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1.
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2.
The fluoroquinolone antimicrobial drug marbofloxacin was administered to yellow cattle intravenously and intramuscularly at a dose of 2 mg/kg of body weight in a two‐period crossover study. The pharmacokinetic properties of marbofloxacin in serum, inflamed tissue‐cage fluid (exudate), and noninflamed tissue‐cage fluid (transudate) were studied by using a tissue‐cage model. The in vitro and ex vivo activities of marbofloxacin in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 155.75, 153.00, and 138.88, respectively, after intravenous dosing and 160.50, 151.00, and 137.63, respectively, after intramuscular dosing. After intramuscular dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 21.13, 9.13, and 8.38, respectively. The ex vivo growth inhibition data after intramuscular dosing were fitted to the inhibitory sigmoid Emax equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria. The respective values for serum were 17.25, 31.29, and 109.62, and slightly lower values were obtained for transudate and exudate. It is proposed that these findings might be used with MIC50 or MIC90 data to provide a rational approach to the design of dosage schedules which optimize efficacy in respect of bacteriological as well as clinical cures.  相似文献   

3.
The study hypothesis is that higher doses of metronomic (low‐dose) chlorambucil will improve outcome without significantly worsening adverse events (AE). Retrospectively, 88 dogs were screened to assess for tolerability and response to chlorambucil utilizing retrospective and prospective data sets, comparing metronomic oral daily doses 4, 6 and 8 mg m2. There were 78 and 70 dogs in the tolerability and efficacy portions, respectively. The severity of gastrointestinal (GI) AE was significantly worse, and time to development of GI events was significantly shorter at 6 mg m2 than at 4 mg m2 (both P < 0.001). Chlorambucil was discontinued earlier in the dogs treated at the 6 mg m2 doses than in the dogs treated at 4 mg m2 (P = 0.015). Thrombocytopenia occurred significantly earlier at 8 mg m2 than at 4 mg m2 (P = 0.017). Higher doses of metronomic (low‐dose) chlorambucil did not provide improved responses and were associated with more AE.  相似文献   

4.
Based on its ideal PK/PD ratios, doxycycline hyclate (DOX‐h), a time‐dependant antibacterial, is ideally expected to achieve sustained plasma drug concentrations at or slightly above the MIC level for as long as possible between dosing intervals. Pursuing this end, a poloxamer‐based matrix was used to produce a 10% long‐acting injectable preparation (DOX‐h‐LA) and its serum concentrations vs. time profile investigated after its injection to pigs in the pericaudal s.c. by parallel design. Results were compared with the forced oral bolus dose and i.v. pharmacokinetics of DOX‐h. For this study, 12 recently weaned pigs per group were included in this trial, and a dose of 20 mg/kg was injected in all cases. DOX‐h‐LA showed the greatest values for bioavailability (115.38%); maximum serum concentration (Cmax) value was 1.5 ± 0.2 with a time to reach Cmax of 3.41 ± 0.04 h and an elimination rate constant of 70.93 ± 0.87 h. Considering minimum effective serum concentration of 0.5 μg/mL, a dose interval of at least 5 days can be achieved for DOX‐h‐LA, whereas p.o. and i.v. dosing of DOX‐h may only last 11 and 15 h, respectively. Pigs were slaughtered on day 30 after this trial, and no visible remnants of the preparation were detected neither fibrosis was observed after a thorough macroscopic and histopathological analysis.  相似文献   

5.
Background: Satraplatin is the 1st orally bioavailable platinum anticancer drug. Objective: Our objectives were to evaluate efficacy in vitro against a canine cancer cell line, to determine the maximally tolerated dose (MTD) of satraplatin in tumor‐bearing dogs, to identify the dose‐limiting and other toxicities in dogs, and to record pharmacokinetics (PK). Animals: Dogs with macro‐ or microscopic malignant neoplasia. Methods: D17 canine osteosarcoma cells first were evaluated in a clonogenic survival assay. Then, dogs with a diagnosis of malignant neoplasia were prospectively entered in standard 3 + 3 cohorts. Additional patients were entered at the MTD to assess efficacy. Total and free platinum (by ultrafiltrate) concentrations were determined with inductively coupled plasma mass spectroscopy. Results: Satraplatin inhibited clonogenic survival in vitro at clinically relevant and achievable concentrations. Twenty‐three dogs were treated, 14 with PK evaluation. The MTD was 35 mg/m2/d for 5 days, repeated every 3–4 weeks. Bioavailability was 41%. PK variables (mean ± SD) at the MTD included Tmax 1.8 (± 0.7) hours, Cmax 72 (± 26) ng/mL, area under concentration (AUC)0–24 h 316 (± 63) h × ng/mL, and MRT 7 (± 1.3) hours. Higher AUC after the 5th versus the 1st dose suggested drug accumulation. Interestingly, platelets consistently reached nadir sooner than did neutrophils (day 14 versus 19). Myelosuppression was dose‐limiting and gastrointestinal toxicity was mild. Conclusions and Clinical Importance: Satraplatin was well tolerated in tumor‐bearing dogs, thus warranting further investigation in a phase II trial.  相似文献   

6.
A colloidal dispersion formulation of 9‐aminocamptothecin (9‐AC) was administered intravenously to 10 dogs with previously untreated, spontaneously occurring, multicentric lymphoma. The dogs received a 72‐h infusion of 9‐AC at a rate of 46.5–51.25 µg m?2 h?1 (total dose range 3.35–3.69 mg m?2). This dose range was associated with myelosuppression, consisting principally of neutropenia with a nadir at 7 days following the start of infusion. Neutropenia and thrombocytopenia were the most common toxicoses and are most likely to be dose‐limiting toxicities; low‐grade gastrointestinal signs were rarely seen. Concentrations of 9‐AC lactone, as well as clinical toxicities, compare favourably with those found in humans. Tumour responses were seen in all treated dogs. Response to other chemotherapy, following cessation of 9‐AC treatment, was not obviously compromised even in dogs clinically resistant to 9‐AC. 9‐AC is a novel treatment drug for canine lymphoma, which appears to show great promise.  相似文献   

7.
Background: Continuous administration of low doses of cyclophosphamide and standard doses of cyclooxygenase‐inhibiting drugs has been shown to suppress tumor angiogenesis, reverse immunosuppression, and deplete regulatory T cells in cancer models. Hypothesis: We hypothesized that continuous treatment with low‐dose cyclophosphamide and full‐dose piroxicam would delay tumor recurrence in dogs with soft tissue sarcomas (STS). Animals: Eighty‐five dogs with incompletely resected STS, 30 treated dogs, and 55 contemporary control dogs. Methods: Treatment outcomes in 85 dogs with incompletely resected STS were evaluated in a retrospective study. Dogs in the treatment group received continuously administered low‐dose cyclophosphamide (10 mg/m2) and standard dose piroxicam (0.3 mg/kg) therapy. Time to local tumor recurrence (disease‐free interval; DFI) was compared between the 30 treated dogs and 55 untreated control dogs matched for age and tumor site and grade. Results: DFI was significantly (P < .0001) prolonged for STS of all sites (trunk and extremity) in treated dogs compared with untreated control dogs. The DFI also was significantly longer in treated dogs when tumor site (trunk and extremity) was compared. Twelve treated dogs (40%) experienced mild toxicity (grade 1 and 2) at some point during treatment and 1 dog developed grade 4 cystitis. Every other day dosing was tolerated better than daily dosing. Conclusions: Metronomic therapy with cyclophosphamide and piroxicam was very effective in preventing tumor recurrence in dogs with incompletely resected STS. These findings suggest that further evaluation of this approach is warranted as adjuvant therapy in dogs with highly metastatic tumors such as osteosarcoma and melanoma.  相似文献   

8.
Background: The identification of dogs defective in ATP‐binding cassette transporter B1 (ABCB1, MDR1) activity has prompted questions regarding pharmacokinetics (PK), efficacy and toxicity of ABCB1 substrates in these dogs. Hypothesis/Objectives: Dogs defective in ABCB1 activity (ABCB1null) have doxorubicin (DOX) PK different from that of normal dogs (ABCB1wt). Utilization of a physiologically based pharmacokinetic (PBPK) model allows computer simulation to study this polymorphism's impact on DOX PK. Animals: None. Methods: A virtual ABCB1wt dog population was generated and DOX distribution, elimination, and metabolism simulated by PBPK modeling. An in silico population of virtual dogs was generated by Monte Carlo simulation, with variability in physiologic and biochemical parameters consistent with the dog population. This population was used in the PBPK model. The ABCB1 components of the model were inactivated to generate an ABCB1null population and simulations repeated at multiple doses. Resulting DOX levels were used to generate PK parameters. Results: DOX exposures in the ABCB1null population were increased in all simulated tissues including serum (24%) and gut (174%). Estimated dosages in the ABCB1null population to approximate exposure in the ABCB1wt population at a dose of 30 mg/m2 were 24.8 ± 3.5 mg/m2 for serum and 10.7 ± 5.9 mg/m2 for gut. Conclusions and Clinical Importance: These results suggest that serum DOX concentrations are not indicative of tissue exposure, especially those with appreciable ABCB1 activity, and that gastrointestinal (GI) toxicosis would be dose limiting in ABCB1null populations. Dosage reductions necessary to prevent GI toxicosis likely result in subtherapeutic concentrations, thereby reducing DOXs efficacy in ABCB1null dogs.  相似文献   

9.
Background: Echocardiographic prediction of congestive heart failure (CHF) in dogs has not been prospectively evaluated. Hypothesis: CHF can be predicted by Doppler echocardiographic (DE) variables of left ventricular (LV) filling in dogs with degenerative mitral valve disease (MVD) and dilated cardiomyopathy (DCM). Animals: Sixty‐three client‐owned dogs. Methods: Prospective clinical cohort study. Physical examination, thoracic radiography, analysis of natriuretic peptides, and transthoracic echocardiography were performed. Diagnosis of CHF was based upon clinical and radiographic findings. Presence or absence of CHF was predicted using receiver‐operating characteristic (ROC) curve, multivariate logistic and stepwise regression, and best subsets analyses. Results: Presence of CHF secondary to MVD or DCM could best be predicted by E : isovolumic relaxation time (IVRT) (area under the ROC curve [AUC]=0.97, P < .001), respiration rate (AUC=0.94, P < .001), Diastolic Functional Class (AUC=0.93, P < .001), and a combination of Diastolic Functional Class, IVRT, and respiration rate (R2=0.80, P < .001) or Diastolic Functional Class (AUC=1.00, P < .001), respiration rate (AUC=1.00, P < .001), and E : IVRT (AUC=0.99, P < .001), and a combination of Diastolic Functional Class and E : IVRT (R2=0.94, P < .001), respectively, whereas other variables including N‐terminal pro‐brain natriuretic peptide, E : Ea, and E : Vp were less useful. Conclusion and Clinical Importance: Various DE variables can be used to predict CHF in dogs with MVD and DCM. Determination of the clinical benefit of such variables in initiating, modulating, and assessing success of treatments for CHF needs further study.  相似文献   

10.
Sixty‐four dogs were treated with single‐agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression‐free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA.  相似文献   

11.
Hewson, J., Johnson, R., Arroyo, L. G., Diaz‐Mendez, A., Ruiz‐López, J. A., Gu, Y., del Castillo, J. R. E. Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals. J. vet. Pharmacol. Therap.  36 , 68–77. Healthy neonatal foals were treated with cefotaxime by bolus (40 mg/kg IV q6h for 12 doses; n = 10) or by infusion (loading dose of 40 mg/kg IV followed by continuous infusion of a total daily dose of 160 mg/kg per 24 h for 3 days; n = 5). Population pharmacokinetics was determined, and concentrations in cavity fluids were measured at steady state (72 h). Highest measured serum drug concentration in the bolus group was 88.09 μg/mL and minimum drug concentration (Cmin) was 0.78 μg/mL at 6‐h postadministration (immediately before each next dose), whereas infusion resulted in a steady‐state concentration of 16.10 μg/mL in the infusion group. Mean cefotaxime concentration in joint fluid at 72 h was higher (P = 0.051) in the infusion group (5.02 μg/mL) compared to the bolus group (0.78 μg/mL). Drug concentration in CSF at 72 h was not different between groups (P = 0.243) and was substantially lower than serum concentrations in either group. Insufficient data on pulmonary epithelial lining fluid were available to compare the methods of administration for cefotaxime in this cavity fluid. Results support continuous drug infusion over bolus dosing in the treatment for neonatal foal septicemia to optimize time that cefotaxime concentration exceeds the minimum inhibitory concentration of common equine pathogens.  相似文献   

12.
The objective of this study was to evaluate the pharmacokinetics of the standard cytarabine (Ara‐C) protocol (50 mg/m2 subcutaneously every 12 hr for 2 days) used for dogs with neuroinflammatory disease and compare it to two more practical protocols (a single 200 mg/m2 subcutaneous dose and two 100 mg/m2 subcutaneous doses every 12 hr). Four client‐owned dogs previously diagnosed with meningoencephalomyelitis of unknown origin were administered three distinct Ara‐C protocols with a 21‐day washout between each protocol. A complete blood count was performed seven days after each dosing protocol to assess for clinically relevant myelosuppression. No adverse events were observed. Plasma Ara‐C concentrations were measured using a validated liquid chromatography coupled to tandem mass spectrometry assay. The mean maximal concentrations in this study were 4,230, 9,293, and 16,675 ng/ml for a single dose of 50, 100, and 200 mg/m2, respectively. There was a linear relationship between dose and drug exposure. Drug exposure was similar regardless of the dosing protocol when the total dose was analyzed, with an area under the concentration versus time curve of 37,026, 38,465, and 32,510 ng × hr/ml for 50, 100, and 200 mg/m2, respectively.  相似文献   

13.
The objective of this study was to evaluate the plasma and serum concentrations of cytarabine (CA) administered via constant rate infusion (CRI) in dogs with meningoencephalomyelitis of unknown etiology (MUE). Nineteen client‐owned dogs received a CRI of CA at a dose of 25 mg/m2/h for 8 h as treatment for MUE. Dogs were divided into four groups, those receiving CA alone and those receiving CA in conjunction with other drugs. Blood samples were collected at 0, 1, 8, and 12 h after initiating the CRI. Plasma (n = 13) and serum (n = 11) cytarabine concentrations were measured by high‐pressure liquid chromatography. The mean peak concentration (CMAX) and area under the curve (AUC) after CRI administration were 1.70 ± 0.66 μg/mL and 11.39 ± 3.37 h·μg/mL, respectively, for dogs receiving cytarabine alone, 2.36 ± 0.35 μg/mL and 16.91 + 3.60 h·μg/mL for dogs administered cytarabine and concurrently on other drugs. Mean concentrations for all dogs were above 1.0 μg/mL at both the 1‐ and 8‐h time points. The steady‐state achieved with cytarabine CRI produces a consistent and prolonged exposure in plasma and serum, which is likely to produce equilibrium between blood and the central nervous system in dogs with a clinical diagnosis of MUE. Other medications commonly used to treat MUE do not appear to alter CA concentrations in serum and plasma.  相似文献   

14.
Six dogs were used to determine single and multiple oral dose pharmacokinetics of ABT‐116. Blood was collected for subsequent analysis prior to and at 15, 30 min and 1, 2, 4, 6, 12, 18, and 24 h after administration of a single 30 mg/kg dose of ABT‐116. Results showed a half‐life of 6.9 h, kel of 0.1/h, AUC of 56.5 μg·h/mL, Tmax of 3.7 h, and Cmax of 3.8 μg/mL. Based on data from this initial phase, a dose of 10 mg/kg of ABT‐116 (no placebo control) was selected and administered to the same six dogs once daily for five consecutive days. Behavioral observations, heart rate, respiratory rate, temperature, thermal and mechanical (proximal and distal limb) nociceptive thresholds, and blood collection were performed prior to and 4, 8, and 16 h after drug administration each day. The majority of plasma concentrations were above the efficacious concentration (0.23 μg/mL previously determined for rodents) for analgesia during the 24‐h sampling period. Thermal and distal limb mechanical thresholds were increased at 4 and 8 h, and at 4, 8, and 16 h respectively, postdosing. Body temperature increased on the first day of dosing. Results suggest adequate exposure and antinociceptive effects of 10 mg/kg ABT‐116 following oral delivery in dogs.  相似文献   

15.
Numerous factors are known to affect the prognosis of dogs with chemotherapy‐treated lymphomas. However, prognostic factors for dogs with specific subtypes of lymphoma are less clearly defined. The objective of this study was to identify prognostic factors for dogs receiving CHOP‐based chemotherapy for primary nodal diffuse large B‐cell lymphoma (DLBCL). Medical records of dogs treated for DLBCL at the Purdue Veterinary Teaching Hospital (PUVTH) from 2006 to 2016 were reviewed. Factors potentially related to prognosis were analysed using multivariable statistical methods. Ninety‐eight dogs were included in the study. Best overall response to chemotherapy was complete remission in 80 dogs (81.6%) and partial remission in 18 dogs (18.4%). Median progression‐free survival (PFS) for the entire population was 252 days (range 19‐1068). Factors significantly associated with achieving partial (rather than complete) remission following CHOP included presence of thrombocytopenia at diagnosis (OR 6.88; 95% CI 1.98‐23.93; P = .002), baseline serum globulin concentration (OR 2.63; 95% CI 1.03‐6.75; P = .044), and age at diagnosis (OR 1.36; 95% CI 1.08‐1.71; P = .009). Factors significantly associated with PFS in the lowest quartile (≤93 days) included presence of thrombocytopenia at diagnosis (OR 8.72; 95% CI 1.54‐49.33; P = .014), age at diagnosis (OR 1.47; 95% CI 1.12‐1.94; P = .005), and baseline neutrophil count (OR 1.18; 95% CI 1.02‐1.37; P = .025). Presence of thrombocytopenia, greater age, higher neutrophil count, and higher serum globulin concentration all may be associated with a particularly poor outcome in dogs receiving CHOP‐based chemotherapy for DLBCL.  相似文献   

16.
Background: Removal of leukocytes (LR) has been shown to eliminate or attenuate many of the adverse effects of transfusion in experimental animals and humans. Hypothesis/Objectives: Transfusion of stored packed red blood cells (pRBCs) is associated with an inflammatory response in dogs and prestorage LR attenuates the inflammatory response. Animals: Thirteen random‐source, clinically healthy, medium and large breed dogs. Methods: Experimental study. On day 0, animals were examined and baseline blood samples were collected for analysis. Whole blood was then collected for processing with and without LR, and stored as pRBC. Twenty‐one days later, stored pRBCs were transfused back to the donor. Blood samples were collected before and 1 and 3 days after transfusion. Results: In the dogs that received non‐LR pRBCs (n = 6) there was a significant increase from baseline in white blood cell count from a mean (SD) of 8.20 (2.74) to 13.95 (4.60) × 103 cells/μL (P < .001) and in segmented neutrophil count from a mean (SD) of 5.76 (2.70) to 11.91 (4.71) × 103 cells/μL (P < .001). There were also significant increases in fibrinogen from a mean (SD) of 129.7 (24.2) to 268.6 (46.7) mg/dL (P < .001) and C‐reactive protein from a mean (SD) of 1.9 (2.1) to 78.3 (39.3) μg/mL (P < .001). There was no significant increase from baseline in any of the markers in the dogs that received LR pRBC (n = 5). Conclusions and Clinical Importance: There is a profound inflammatory response to transfusion in normal dogs, which is eliminated by LR of the pRBC units.  相似文献   

17.
The single‐dose disposition kinetics of the antibiotic marbofloxacin were determined in Chinese soft‐shelled turtles (n = 10) after oral and intramuscular (i.m.) dose of 10 mg/kg bodyweight. The in vitro and ex vivo activities of marbofloxacin in serum against a pathogenic strain of Aeromonas hydrophila were determined. A concentration‐dependent antimicrobial activity of marbofloxacin was confirmed for levels lower than 4 × MIC. For in vivo PK data, values of AUC: minimum inhibitory concentration (MIC) ratio for serum were 1166.6 and 782.4 h, respectively, after i.m. and oral dosing of marbofloxacin against a pathogenic strain of A. hydrophila (MIC = 0.05 μg/mL). The ex vivo growth inhibition data after oral dosing were fitted to the inhibitory sigmoid Emax equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity and elimination of bacteria. The respective values were 23.79, 36.35 and 126.46 h. It is proposed that these findings might be used with MIC50 or MIC90 data to provide a rational approach to the design of dosage schedules, which optimize efficacy in respect of bacteriological as well as clinical cures.  相似文献   

18.
A two‐period cross‐over study was carried to investigate the pharmacokinetics (PK) and ex‐vivo pharmacodynamics (PD) of cefquinome when administrated intravenously (IV) and intramuscularly (IM) in seven healthy dogs at a dose of 2 mg/kg of body weight. Serum concentrations were determined by HPLC‐MS/MS assay and cefquinome concentration vs. time data after IV and IM were best fit to a two‐compartment open model. Cefquinome mean values of area under concentration–time curve (AUC) were 5.15 μg·h/mL for IV dose and 4.59 μg·h/mL for IM dose. Distribution half‐lives and elimination half‐lives after IV dose and IM dose were 0.27 and 0.44 h, 1.53 and 1.94 h, respectively. Values of total body clearance (ClB) and volume of distribution at steady‐state (Vss) were 0.49 L·kg/h and 0.81 L/kg, respectively. After IM dose, Cmax was 2.53 μg/mL and the bioavailability was 89.13%. For PD profile, the determined MIC and MBC values against K. pneumonia were 0.030 and 0.060 μg/mL in MHB and 0.032 and 0.064 μg/mL in serum. The ex vivo time‐kill curves also were established in serum. In conjunction with the data on MIC, MBC values and the ex vivo bactericidal activity in serum, the present results allowed prediction that a single cefquinome dosage of 2 mg/kg may be effective in dogs against K. pneumonia infection.  相似文献   

19.
Imepitoin is a novel anti‐epileptic licensed in the European Union for the treatment of canine idiopathic epilepsy. The aim of this study was to characterize the pharmacokinetics of imepitoin in dogs and to evaluate the interaction with drug metabolizing enzymes. Upon administration of imepitoin tablets at a dose of 30 mg/kg to beagle dogs, high plasma levels were observed within 30 min following oral dosing, with maximal plasma concentrations of 14.9–17.2 μg/mL reached after 2–3 h. In a crossover study, co‐administration of imepitoin tablets with food reduced the total AUC by 30%, but it did not result in significant changes in Tmax and Cmax, indicating lack of clinical relevance. No clinically relevant effects of sex and no accumulation or metabolic tolerance were observed upon twice daily dosing. Following single dose administration of 10–100 mg/kg, dose linearity was found. Administering [14C] imepitoin, high enteral absorption of 92% and primary fecal excretion were identified. Plasma protein binding was only 55%. At therapeutic plasma concentrations, imepitoin did not inhibit microsomal cytochrome P450 family liver enzymes in vitro. In rats, no relevant induction of liver enzymes was found. Therefore, protein binding or metabolism‐derived drug–drug interactions are unlikely. Based on these data, imepitoin can be dosed twice daily, but the timing of tablet administration in relation to feeding should be kept consistent.  相似文献   

20.
The pharmacokinetics of dantrolene and its active metabolite, 5‐hydroxydantrolene, after a single oral dose of either 5 or 10 mg/kg of dantrolene was determined. The effects of exposure to dantrolene and 5‐hydroxydantrolene on activated whole‐blood gene expression of the cytokines interleukin‐2 (IL‐2) and interferon‐γ (IFN‐γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (Cmax) was 0.43 μg/mL, terminal half‐life (t1/2) was 1.26 h, and area under the time–concentration curve (AUC) was 3.87 μg·h/mL. For the 10 mg/kg dose, Cmax was 0.65 μg/mL, t1/2 was 1.21 h, and AUC was 5.94 μg·h/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t1/2, for example, ranged from 0.43 to 6.93 h, Cmax ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole‐blood expression of IL‐2 and IFN‐γ as measured by qRT‐PCR was markedly suppressed following exposure to very high concentrations (30 and 50 μg/mL, respectively) of both dantrolene and 5‐hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing.  相似文献   

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