Aims The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation. Methods Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 mg ) of FP via DiskhalerA and repeated inhalations (1000 mg twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 mg FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values. Results The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6-18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20-65]% and 95 [93-97]% for the single and repeated doses, respectively. Conclusions To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.
We have previously shown that nicotine, the addictive component of tobacco products, alters the blood-brain barrier (BBB) Na ϩ ,K ϩ ,2Cl Ϫ cotransporter (NKCC) during in vitro hypoxiaaglycemia exposure. Attenuation of abluminal NKCC suggests that accumulation of ions in the brain extracellular fluid would result in an increase of fluid or cytotoxic edema in the brain during hypoxia-aglycemia or stroke conditions. To further investigate whether nicotine products have the potential to worsen stroke outcome by increasing edema formation, two separate models to mimic stroke conditions were utilized to decipher the effects of short-term and long-term administrations of nicotine products on brain edema following stroke. Oxygen glucose deprivation (OGD) was studied in rat hippocampal slices with short-term or long-term exposure to nicotine and cigarette smoke constituents. During short-term exposure, the presence of nicotine at a concentration mimicking heavy smokers increased water content of hippocampal slices during OGD. Furthermore, long-term 1-week administration of nicotine increased water content in hippocampal slices that could be attenuated with nicotine acetylcholine receptor (nAChR) antagonists, suggesting nicotine increase edema during OGD via nAChRs. A second model of focal ischemia, middle cerebral artery occlusion, showed an increase of infarct size during short-term exposure to nicotine and an increase of edema during both short-term and long-term administration of nicotine, compared with saline controls. These findings support the paradigm that nicotine products not only increase the incidence of stroke but also have the potential to worsen stroke outcome by increased edema formation.
Of the cyclodextrins tested, DMbetaCD was the most efficacious in enhancing absorption of LMWHs both in vivo and in vitro. The study also suggests that cyclodextrins enhance nasal drug absorption by opening of cell-cell tight junctions.
Smoking tobacco, including cigarettes, has been associated with an increased incidence and relative risk for cerebral infarction in both men and women. Recently, we have shown that nicotine and cotinine attenuate abluminal (brain facing) K ϩ uptake mediated by the Na,K,2Cl-cotransporter (NKCC) in bovine brain microvessel endothelial cells (BBMECs) after hypoxic/ aglycemic exposure (stroke conditions). The purpose of the current study was to explore the effects of nicotine and tobacco smoke chemicals on K ϩ movement through the blood-brain barrier during both hypoxia/aglycemia and reoxygenation. BBMECs were exposed to nicotine/cotinine, nicotine-containing cigarette smoke extract (N-CSE), or nicotine-free cigarette smoke extract (NF-CSE) in quantities designed to mimic plasma concentrations of smokers. Stroke conditions were mimicked in vitro in BBMECs through 6 h of hypoxia/aglycemia with or without 12 h of reoxygenation, after which NKCCmediated K ϩ uptake and paracellular integrity were measured with 86 Rb and [ 14 C]sucrose, respectively. In addition, K ϩ concentrations in brain extracellular fluid were estimated in 86 Rb-injected rats that were administered nicotine, N-CSE, or NF-CSE and on whom global ischemia/reperfusion by in vivo four-vessel occlusion was performed. Both in vitro and in vivo paradigms showed nicotine, the major alkaloid present in tobacco smoke, to be the determining factor of an inhibited response of abluminal NKCC in BBMECs during and after stroke conditions. This was measured as a decrease in abluminal brain endothelial cell NKCC activity and as an increase in brain extracellular K ϩ concentration measured as the brain extracellular fluid 86 Rb/plasma ratio after in vivo four-vessel occlusion with reperfusion.
We investigated the effects of a soluble sialyl Lewisx-containing oligosaccharide (SLex-OS) in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, a survival time of 85 +/- 15 min, significant increases in ileal myeloperoxidase (P < 0.01), and plasma free amino-nitrogen activities (P < 0.01). Treatment with SLex-OS (10 mg/kg) 10 min posttrauma prolonged survival time to 198 +/- 29 min (P < 0.01), significantly attenuated ileal myeloperoxidase activity (P < 0.01), and diminished the accumulation of plasma free amino-nitrogen (P < 0.01), drug vs. vehicle, respectively. Furthermore, endothelium-dependent relaxation to acetylcholine in superior mesenteric artery rings isolated from SLex-OS-treated shock rats was significantly preserved (70 +/- 6 vs. 40 +/- 5% relaxation). No beneficial effects were observed using a nonfucosylated control oligosaccharide. Moreover, addition of SLex-OS significantly inhibited unstimulated human polymorphonuclear neutrophil (PMN) adherence in vitro to trauma-activated superior mesenteric artery endothelium ex vivo (P < 0.001). Our results indicate that SLex-OS exerts beneficial effects in traumatic shock states by blocking selectin-mediated leukocyte-endothelium interaction, thus improving survival, attenuating intestinal PMN accumulation, and diminishing shock-induced tissue injury.
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