxacin (> 1,000 microg/ml) effectively eliminated proteoglycan synthesis regardless of horse age. Proteoglycan degradation at low concentrations (2 microg/ml and 10 microg/ml) was not different than control. High concentrations of enrofloxacin (> 1,000 microg/ml) caused significant degradation. Different concentrations of enrofloxacin did not affect endogenous proteoglycan. High concentrations of enrofloxacin were associated with a significant increase in number of pyknotic nuclei. CONCLUSION: Concentrations of enrofloxacin that might be achieved following systemic administration did not suppress chondrocyte metabolism in vitro. High concentrations of enrofloxacin (> 1,000 microg/ml) were toxic to chondrocytes.  相似文献   

11.
Background: A liquid solution of levothyroxine (L-T4) is available for treatment of canine hypothyroidism.
Hypothesis: Once daily oral administration of a liquid L-T4 solution is effective and safe for controlling hypothyroidism in dogs.
Animals: Thirty-five dogs with naturally occurring hypothyroidism.
Methods: Dogs received L-T4 solution PO once daily at a starting dosage of 20 μg/kg body weight (BW). The dose was adjusted every 4 weeks, based on clinical signs and peak serum total T4 (tT4) concentrations. Target peak serum tT4 and thyroid stimulating hormone (TSH) concentrations, 4–6 hours posttreatment, were 35–95 nmol/L and < 0.68 ng/mL, respectively. Dogs were followed for up to 22 weeks after establishment of the maintenance dose.
Results: Clinical signs of hypothyroidism improved or resolved in 91% of dogs after 4 weeks of L-T4 treatment at 20 μg/kg once daily. The maintenance dose was established in 76, 94, and 100% of dogs after 4, 8, and 12 weeks of treatment, respectively. This was 20 μg L-T4/kg BW for 79% of the dogs, 30 μg/kg BW for 15%, and 10–15 μg/kg BW in the remaining 6%, once daily. Thereafter, median peak tT4 and TSH concentrations were 51 nmol/L and 0.18 ng/mL, respectively, and remained stable during the 22-week follow-up; clinical signs did not recur.
Conclusions and Clinical Importance: All of the hypothyroid dogs had rapid clinical and hormonal responses to supplementation with the PO-administered L-T4 solution. The starting dosage of 20 μg L-T4/kg BW once daily was suitable for 79% of dogs.  相似文献   

12.
NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine, as in human, patients receiving these drugs for treatment of pain in osteoarthritis and other acute and chronic painful conditions. To determine the potential effects of the new NSAID meloxicam on cartilage integrity, the effects of this drug on proteoglycan biosynthesis in vitro and ex vivo were compared with those of indomethacin, a known inhibitor of sulphated proteoglycans that accelerates joint injury in human osteoarthritis.In vitro cartilage proteoglycan synthesis from a radiosulphate precursor was unaffected by 0.5–10.0 mol/L meloxicam but was significantly inhibited by 50 mol/L indomethacin after 6 or 24 h incubation of femoral or tibial cartilage explants in organ culture. This is in accord with previous observations in human or porcine articular cartilage under the same culture conditions.Studies were performed in vivo to establish the effects of the NSAIDs on joint integrity. This involved determining cartilage proteoglycan synthesis ex vivo, leukocyte, fluid and protein accumulation, as well as pain relief. Thus, meloxicam (0.2 mg/kg i.v.×3 doses) or indomethacin (0.5 mg/kg i.v.×3 doses) was given for 26 h and the effects were compared with a control (1.0 ml saline i.v.×3 doses) in dogs in which acute inflammation had been induced by intra-articular (i.a.) injection of calcium pyrophosphate dihydrate (CPPD) crystals into the right stifle joint, an equivalent volume of saline being injected into the left stifle joint as a control. No effects were observed of the treatment with the NSAIDs on ex vivo sulphated proteoglycan synthesis. The lack of the expected inhibitory effects of indomethacin may be related to the relatively low plasma concentrations of this drug obtained during the 26 h period of treatment.The pain response, which was elicited up to 6 h following i.a. injection of CPPD crystals, was totally prevented by the treatment with meloxicam and to a lesser extent with indomethacin. There were no effects from the drug treatment on synovial inflammatory reactions (fluid and cell accumulation), although the protein concentration of the exudate was reduced by meloxicam. This indicates that, at the doses given, it was possible to discriminate the analgesic action from the anti-inflammatory action of the two NSAIDs, this being achieved at relatively low plasma concentrations of these drugs.In conclusion, while relatively high therapeutic concentrations of indomethacin inhibit cartilage proteoglycan synthesis, this is not an effect seen even at high concentrations of meloxicam. Furthermore, the lack of effects on proteoglycan synthesis was evident when these two drugs were given in vivo to dogs. However, the signs of pain, but not the inflammation in the joint, were relieved by low plasma concentrations of the drugs. Meloxicam may thus be safely employed for acute analgesia without the potential risks of joint cartilage damage that occurs with indomethacin given at anti-inflammatory doses for long periods of time.  相似文献   

13.
Fifty-one isolates of Corynebacterium equi recovered from pigs and horses belonging to two capsular serotypes were tested for susceptibility to antimicrobial agents. No clear differences were detected in sensitivity between isolates of different sources or serotypes. All isolates were sensitive to <0.25 μg/ml of erythromycin and gentamicin. The following minimum inhibitory concentrations (MICs) of antimicrobial agents were determined for ≤90% of isolates: methicillin >16 μg/ml, clindamycin 1–2 μg/ml, tobramycin ≤1 μg/ml, cephalothin 8–64 μg/ml, kanamycin 2–8 μg/ml, amikacin ≤1–2 μg/ml, penicillin 2–≤4 μg/ml, ampicillin 2–8 μg/ml, trimethoprim-sulfa 4/76–32/608 μg/ml tetracycline 1–4 μg/ml and chloramphenicol 8–16 μg/ml.  相似文献   

14.
Objective— To report the minimum inhibitory concentration (MIC) of amikacin sulfate for equine clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and characterize the initial kill and duration of the postantibiotic effect (PAE) for selected strains.
Study Design— Experimental study.
Methods— Isolates of MRSA (n=35) had their amikacin MIC determined using the E-test agar diffusion method. Two isolates with MICs>256 μg/mL limit were further characterized using broth macrodilution. Six distinct isolates with amikacin MICs of 32, 48, 128 (2 isolates) and 500 (2 isolates) μg/mL had PAE determinations made over a range of amikacin concentrations from 31.25–1000 μg/mL using standard culture-based techniques.
Results— Median MIC of the 35 isolates was 32 μg/mL (range 2 to >256 μg/mL). Mean PAE of selected MRSA strains had an overall mean (all amikacin doses) of 3.43 hours (range 0.10–9.57 hours). PAE for MRSA exposed to amikacin at 1000 μg/mL was 6.18 hours (range 3.30–9.57 hours), significantly longer than that for all other concentrations ( P <.0001). There was no statistically significant effect of isolate MIC on PAE.
Conclusions— Isolates had a wide range of MIC; however, growth of all 6 selected strains were inhibited within the range of concentrations tested, including 2 strains with MICs of 500 μg/mL. PAE duration was not influenced by the MIC of amikacin but was significantly longer with treatment at 1000 μg/mL than at lower concentrations.
Clinical Relevance— Clinical isolates of MRSA are susceptible to amikacin at concentrations achieved by regional perfusion: however, the modest duration of PAE observed suggest that further laboratory and in vivo evaluation be conducted before recommending the technique for clinical use.  相似文献   

15.
Nine male dogs (10.3–13.5 kg body weight) were randomly assigned to three groups of three dogs each and administered ceftiofur sodium subcutaneously as a single dose of 0.22, 2.2, or 4.4 mg ceftiofur free acid equivalents/kg body weight. Plasma and urine samples were collected serially for 72 h and assayed for ceftiofur and metabolites (derivatized to desfuroylceftiofur acetamide) using high-performance liquid chromatography. Urine concentrations remained above the MIC 90 for Escherichia coll (4.0 μg/mL) and Proteus mirabilis (1.0 μg/mL) for over 24 h after doses of 2.2 mg/kg (8.1 μg/mL) and 4.4 mg/kg (29.6 μg/mL), the interval between treatments for ceftiofur sodium in dogs, whereas urine concentrations 24 h after dosing at 0.22 mg/kg (0.1 mg/Ib) were below the MIC 90 for E.coli and P. mirabills (0.6 μg/mL). Plasma concentrations were dose-proportional, with peak concentrations of 1.66 ± 0.0990 μg/mL, 8.91 ± 6.42 μg/mL, and 26.7 ± 1.07 μg/mL after doses of 0.22, 2.2, and 4.4 mg/kg, respectively. The area under the plasma concentration versus time curve, when normalized to dose, was similar across all dosage groups.  相似文献   

16.
Cefixime is a unique third-generation oral cephalosporin. Its in vitro activity and pharmacokinetic properties have been studied to assess its potential for use in the therapy of newborn calf infections due to gram-negative bacteria. The minimum inhibitory concentrations of cefixime for 90% (MIC50) of field isolates of Escherichia coli. Salmonella and Pasteurella were 0.10–0.40 μg/mL. The serum disposition kinetics of cefixime following intravenous and oral administration was evaluated. The elimination half-life of cefixime after intravenous and oral administration was 3.5–4.0 h, the steady-state volume of distribution was 0.34 L/kg and approximately 90% of the drug was bound to serum proteins. Oral absorption was comparatively slow and bioavailability values for single 5 mg/kg doses were 20.2% after the administration of 200 mg of cefixime in capsules, 28.3% after dosing an aqueous solution of cefixime and 35.7% after fasted calves received the solution of cefixime. Mean serum drug concentrations 12 h after the cefixime solution was administered orally (5 mg/kg) were 1.05 μg/mL for the milk-fed calves and 1.76 μg/mL for the fasted calves. Computations showed that mean free drug concentrations equal to the MIC50 of the drug for gram-negative pathogens associated with newborn calf infections can be maintained in tissues by multiple treatments at 5 mg/kg every 12 h or 10 mg/kg every 24 h.  相似文献   

17.
The effect of human recombinant insulin-like growth factor 1 (rhIGF-1) on proteoglycan (PG) metabolism of full thickness equine articular cartilage explants was investigated. PG synthesis was stimulated at all ages, but higher concentrations of rhIGF-1 were required for maximal stimulation of adult cartilage. There were no changes in the hydrodynamic size, electrophoretic heterogeneity or composition of proteoglycans isolated from rhIGF-1-stimulated cartilage. rhIGF-1 reduced the rate of turnover of both newly synthesized and endogenous proteoglycans in all ages of cartilage investigated. The structure of proteoglycan fragments retained within the matrix and those released into the culture medium was unaffected by IGF-1 stimulation, suggesting that this peptide is a key regulator of the proteoglycan composition of equine articular cartilage extracellular matrix.  相似文献   

18.
The aim of this study was to determine the in vitro antifungal activity of several antifungal drugs (posaconazole, nystatin, miconazole and clotrimazole) against Malassezia pachydermatis with microdilution and agar dilution techniques. Malassezia pachydermatis isolates were obtained from the skin and ears of dogs. Tests on solid media were performed using 25-well Petri dishes (2 mL/well containing Sabouraud's dextrose agar and diluted antifungal drug) inoculated with 5 μL suspensions of M. pachydermatis . Microtitre broth dilution used 96-well microtitre plates containing Sabourauds dextrose broth and appropriate dilutions of antifungal drugs, inoculated with 10 μL standard suspensions of M. pachydermatis . Plates were inoculated in duplicate and incubated at 30°C for 5 days and growth assessed. The four antifungal drugs were tested in 10 dilutions (4.0-0.007 μg/mL for posaconazole, and 32--0.06 μg/mL for clotrimazole, miconazole and nystatin). Results obtained for 83 strains of M. pachydermatis and a control reference strain (CBS 1879) exhibited the same pattern. Results of the MIC between microtitre and agar methodologies showed no significant differences (≤ 2-fold) across all drugs. For both solid and liquid methods, posaconazole was the most effective antifungal drug of the four tested with MIC90 of 1–2 μg/mL for posaconazole, 16–32 μg/mL for clotrimazole, and ≥ 32 μg/mL for miconazole and nystatin.
Funding: Schering-Plough.  相似文献   

19.
Clinical mastitis in dairy cows is commonly treated with intramammary (IMM) antimicrobial agents. Pharmacokinetic data are used to design treatment regimens and determine withholding times. In some pharmacokinetic studies, investigators measure antimicrobial concentrations in foremilk, whereas in others, they use bucket milk or do not specify the milk fraction sampled. Our objective was to compare antimicrobial concentrations in foremilk, bucket milk, and strippings after IMM treatment of six healthy Holsteins. One mammary gland/cow was infused with 200 mg of cephapirin (CEPH) after each of the two milkings, using different milking frequencies and treatment intervals in a randomized crossover design. Treated glands were sampled at the first milking following each infusion. Antimicrobial concentrations in milk were measured using HPLC/MS/MS. CEPH concentration was higher in foremilk (geometric mean 44.2 μg/mL) than in bucket milk (15.7 μg/mL) or strippings (18.5 μg/mL), as it was true for desacetylcephapirin (DAC) (59.5, 23.0, and 30.2 μg/mL, respectively). This finding, which was based on milk samples collected at the first milking after IMM infusion, suggests that pharmacokinetic data based on drug concentrations in foremilk may be misleading. Strippings were more representative of bucket milk than foremilk. The relationship between milk fraction and antimicrobial concentration should be investigated for other IMM antimicrobial agents. Meanwhile, it is essential that pharmacokinetic and residue studies report the fraction of milk that was analyzed.  相似文献   

20.
Plasma concentrations of doramectin in 40 cattle dosed by subcutaneous (sc) or intramuscular (i.m.) injection (200 μg/kg) were compared to assess the bioequivalence of the two routes of administration. Peak concentration ( C max), and areas under the concentration curve ( AUC0– ) were determined from plasma concentrations. Animals treated by the sc route showed a mean AUC0– of 457 ± 66 ng±day/mL (± SD) and a mean C max of 27.8 ± 7.9 ng/mL. Results from the i.m. treatment group showed a mean AUC 0– of 475 ± 82 ng-day/mL and a mean C max of 33.1 ± 9.0 ng/mL Absorption constants ( k a) determined by modelling were 0.542 ± 0.336 day-1after sc administration and 0.710 ± 0.357 day-1after i.m. administration. The 90% confidence limits on the difference between mean AUC 0– values for the sc and i.m. groups fell within 20% of the mean value for the subcutaneous group. C max was somewhat greater for the i.m. route. The 90% confidence limits on the difference in mean In ( T max+1) also fell within 20% of the mean sc value. Based on this analysis, bioequivalence of the sc and i.m. formulation has been established.  相似文献   

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