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High Bioavailability (high + bioavailability)
Selected AbstractsWeathering and aging of 2,4,6-trinitrotoluene in soil increases toxicity to potworm Enchytraeus crypticusENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2005Roman G. Kuperman Abstract Energetic materials are employed in a wide range of commercial and military activities and often are released into the environment. Scientifically based ecological soil-screening levels (Eco-SSLs) are needed to identify contaminant explosive levels in soil that present an acceptable ecological risk. Insufficient information for 2,4,6-trinitrotoluene (TNT) to generate Eco-SSLs for soil invertebrates necessitated toxicity testing. We adapted the standardized Enchytraeid Reproduction Test and selected Enchytraeus crypticus for these studies. Tests were conducted in Sassafras sandy loam soil, which supports relatively high bioavailability of TNT. Weathering and aging procedures for TNT amended to test soil were incorporated into the study design to produce toxicity data that better reflect the soil exposure conditions in the field compared with toxicity in freshly amended soils. This included exposing hydrated TNT-amended soils in open glass containers in the greenhouse to alternating wetting and drying cycles. Definitive tests showed that toxicity for E. crypticus adult survival and juvenile production was increased significantly in weathered and aged soil treatments compared with toxicity in freshly amended soil based on 95% confidence intervals. The median effect concentration and 20% effective concentration for reproduction were 98 and 77 mg/kg, respectively, for TNT freshly amended into soil and 48 and 37 mg/kg, respectively, for weathered and aged TNT soil treatments. These findings of increased toxicity to E. crypticus in weathered and aged TNT soil treatments compared with exposures in freshly amended soils show that future investigations should include a weathering and aging component to generate toxicity data that provide more complete information on ecotoxicological effects of energetic contaminants in soil. [source] Meta-Analysis Examining the Efficacy and Safety of Almotriptan in the Acute Treatment of MigraineHEADACHE, Issue 8 2007Li-Chia Chen PhD Objective.,To evaluate the comparative efficacy and safety of oral almotriptan in treating acute migraine attacks. Background.,Almotriptan is an oral selective sertonin1B/1D receptor agonist (triptan) with a high bioavailability and short half-life, developed for the treatment of migraine. In recent years, a number of randomized controlled trials have been published examining the efficacy and safety of almotriptan in the acute treatment of migraine. Methods.,Systematic review and meta-analysis of randomized controlled trials (RCTs) using a random-effects model to estimate the pooled rate ratios (RRs) and 95% confidence intervals (95%CI) for the proportions of patients achieving headache relief and pain-free responses at 1 or 2 hours post-dose, sustained pain-free response at 2,24 hours post-dose, and safety outcomes (proportions of patients experiencing any adverse events, dizziness, somnolence, asthenia, and chest tightness) comparing almotriptan against placebo, other triptans, and different dosages of almotriptan. Absolute rate differences (ARDs) for 2-hour headache relief, pain free, and sustained pain free responses between almotriptan and placebo were also calculated. Results.,Eight RCTs involving 4995 patients were included in the analysis. Almotriptan 12.5 mg was significantly more effective than placebo for all efficacy outcomes (RRs ranged from 1.47 to 2.15; ARDs ranged from 0.01 to 0.28) and there were no significant differences in any of the safety outcomes. There were also no significant differences in efficacy outcomes comparing almotriptan 12.5 mg against sumatriptan 100 mg and zolmitriptan 2.5 mg, but almotriptan 12.5 mg was associated with significantly fewer adverse events than sumatriptan 100 mg (RR: 0.39, 95%CI: 0.23, 0.67). However, there was no significant difference between almotriptan and sumatriptan in terms of clinically important adverse effects, such as dizziness, somnolence, asthenia, and chest tightness. Almotriptan 12.5 mg was significantly less effective than almotriptan 25 mg for 1-hour pain-free response (RR: 0.45, 95%CI: 0.21, 0.95), but associated with significantly fewer patients experiencing adverse events (RR: 0.61, 95%CI: 0.41, 0.91) than almotriptan 25 mg. Conclusions.,Almotriptan 12.5 mg is an effective treatment for acute attacks of migraine, in particular, it has been found to be as effective as sumatriptan 100 mg and zolmitriptan 2.5 mg. The risk of adverse events associated with almotriptan 12.5 mg was similar to placebo and significantly lower than sumatriptan 100 mg. Further research is required to assess the comparative efficacy of almotriptan against other triptans. [source] BRIEF COMMUNICATIONS: A quantity survey of intravenous administration of metronidazole in its different forms in a tertiary teaching hospitalINTERNAL MEDICINE JOURNAL, Issue 8 2010L. L. Lee Abstract The aim of this paper is to examine the prescribing patterns and cost of various formulations of metronidazole in a hospital setting over a 3-month period. Oral metronidazole has high bioavailability (98.9%) with peak plasma concentrations averaged at 2.3 h after dosing. Despite the high bioavailability of oral metronidazole, many patients continue to receive metronidazole intravenously when they are suitable for oral preparation. An audit of 120 consecutive patients prescribed metronidazole was conducted at the Liverpool Hospital, NSW, from March to July 2005. There were 65 men and 55 women (age 18,93). Of the 120 patients, 16 were on oral, 1 on rectal and 103 were on intravenous metronidazole. Treatment was initiated based on clinical diagnoses. Potential pathogens were subsequently identified on only 21 occasions. The use of metronidazole as an oral preparation was contraindicated in 27 patients (22.5%) who were nil-by-mouth. Of these, rectally administered metronidazole was contraindicated in only eight patients. The average course of intravenous metronidazole was 8.0 ± 9.7 days (mean ± SD). The total number of intravenous metronidazole treatment days was 824. Oral metronidazole would have been possible in 618 out of the 824 days. The estimated cost to administer each dose of oral, suppository and intravenous forms of metronidazole is $A0.11, $A1.34 and $A6.09 respectively. Thus, substantial savings could be achieved if oral metronidazole were to be administered whenever possible. The early use of oral or rectal metronidazole should be encouraged when there are no clinical contraindications. [source] Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activityJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010R. A. HUANG Huang, R. A., Letendre, L. T., Banav, N., Fischer, J., Somerville, B. Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. J. vet. Pharmacol. Therap.33, 227,237. The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN®), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUCinf) was 4.28 ± 0.536 ,g·h/mL, and mean elimination half-life (t1/2) was 44.9 ± 4.67 h, with a large volume of distribution (Vss) of 24.9 ± 2.99 L/kg and a high clearance rate (Clobs) of 712 ± 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUCinf values were 4.55 ± 0.690, 9.42 ± 1.11 and 12.2 ± 1.13 ,g·h/mL, respectively, and the mean elimination half-lives (t1/2) were 51.2 ± 6.10, 50.8 ± 3.80 and 58.5 ± 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6,112%) after s.c. administration. No statistically significant (, = 0.05) gender differences in the AUCInf or elimination half-life values were observed. Dose proportionality was established based on AUCInf over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day (,24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUCinf was 194 times higher than the corresponding plasma AUCinf. The apparent elimination half-life for gamithromycin in lung was 90.4 h (,4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 ± 0.60% bound over a range of 0.1,3.0 ,g/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease. [source] Pharmacokinetic,pharmacodynamic integration of danofloxacin after intravenous, intramuscular and subcutaneous administration to rabbitsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2007E. FERNÁNDEZ-VARÓN The pharmacokinetics of danofloxacin was studied following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of 6 mg/kg to healthy rabbits. Danofloxacin concentration were determined by high-performance liquid chromatography assay with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of danofloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The danofloxacin plasma concentration versus time data after i.v. administration could best be described by a two-compartment open model. The disposition of i.m. and subcutaneously administered danofloxacin was best described by a one-compartment model. The terminal half-life for i.v., i.m. and s.c. routes was 4.88, 6.70 and 8.20 h, respectively. Clearance value after i.v. dosing was 0.76 L/kg·h. After i.m. administration, the absolute bioavailability was mean (±SD) 102.34 ± 5.17% and the Cmax was 1.87 mg/L. After s.c. administration, the absolute bioavailability was mean (±SD) 96.44 ± 5.95% and the Cmax was 1.79 mg/L. Danofloxacin shows a favourable pharmacokinetics profile in rabbits reflected by parameters such as a long half-life and a high bioavailability. However, in consideration of the low AUC/MIC indices obtained, its use by i.m. and s.c. route against the S. aureus strains assayed in this study cannot be recommended given the risk for selection of first mutant subpopulations. [source] Bound and unextractable pesticidal plant residues: chemical characterization and consumer exposurePEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 7 2004Heinrich Sandermann Jr Abstract Plants are well known to incorporate pesticides into bound and unextractable residues that resist solubilization in common laboratory solvents and are therefore not accessible to standard residue analysis. A characterization of such residues has been proposed for incorporation rates above trigger values of 0.05 mg kg,1 parent pesticide equivalents, or percentage values of 10% (United States Environmental Protection Agency, 1995) or 25% (Commission of the European Communities, 1997) of the total radioactive residue. These trigger values are often exceeded. The present review describes the current status of the chemical characterization and animal bioavailability of bound and unextractable residues that may be xenobiotic in nature or result from natural recycling of simple degradation products. The latter case represents a mechanism of detoxification. Bound residues have been shown to be covalent or non-covalent in nature. With regard to the plant matrix molecules involved, incorporation into proteins, lignins, pectins, hemicelluloses and cutins has been demonstrated, and four covalent linkage types are known. Animal feeding experiments have revealed cases of low as well as high bioavailability. Many of the studies are limited by experimental uncertainties and by results only being reported as relative percentage values rather than absolute exposure. A preliminary value of absolute exposure from bound and unextractable residues is derived here for the first time from eight case studies. The mean exposure (ca 1.5 mg kg,1 pesticidal equivalents) exceeds some of the existing maximum residue levels (MRLs) of residual free pesticides that are typically in the range of 0.05,1 mg kg,1. A mathematical framework for the correction of current maximum residue levels is presented for cases of highly bioavailable bound residues. As bound pesticidal residues in food plants could represent a source of significant consumer exposure, an experimental test scheme is proposed here. It consists of basic chemical characterization, model digestibility tests and, in exceptional cases, animal bioavailability and additional toxicological studies. Copyright © 2004 Society of Chemical Industry [source] Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine, a novel and selective p38, inhibitor: identification of an active metabolite in preclinical species and human liver microsomesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2006Amit S. Kalgutkar Abstract The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38,, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vdss) ranging from 0.4,1.3 l/kg (2.4,26 l/m2) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m2) and Sprague-Dawley rats (7.65±1.08 ml/min/kg, 45.9±6.48 ml/min/m2 in male rats and 3.15±0.27 ml/min/kg, 18.9±1.62 ml/min/m2 in female rats) and moderate in beagle dogs (12.3±5.1 ml/min/kg, 246±102 ml/min/m2) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30,65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38, in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (fu,0.1,0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50>50 µM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent. Copyright © 2006 John Wiley & Sons, Ltd. [source] | ||||||||||