Purpose To establish a lymph-cannulated mouse model, and use the model to investigate the impact of lipid dose on exogenous and endogenous lipid recruitment, and drug transport, into the lymph of males versus females. Finally, lymphatic transport and drug absorption in the mouse were compared to other pre-clinical models (rats/dogs). Methods Animals were orally or intraduodenally administered 1.6 mg/kg halofantrine in low or high 14C-lipid doses. For bioavailability calculation, animals were intravenuosly administered halofantrine. Lymph or blood samples were taken and halofantrine, triglyceride, phospholipid and 14C-lipid concentrations measured. Results Lymphatic lipid transport increased linearly with lipid dose, was similar across species and in male/female animals. In contrast, lymphatic transport of halofantrine differed markedly across species (dogs>rats>mice) and plateaued at higher lipid doses. Lower bioavailability appeared responsible for some species differences in halofantrine lymphatic transport; however other systematic differences were involved. Conclusions A contemporary lymph-cannulated mouse model was established which will enable investigation of lymphatic transport in transgenic and disease models. The current study found halofantrine absorption and lymphatic transport are reduced in small animals. Future analyses will investigate mechanisms involved, and if similar trends occur for other drugs, to establish the most relevant model(s) to predict lymphatic transport in humans.
We tested the activity of anidulafungin against 30 Candida albicans isolates. The planktonic MICs for 50 and 90% of the isolates tested (MIC 50 and MIC 90 ) were <0.03 and 0.125 g/ml, respectively (MIC range, <0.03 to 2 g/ml). The sessile MIC 50 and MIC 90 were <0.03 and <0.03 g/ml, respectively (MIC range, <0.03 to >16 g/ml).Candida albicans infections seen in modern clinical practice, such as device-and intravascular catheter-related infections (2, 5), are associated with the growth of organisms in a biofilm state. Device removal is often necessary for a cure (7) since antimicrobials have traditionally been considered to be poorly active against microorganisms in biofilms. If, however, antimicrobials are active against microbial biofilms, device removal may be unnecessary. It has been proposed that antifungal agents that target cell wall synthesis may be active against C. albicans biofilms (1).We recently determined the in vitro antifungal activities of caspofungin and voriconazole against 30 clinical C. albicans isolates in their planktonic and sessile states. Susceptibility testing of the isolates in their planktonic and sessile forms revealed a marked rise in the voriconazole MIC for 90% of the isolates tested (MIC 90 ), which was much less marked for caspofungin (8). We also demonstrated that caspofungin was active in vivo in an experimental intravascular catheter infection model (9). Recently, Choi et al. reported that micafungin was active against biofilms formed by C. albicans (3), and Katragkou et al. reported that anidulafungin was active against two C. albicans strains in the biofilm state (6). The purpose of this study was to determine the in vitro activity of anidulafungin against our collection of C. albicans (8) grown in planktonic and sessile states.Thirty C. albicans clinical isolates obtained from sterile-site infections from October 2003 through October 2004 were studied (8). One isolate per patient was studied. Ten isolates were from blood cultures, including eight from patients with central venous catheters. The other 20 isolates were from peritoneal fluid (n ϭ 6), abscess fluid (n ϭ 5), soft tissue (n ϭ 5), bone (n ϭ 2), and pleural fluid and urine (n ϭ 1 each). C. albicans GDH2346 was used as a positive control. Anidulafungin concentrations ranging from 16 to 0.03 g/ml were tested.Planktonic MICs were determined by Clinical and Laboratory Standards Institute broth microdilution methods (4). The lowest concentration associated with a significant reduction in turbidity compared with the control well at 48 h was reported as the MIC (4). Isolates for which the MICs were Ͼ0.125 g/ml were retested and read at 24 and 48 h, as others have reported MICs after 24 h (6).Sessile MICs were determined with biofilms formed in 96-well flat-bottom microtiter plates as previously described (8). Yeast cells were grown overnight in yeast nitrogen base medium, washed twice in sterile phosphate-buffered saline (PBS), and standardized to 1 ϫ 10 7 CFU/ml in RPMI medium. Each well was filled with 100 l C. albican...
Consistent with their role in the cellular transport of endogenous lipophilic substrates, FABPs appear to facilitate the intracellular disposition of drug molecules that bind FABPs in vitro. Drug binding to FABPs in the enterocyte may also attenuate gut wall metabolism in a manner analogous to the reduction in hepatic extraction mediated by drug binding to plasma proteins in the systemic circulation.
Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.
BackgroundIL-4 and IL-13 play a critical yet poorly understood role in orchestrating the recruitment and activation of effector cells of the asthmatic response and driving the pathophysiology of allergic asthma. The house dust mite (HDM) sheep asthma model displays many features of the human condition and is an ideal model to further elucidate the involvement of these critical Th2 cytokines. We hypothesized that airway exposure to HDM allergen would induce or elevate the expression profile of IL-4 and IL-13 during the allergic airway response in this large animal model of asthma.MethodsBronchoalveolar lavage (BAL) samples were collected from saline- and house dust mite (HDM)- challenged lung lobes of sensitized sheep from 0 to 48 h post-challenge. BAL cytokines (IL-4, IL-13, IL-6, IL-10, TNF-α) were each measured by ELISA. IL-4 and IL-13 expression was assessed in BAL leukocytes by flow cytometry and in airway tissue sections by immunohistology.ResultsIL-4 and IL-13 were increased in BAL samples following airway allergen challenge. HDM challenge resulted in a significant increase in BAL IL-4 levels at 4 h compared to saline-challenged airways, while BAL IL-13 levels were elevated at all time-points after allergen challenge. IL-6 levels were maintained following HDM challenge but declined after saline challenge, while HDM administration resulted in an acute elevation in IL-10 at 4 h but no change in TNF-α levels over time. Lymphocytes were the main early source of IL-4, with IL-4 release by alveolar macrophages (AMs) prominent from 24 h post-allergen challenge. IL-13 producing AMs were increased at 4 and 24 h following HDM compared to saline challenge, and tissue staining provided evidence of IL-13 expression in airway epithelium as well as immune cells in airway tissue.ConclusionIn a sheep model of allergic asthma, airway inflammation is accompanied by the temporal release of key cytokines following allergen exposure that primarily reflects the Th2-driven nature of the immune response in asthma. The present study demonstrates for the first time the involvement of IL-4 and IL-13 in a relevant large animal model of allergic airways disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.