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1.
Benzimidazole anthelmintics have reported anti‐neoplastic effects both in vitro and in vivo. The purpose of this study was to evaluate the in vitro chemosensitivity of three canine glioma cell lines to mebendazole and fenbendazole. The mean inhibitory concentration (IC50) (±SD) obtained from performing the MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assay after treating J3T, G06‐A, and SDT‐3G cells for 72 h with mebendazole were 0.030 ± 0.003, 0.080 ± 0.015 and 0.030 ± 0.006 μM respectively, while those for fenbendazole were 0.550 ± 0.015, 1.530 ± 0.159 and 0.690 ± 0.095 μM; treatment of primary canine fibroblasts for 72 h at IC50 showed no significant effect. Immunofluorescence studies showed disruption of tubulin after treatment. Mebendazole and fenbendazole are cytotoxic in canine glioma cell lines in vitro and may be good candidates for treatment of canine gliomas. Further in vivo studies are required.  相似文献   

2.
Canine osteosarcoma is an aggressive cancer, comprising 85% of canine bone neoplasms. Current treatment practices of surgery and chemotherapy increase 1-year survival by only 45%. The curcumin analogue RL71, has demonstrated potent in vitro and in vivo efficacy in several models of human breast cancer through increased apoptosis and cell cycle arrest. Thus, the present study aimed to investigate efficacy of curcumin analogues in two canine osteosarcoma cell lines. Osteosarcoma cell viability was assessed using the sulforhodamine B assay and mechanisms of action were determined by analysing the levels of cell cycle and apoptotic regulatory proteins via Western blotting. Further evidence was obtained using flow cytometry to detect cell cycle distribution and the number of apoptotic cells. RL71 was the most potent curcumin analogue with EC50 values of 0.64 ± 0.04 and 0.38 ± 0.009 μM (n = 3) in D-17 (commercial) and Gracie canine osteosarcoma cells, respectively. RL71 significantly increased the ratio of cleaved-caspase 3 to pro-caspase 3 and the level of apoptotic cells at the 2× and 5× EC50 concentration (p < 0.001, n = 3). Furthermore, at the same concentration, RL71 significantly increased the number of cells in the G2/M phase. In conclusion, RL71 has potent cytotoxic activity in canine osteosarcoma cells triggering G2/M arrest and apoptosis at concentrations achievable in vivo. Future research should further investigate molecular mechanisms for these changes in other canine osteosarcoma cell lines prior to in vivo investigation.  相似文献   

3.
Flavonoids are a group of modified triphenolic compounds from plants with medicinal properties. Baicalein, a specific flavone primarily isolated from plant roots (Scutellaria baicalensis), is commonly used in Eastern medicine for its anti‐inflammatory and antineoplastic properties. Previous research shows greater efficacy for baicalein than most flavonoids; however, there has been little work examining their effects on sarcoma cells, let alone canine cells. Three canine osteosarcoma cell lines (HMPOS, D17 and OS 2.4) were treated with baicalein to examine cell viability, cell cycle kinetics, anchorage‐independent growth and apoptosis. Results showed that osteosarcoma cells were sensitive to baicalein at concentrations from approximately 1 to 25 μM. Modest cell cycle changes were observed in one cell line. Baicalein was effective in inducing apoptosis and did not prevent doxorubicin cell proliferation inhibition in all the cell lines. The mechanism for induction of apoptosis has not been fully elucidated; however, changes in mitochondrial permeability supersede the apoptotic response.  相似文献   

4.
Background: Critically ill horses are susceptible to thrombotic disease, which might be related to increased platelet reactivity and activation. Objectives: To compare the effect of oral clopidogrel and aspirin (ASA) on equine platelet function. Animals: Six healthy adult horses. Methods: Horses received clopidogrel (2 mg/kg PO q24h) or ASA (5 mg/kg PO q24h) for 5 days in a prospective randomized cross‐over design. Platelet aggregation responses to adenosine diphosphate (ADP) and collagen via optical aggregometry, and platelet secretion of serotonin (5HT) and production of thromboxane B2 (TXB2) by ELISA were evaluated. In horses receiving clopidogrel, high‐performance liquid chromatography analysis for clopidogrel and its carboxylic‐acid metabolite SR 26334 was performed. Results: SR 26334 was identified in all clopidogrel‐treated horses, although the parent compound was not detected. Clopidogrel resulted in decreases in ADP‐induced platelet aggregation persisting for 120 hours after the final dose. ADP‐induced platelet aggregation decreased from a baseline of 70.2 ± 14.7% to a minimum of 15.9 ± 7.7% 24 hours after the final dose (P < .001). Collagen‐induced aggregation decreased from a baseline of 93 ± 9.5% to a minimum of 70.8 ± 16.9% 48 hours after the final dose (P < .001). ASA did not decrease platelet aggregation with either agonist. ASA decreased serum TXB2 from a baseline value of 1310 ± 1045 to 128 ± 64 pg/mL within 24 hours (P < .01). Conclusions and Clinical Importance: Clopidogrel effectively decreases ADP‐induced platelet aggregation in horses, and could have therapeutic applications for equine diseases associated with platelet activation.  相似文献   

5.
Albarellos, G. A., Montoya, L., Denamiel, G. A. A., Velo, M. C., Landoni, M. F. Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats. J. vet. Pharmacol. Therap.  35 , 534–540. The pharmacokinetic properties and bone concentrations of lincomycin in cats after single intravenous and intramuscular administrations at a dosage rate of 10 mg/kg were investigated. Lincomycin minimum inhibitory concentration (MIC) for some gram‐positive strains isolated from clinical cases was determined. Serum lincomycin disposition was best‐fitted to a bicompartmental and a monocompartmental open models with first‐order elimination after intravenous and intramuscular dosing, respectively. After intravenous administration, distribution was rapid (T1/2(d) = 0.22 ± 0.09 h) and wide as reflected by the volume of distribution (V(d(ss))) of 1.24 ± 0.08 L/kg. Plasma clearance was 0.28 ± 0.09 L/h·kg and elimination half‐life (T1/2) 3.56 ± 0.62 h. Peak serum concentration (Cmax), Tmax, and bioavailability for the intramuscular administration were 7.97 ± 2.31 μg/mL, 0.12 ± 0.05 h, and 82.55 ± 23.64%, respectively. Thirty to 45 min after intravenous administration, lincomycin bone concentrations were 9.31 ± 1.75 μg/mL. At the same time after intramuscular administration, bone concentrations were 3.53 ± 0.28 μg/mL. The corresponding bone/serum ratios were 0.77 ± 0.04 (intravenous) and 0.69 ± 0.18 (intramuscular). Lincomycin MIC for Staphylococcus spp. ranged from 0.25 to 16 μg/mL and for Streptococcus spp. from 0.25 to 8 μg/mL.  相似文献   

6.
Recent evidence in in vitro and in vivo models suggests that sulforaphane (SFN), found in raw cruciferous vegetables, may have utility in chemoprevention, as an antineoplastic agent and as a free radical scavenger. The effects of SFN alone or with doxorubicin on cell viability were examined, as well as cell cycle kinetics, invasion capabilities and apoptosis in three canine osteosarcoma cell line (D17, OS 2.4 and HMPOS). Results showed that SFN could not induce cell death at potentially physiological concentrations (<50 μM), but significantly diminished cell invasion and downregulation of focal adhesion kinase (FAK) signaling. Modest cell cycle changes were observed in each cell line. When doxorubicin was used in conjunction with SFN, there was a protective effect to doxorubicin‐induced cytotoxicity in D17 and OS 2.4 cells. Further studies examining SFN as a supplement are warranted, particularly in light of pro‐proliferative and cytoprotective properties in canine osteosarcoma.  相似文献   

7.
The effective storage time of sperm after stripping (for 48 hr in 6‐hr intervals) and after thawing (for 6 hr in 2‐hr intervals) in Black moor, Oranda and Calico goldfish types was investigated. Variations in sperm density were also measured in all lines. The efficiency of a sperm cryopreservation method formerly developed for common carp was recorded in all three goldfish lines. Motility parameters ((pMOT, %), curvilinear velocity (VCL, μm/s) and straightness (STR, %)) of Black moor sperm did not decrease significantly during 48 hr of storage. A significant reduction in the Oranda type compared to the fresh control was observed in pMOT after 42 (23 ± 2%) and VCL after 36 (94 ± 12 μm/s) hours (pMOT 84 ± 5%, VCL 150 ± 11 μm/s). In the Calico type, pMOT decreased significantly already after 18 (42 ± 26%) and VCL after 6 (105 ± 8 μm/s) hours (fresh: pMOT 92 ± 5%, VCL 151 ± 6 μm/s). A high pMOT immediately following thawing was measured in Oranda (46 ± 12%) and Calico (55 ± 15%) types, whereas a reduced pMOT was recorded in Black moor (24 ± 19%). In Calico, pMOT showed a significant reduction after 6 hr (19 ± 11%) in comparison with the initial value, with no changes observed in VCL and STR. None of the parameters changed in the Black moor and Oranda types. Evidence was found that different goldfish lines have different sperm quality and characteristics. Further studies can investigate the possible effects of chilled and post‐thaw storage on the fertilizing capacity of sperm in the Black moor, Oranda and Calico goldfish types.  相似文献   

8.
Buprenorphine is an effective analgesic when administered epidurally to humans. The purpose of this study was to compare epidural buprenorphine (B; n = 10) with epidural morphine (M; n = 10) for post‐operative analgesia in dogs undergoing cranial cruciate ligament repair. All dogs were premedicated with acepromazine (0.1 mg kg?1 IM), induced with propofol (4–6 mg kg?1 IV) and maintained with halothane in oxygen. Dogs were randomly assigned to receive B (0.004 mg kg?1) or M (0.1 mg kg?1) in the lumbosacral epidural space in a total volume of 0.2 mL kg?1. End‐tidal halothane and CO2 and temperature were recorded every 15 minutes until extubation (t = 0). A numerical rating pain score (SPS) was recorded at t = 0, 1, 2, 4, 6, 10 and 24 hours by a blinded observer. Dogs received rescue morphine (1.0 mg kg?1 IM) if indicated by SPS and the time of rescue analgesic administration was recorded. Observable side‐effects such as urinary retention, sedation or pruritus were recorded. Data were analyzed with repeated measures anova . Mean ± SD body weight (kg) and age (yrs) for B dogs was 34.2 ± 10.8 and 5.5 ± 2.8; for M dogs these values were 36.6 ± 13.5 and 5.9 ± 3.3. Mean ± SD SPS for B dogs at t = 0, 1, 2, 4, 6, 10 and 24 hours were 1.2 ± 0.75, 3.2 ± 2.0, 4.5 ± 4.3, 4.6 ± 3.4, 4.7 ± 3.0, 5.0 ± 4.9 and 5.1 ± 3.5. For M dogs these values were 1.7 ± 0.5, 2.6 ± 2.0, 3.7 ± 0.75, 4.2 ± 2.2, 4.1 ± 3.0, 3.1 ± 2.1 and 3.9 ± 1.9. There were no significant differences between B and M with respect to SPS, times or frequency of rescue morphine administration, end‐tidal halothane and CO2, or esophageal temperature. Fifty per cent of dogs in both groups required rescue morphine. Buprenorphine is as effective as morphine for epidural analgesia in healthy dogs undergoing hindlimb orthopedic surgery.  相似文献   

9.
Lucas, M. F., Errecalde, J. O., Mestorino, N. Pharmacokinetics of azithromycin in lactating dairy cows with subclinical mastitis caused by Staphylococcus aureus. J. vet. Pharmacol. Therap. 33 , 132–140. Azithromycin is a time‐dependent antimicrobial with long persistence. The main characteristics of azithromycin suggest that it could be useful for treating bovine mastitis caused by Staphylococcus aureus. To investigate this possibility, its pharmacokinetic (PK) behavior was studied. Six Holstein lactating cows with subclinical mastitis were administered two 10 mg/kg intramuscular (i.m.) doses of azithromycin, with a 48‐h interval. Milk and plasma concentrations were measured by microbiological assay. The MIC90 was determined in 51 S. aureus isolations to calculate pharmacokinetic/pharmacodynamic (PK/PD) parameters. Milk maximal concentration (Cmax) was 7.76 ± 1.76 μg/mL (16.67 h post‐first administration) and 7.82 ± 2.18 μg/mL (14 h post‐2nd administration). In plasma Cmax was 0.18 ± 0.03 μg/mL (2 h post‐1rst administration) and 0.11 ± 0.03 μg/mL (14 h post‐2nd administration). Azithromycin was eliminated from the milk with a half‐life (T½λ) of 158.26 ± 137.7 h after 2nd administration, meanwhile plasma T½λ resulted shorter(13.97 ± 11.1 h). The mean area under the concentration vs. time curve from 0 to 24 h (AUC0‐24h) was 153.82 ± 34.66 μg·h/mL in milk secretion and 2.61 ± 0.59 μg·h/mL in plasma. Infection presence in the quarters had a significant effect (P < 0.05) on the area under the concentration vs. time curve from 0 to infinity (AUC0‐∞) and clearance from the mammary gland (Clmam/F). Moreover, it had influence on milk bioavailability (Fmilk), T½λ, AUC0‐∞ and mean residence time (MRT) in milk, which values resulted increased in mastitic quarters. In this study, it was determined that the production level and the mammary health status have an influence on PK parameters of azithromycin treatments in bovine mastitis.  相似文献   

10.
Raekallio M. R., Honkavaara J. M., Vainio O. M. The effects of L‐659,066, a peripheral α2‐adrenoceptor antagonist, and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep. J. vet. Pharmacol. Therap. 33 , 434–438. We investigated whether administration of L‐659,066, a peripheral α2‐adrenoceptor antagonist, or verapamil, a calcium‐channel antagonist, would prevent the cardiovascular effects of dexmedetomidine. Eleven sheep received three intravenous treatments with a randomized, cross‐over design: dexmedetomidine (5 μg/kg, DEX); DEX with L‐659,066 (250 μg/kg, DEX + L); and verapamil (0.05 mg/kg) 10 min prior to DEX (Ver + DEX). Haemodynamics were recorded at intervals upto 40 min. Acute increases in mean arterial pressure (MAP) (106 ± 10.7 to 120.8 ± 11.7 mmHg), central venous pressure (CVP) (3.3 ± 3.2 to 14.7 ± 5.0 mmHg) and systemic vascular resistance (SVR) (1579 ± 338 to 2301 ± 523 dyne s/cm5), and decreases in cardiac output (CO) (5.36 ± 0.87 to 3.93 ± 1.30 L/min) and heart rate (HR) (88.6 ± 15.3 to 49.7 ± 5.5/min) were detected with DEX. The peak SVR remained lower after Ver + DEX (1835 ± 226 dyne s/cm5) than DEX alone, but the other parameters did not significantly differ between these treatments. 2 min after drug delivery, differences between DEX and DEX + L were statistically significant for all measured haemodynamic parameters. With DEX + L, an early decrease in MAP (99.9 ± 6.8 to 89.3 ± 6.6 mmHg) was detected, and DEX + L induced a slight but significant increase in CVP and a decrease in HR at the end of the observation period, while SVR and CO did not significantly change. All animals were assessed as deeply sedated from 2–20 min with no differences between treatments. L‐659,066 has great potential for clinical use to prevent the cardiovascular effects of dexmedetomidine mediated by peripheral α2‐adrenoceptors, whereas the effects of verapamil were marginal.  相似文献   

11.
Bistoletti, M., Alvarez, L., Lanusse, C., Moreno, L. Disposition kinetics of albendazole and metabolites in laying hens. J. vet. Pharmacol. Therap.  36 , 161–168. An increasing prevalence of roundworm parasites in poultry, particularly in litter‐based housing systems, has been reported. However, few anthelmintic drugs are commercially available for use in avian production systems. The anthelmintic efficacy of albendazole (ABZ) in poultry has been demonstrated well. The goal of this work was to characterize the ABZ and metabolites plasma disposition kinetics after treatment with different administration routes in laying hens. Twenty‐four laying hens Plymouth Rock Barrada were distributed into three groups and treated with ABZ as follows: intravenously at 10 mg/kg (ABZ i.v.); orally at the same dose (ABZ oral); and in medicated feed at 10 mg/kg·day for 7 days (ABZ feed). Blood samples were taken up to 48 h posttreatment (ABZ i.v. and ABZ oral) and up to 10 days poststart feed medication (ABZ feed). The collected plasma samples were analyzed using high‐performance liquid chromatography. ABZ and its albendazole sulphoxide (ABZSO) and ABZSO2 metabolites were recovered in plasma after ABZ i.v. administration. ABZ parent compound showed an initial concentration of 16.4 ± 2.0 μg/mL, being rapidly metabolized into the ABZSO and ABZSO2 metabolites. The ABZSO maximum concentration (Cmax) (3.10 ± 0.78 μg/mL) was higher than that of ABZSO2Cmax (0.34 ± 0.05 μg/mL). The area under the concentration vs time curve (AUC) for ABZSO (21.9 ± 3.6 μg·h/mL) was higher than that observed for ABZSO2 and ABZ (7.80 ± 1.02 and 12.0 ± 1.6 μg·h/mL, respectively). The ABZ body clearance (Cl) was 0.88 ± 0.11 L·h/kg with an elimination half‐life (T1/2el) of 3.47 ± 0.73 h. The T1/2el for ABZSO and ABZSO2 were 6.36 ± 1.50 and 5.40 ± 1.90 h, respectively. After ABZ oral administration, low ABZ plasma concentrations were measured between 0.5 and 3 h posttreatment. ABZ was rapidly metabolized to ABZSO (Cmax, 1.71 ± 0.62 μg/mL) and ABZSO2 (Cmax, 0.43 ± 0.04 μg/mL). The metabolite systemic exposure (AUC) values were 18.6 ± 2.0 and 10.6 ± 0.9 μg·h/mL for ABZSO and ABZSO2, respectively. The half‐life values after ABZ oral were similar (5.91 ± 0.60 and 5.57 ± 1.19 h for ABZSO and ABZSO2, respectively) to those obtained after ABZ i.v. administration. ABZ was not recovered from the bloodstream after ABZ feed administration. AUC values of ABZSO and ABZSO2 were 61.9 and 92.4 μg·h/mL, respectively. The work reported here provides useful information on the pharmacokinetic behavior of ABZ after both i.v. and oral administrations in hens, which is a useful first step to evaluate its potential as an anthelmintic tool for use in poultry.  相似文献   

12.
Hypericin (Hyp) is a necrosis‐avid compound that can be efficiently labelled with radioiodine for both diagnostic and therapeutic purposes. Before 131I‐Hyp can be considered as a clinically useful drug in a combination therapy for canine cancer patients, evaluation of its toxicity is necessary. The aim of this study was to investigate the biodistribution and tolerance of a single dose administration of 131I‐Hyp. Three healthy dogs were included. 131I‐Hyp at a dose of 0.2 mg/kg and an activity of 185 MBq was intravenously injected. The effects on physical, haematological and biochemical parameters were characterized and the biodistribution and elimination pattern, the effective half‐life and dose rate were assessed. Drug‐related adverse events were limited to mild gastrointestinal signs, resolving within 48 hours. No significant differences were found in blood haematology and serum biochemistry before and after treatment. Following administration, highest percentage of injected dose (%ID ± SD) was found in the liver (5.5 ± 0.33), the lungs (4.17 ± 0.14) and the heart (3.11 ± 0.78). After 24 hours, highest %ID was found in colon (4.25 ± 1.45) and liver (3.45 ± 0.60). Clearance from all organs was effective within 7 days. Effective half‐life was established at 80 hours, and the dose rate fell below <20 μSv/h at 1 m within 1 day. The current study reveals that single dose treatment with 131I‐Hyp at the described dose is well tolerated by healthy dogs and supports the use of radioiodinated hypericin in a combination therapy for canine cancer patients.  相似文献   

13.
Objective—To compare plasma fentanyl concentrations attained after the application of three transdermal fentanyl patch sizes (50, 75, and 100 μg/hour) in dogs. Design—Repeated Latin square controlled study. Animals—Six intact, mixed-breed adult dogs (2 males, 4 females) weighing 19.9 ± 3.4 kg. Methods—Each dog was randomly assigned to receive each of three treatments: 50 (P50), 75 (P75), or 100 (P100) μg/hour transdermal patches. Patches were left in place for 72 hours. Jugular venous blood was collected at 1,2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after patch application and for 1, 2, 4, 8, and 12 hours after patch removal. Plasma fentanyl concentrations were measured using a radioimmunoassay technique. After a 96-hour washout period, each dog was moved to another treatment group and received a different patch size. Results—The following results were obtained (mean ± SD): average plasma fentanyl concentration from 24 to 72 hours, 0.7 ± 0.2 ng/mL (P50), 1.4 ± 0.5 ng/mL (P75), 1.2 ± 0.5 ng/mL (P100); the total area under the concentration versus time curve (0 hours to infinity), 46 ± 12.2 ng/h/mL (P50), 101.2 ± 41.4 ng/h/mL (P75), 80.4 ± 38.3 ng/h/mL (P100); and the apparent elimination half-life, 3.6 ± 1.2 hours (P50), 3.4 ± 2.7 hours (P75), and 2.5 ± 2.0 hours (P100). There was a high degree of variability in plasma fentanyl concentrations achieved. Plasma fentanyl concentrations declined rapidly after patch removal. Conclusions—The attainment of steady-state plasma concentrations takes up to 24 hours, and there is a great deal of variability in the final concentrations reached in different individuals. In this study, the 100 μg/hour patches did not provide statistically increased plasma concentrations when compared with the 50 μg/hour patches. Clinical Relevance—Because of the interindividual and intraindividual variation in plasma fentanyl concentrations, patches should be applied 24 hours before the anticipated time that analgesia will be required. Adequacy of analgesia and potentially deleterious side effects, such as sedation and respiratory depression, should be monitored while the patches are in place. Skin reactions may occur, and the patches should be removed if such skin irritation is seen. After the patch is removed, it is expected that analgesia will wane rapidly because of the brief elimination half-life.  相似文献   

14.
To determine the influence of the transplantation site of canine osteosarcoma (OS) cell lines on tumour growth and pulmonary metastasis, three OS cell lines were transplanted into nude mice via subcutaneous (SC), intratibial (IT) or intravenous (IV) injection. IT‐xenografts exhibited greater potential for developing primary masses and pulmonary metastasis than SC‐xenografts. In IT and IV xenografts, lung micrometastases along with phosphorylated ezrin–radixin–moesin (p‐ERM) overexpression were found in mice xenografted with HMPOS and OOS cells after 1 week and metastasis was found with decreased p‐ERM expression at later time points. The expression of ezrin and p‐ERM in the primary tumours of IT‐xenografted mice was higher than those in SC‐xenografted mice with HMPOS and OOS cells. The results suggest that the orthotopic transplantation site plays an important role in the spontaneous metastasis of canine OS and that ezrin phosphorylation may be involved in the early metastatic mechanism of canine OS cells.  相似文献   

15.
Introduction: Pamidronate is used to treat metastatic bone lesions in human cancer patients. By directly inhibiting the mevalonate pathway, pamidronate disrupts GTPase‐binding protein prenylation, resulting in osteoclast apoptosis. Pamidronate has been demonstrated to exert dose‐ and time‐dependent cytotoxic effects in several canine malignant osteoblastic cell lines. However, the exact cytotoxic mechanism remains speculative. The purpose of this study was to investigate and characterize the molecular mechanism of pamidronate‐induced cytotoxicity in canine malignant osteoblasts. Methods: The involvement of farnesyl or geranylgeranyl pyrophosphate synthase inhibition was evaluated by performing rescue experiments with cells incubated for 48 hours with cytotoxic concentrations of pamidronate (50 and 100 μM), with or without farnesol (FOH) and geranylgeraniol (GGOH). Cell lysates were fluorometrically‐assessed for caspase‐3‐like activity (R&D Systems) following incubation with varying concentrations of pamidronate (control, 50 and 100 μM) for 48 hours. The expression of a prenylated GTPase protein, Rap1 A, was qualitatively evaluated with immunoblotting using a polyclonal goat antibody (Santa Cruz Biotechnology) in cells incubated for 48 hours with varying concentrations of pamidronate (0, 1, 10, 50, and 100 μM). Results: In cells treated with lower cytotoxic concentrations of pamidronate (50 μM) for 48 hours, the addition of GGOH, but not FOH, was able to diminish the degree cytotoxicity, p ≤ 0.05. However, cells incubated with higher cytotoxic concentrations of pamidronate (100 μM), neither GGOH nor FOH were able to reduce the level of pamidronate‐induced cytotoxicity. Caspase‐3‐like activity directly correlated with the degree of pamidronate‐induced cytotoxicity. Cells treated with pamidronate at 50 μM and 100 μM increased caspase‐3‐like activity by 5.3 and 7.1‐fold, respectively over untreated controls. The detection of Rap1A by immunoblotting requires further optimization. Conclusions: Pamidronate‐induced cytotoxicity in canine osteosarcoma cells may share a similar mechanism as has been demonstrated for osteoclasts. Inhibition of the mevalonate pathway appears to contribute to the observed cytotoxicity at lower doses of pamidronate. In addition, caspase‐3‐like activity contributes to the apoptotic process induced by pamidronate in malignant canine osteoblasts.  相似文献   

16.
Summary

The oral absorption and bioavailability of flumequine was studied in 1‐, 5‐ and 18‐week‐old calves following intravenous and oral administration of different formulations of flumequine (Flumix®, Flumix C® and pure flumequine). Increasing age had a negative influence on the Cmax after the administration of Flumix®, based on a larger VD in the older calves. The Cmax decreased from 5.02 ± 1.46 μg/ml in the first week to 3.28 ± 0.42 μg/ml in the 18th week. Adding colistin sulfate to the flumequine formulation and administring pure flumequine mixed with milk replacer had a negative effect on the Cmax of flumequine after oral administration of 5 and 10 mg/kg body weight. The bioavailability of the orally administered flumequine formulations was 100% in all cases except after the administration of Flumix C®, for which it was 75.9 ± 18.2%. The urinary recovery of flumequine after intravenous injection of a 10% solution varied from 35.2 ± 2.3% for Group B. to 41.2 ± 6.3% for Group C.

The dosage of 5 mg/kg body weight Flumix® twice daily in 1‐week‐old veal calves is sufficient to reach therapeutic plasma concentrations, based on a MIC value of 0.8 μg/ml of the target bacteria.

In older calves it is advisable to increase the dosage 7.5 or 10 mg/kg body weight every 12 hours. In combination with colistin sulfate it is also advisable to increase the dosage slightly because of the negative effect of the colistin sulfate on the Cmax of flumequine.  相似文献   

17.
Objective— To estimate maximum plasma concentration (Cmax) and time to maximum plasma (tmax) bupivacaine concentration after intra‐articular administration of bupivacaine for single injection (SI) and injection followed by continuous infusion (CI) in normal dogs. Study Design— Cross‐over design with a 2‐week washout period. Animals— Healthy Coon Hound dogs (n=8). Methods— Using gas chromatography/mass spectrometry, canine plasma bupivacaine concentration was measured before and after SI (1.5 mg/kg) and CI (1.5 mg/kg and 0.3 mg/kg/h). Software was used to establish plasma concentration–time curves and estimate Cmax, Tmax and other pharmacokinetic variables for comparison of SI and CI. Results— Bupivacaine plasma concentration after SI and CI best fit a 3 exponential model. For SI, mean maximum concentration (Cmax, 1.33±0.954 μg/mL) occurred at 11.37±4.546 minutes. For CI, mean Cmax (1.13±0.509 μg/mL) occurred at 10.37±4.109 minutes. The area under the concentration–time curve was smaller for SI (143.59±118.390 μg/mL × min) than for CI (626.502±423.653 μg/mL × min, P=.02) and half‐life was shorter for SI (61.33±77.706 minutes) than for CI (245.363±104.415 minutes, P=.01). The highest plasma bupivacaine concentration for any dog was 3.2 μg/mL for SI and 2.3 μg/mL for CI. Conclusion— Intra‐articular bupivacaine administration results in delayed absorption from the stifle into the systemic circulation with mean Cmax below that considered toxic and no systemic drug accumulation. Clinical Relevance— Intra‐articular bupivacaine can be administered with small risk of reaching toxic plasma concentrations in dogs, though toxic concentrations may be approached. Caution should be exercised with multimodal bupivacaine administration because plasma drug concentration may rise higher than with single intra‐articular injection.  相似文献   

18.
Holmes, K., Bedenice, D., Papich, M. G. Florfenicol pharmacokinetics in healthy adult alpacas after subcutaneous and intramuscular injection. J. vet. Pharmacol. Therap.  35 , 382–388. A single dose of florfenicol (Nuflor®) was administered to eight healthy adult alpacas at 20 mg/kg intramuscular (i.m.) and 40 mg/kg subcutaneous (s.c.) using a randomized, cross‐over design, and 28‐day washout period. Subsequently, 40 mg/kg florfenicol was injected s.c. every other day for 10 doses to evaluate long‐term effects. Maximum plasma florfenicol concentrations (Cmax, measured via high‐performance liquid chromatography) were achieved rapidly, leading to a higher Cmax of 4.31 ± 3.03 μg/mL following administration of 20 mg/kg i.m. than 40 mg/kg s.c. (Cmax: 1.95 ± 0.94 μg/mL). Multiple s.c. dosing at 48 h intervals achieved a Cmax of 4.48 ± 1.28 μg/mL at steady state. The area under the curve and terminal elimination half‐lives were 51.83 ± 11.72 μg/mL·h and 17.59 ± 11.69 h after single 20 mg/kg i.m. dose, as well as 99.78 ± 23.58 μg/mL·h and 99.67 ± 59.89 h following 40 mg/kg injection of florfenicol s.c., respectively. Florfenicol decreased the following hematological parameters after repeated administration between weeks 0 and 3: total protein (6.38 vs. 5.61 g/dL, P < 0.0001), globulin (2.76 vs. 2.16 g/dL, P < 0.0003), albumin (3.61 vs. 3.48 g/dL, P = 0.0038), white blood cell count (11.89 vs. 9.66 × 103/μL, P < 0.044), and hematocrit (27.25 vs. 24.88%, P < 0.0349). Significant clinical illness was observed in one alpaca. The lowest effective dose of florfenicol should thus be used in alpacas and limited to treatment of highly susceptible pathogens.  相似文献   

19.
OBJECTIVE: To evaluate the biological activity of dihydroartemisinin on canine osteosarcoma cell lines in vitro. SAMPLE POPULATION: 4 canine osteosarcoma cell lines. PROCEDURES: Cell viability assays were performed on canine osteosarcoma cell lines OSCA2, OSCA16, OSCA50, and D17 after 24, 48, and 72 hours of treatment with dihydroartemisinin at concentrations of 0.1 to 100 microM. Apoptosis was assessed by use of an ELISA for free nuclosomal DNA fragmentation and by western blot analysis for cleavage of caspase 3. Cell cycle analysis was performed by use of staining with propidium iodide and flow cytometry. Detection of reactive oxygen species (ROS) was conducted in the D17 cell line by use of 6-carboxy-2',7'-dihydrofluorescein diacetate and flow cytometry. RESULTS: The concentration of dihydroartemisinin required for 50% inhibition of cell viability (IC50) was achieved in all 4 canine osteosarcoma cell lines and ranged from 8.7 to 43.6 microM. Induction of apoptosis was evident as an increase in nucleosomal DNA fragmentation, cleavage of caspase 3, and an increase in the population in the sub G0/G1 phase of the cell cycle detected by flow cytometry. Exposure to dihydroartemisinin also resulted in a decrease in the G0/G1 population. Iron-dependent generation of ROS was detected in dihydroartemisinin-treated D17 cells; ROS generation increased in a dose-dependent manner. CONCLUSIONS AND CLINICAL RELEVANCE: Incubation with dihydroartemisinin resulted in biological activity against canine osteosarcoma cell lines, which included induction of apoptosis and arrest of the cell cycle. Clinical trials of dihydroartemisinin in dogs with osteosarcoma should be conducted.  相似文献   

20.
Kumar, V., Madabushi, R., Lucchesi, M. B. B., Derendorf, H. Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs. J. vet. Pharmacol. Therap. 34 , 130–135. Pharmacokinetics of cefpodoxime in plasma (total concentration) and subcutaneous fluid (free concentration using microdialysis) was investigated in dogs following single oral administration of prodrug cefpodoxime proxetil (equivalent to 5 and 10 mg/kg of cefpodoxime). In a cross over study design, six dogs per dose were utilized after a 1 week washout period. Plasma, microdialysate, and urine samples were collected upto 24 h and analyzed using high performance liquid chromatography. The average maximum concentration (Cmax) of cefpodoxime in plasma was 13.66 (±6.30) and 27.14 (±4.56) μg/mL with elimination half‐life (t1/2) of 3.01 (±0.49) and 4.72 (±1.46) h following 5 and 10 mg/kg dose, respectively. The respective average area under the curve (AUC0–∞) was 82.94 (±30.17) and 107.71 (±30.79) μg·h/mL. Cefpodoxime was readily distributed to skin and average free Cmax in subcutaneous fluid was 1.70 (±0.55) and 3.06 (±0.93) μg/mL at the two doses. Urinary excretion (unchanged cefpodoxime) was the major elimination route. Comparison of subcutaneous fluid concentrations using pharmacokinetic/pharmacodynamic indices of fT>MIC indicated that at 10 mg/kg dose; cefpodoxime would yield good therapeutic outcome in skin infections for bacteria with MIC50 upto 0.5 μg/mL while higher doses (or more frequent dosing) may be needed for bacteria with higher MICs. High urine concentrations suggested cefpodoxime use for urinary infections in dogs.  相似文献   

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