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1.
Drug Dev Ind Pharm ; 42(8): 1334-9, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26755336

ABSTRACT

The objective of this study was to utilize physiologically relevant dynamic dissolution testing with the TNO intestinal model (TIM-1) in vitro gastrointestinal model to investigate the bioaccessibility of celecoxib. A single 200-mg dose of celecoxib was evaluated under average adult human physiological conditions simulated in the TIM-1 system. The in vitro data were compared with the clinically established pharmacokinetic data. When expressed as a percent of drug that progresses from the duodenum to the jejunum and ileum compartments (bioaccessible sites), the study demonstrated a 2-fold increase in the total bioaccessibility for celecoxib when co-administered with a high-fat meal as opposed to co-administration with a glass of water (fasted conditions). That increase in bioaccessibility was similar to a 1.2 to 1.6-fold increase in systemic exposure in adults and children following co-administration with a high-fat meal when compared to the exposure measured when celecoxib was co-administered with only water. Following that comparison, the flexibility of the TIM-1 system was used to more specifically investigate individual parameters of gastrointestinal conditions, such as the rate of bile secretion (emptying of the bile bladder) that accompanies high-fat meal consumption. We demonstrated that increased bile secretion after co-administration of a high-fat meal played a more important role in the increased celecoxib bioaccessibility than did the food matrix. This indicates that in humans without a bile bladder the exposure of celecoxib administered with food might be as low as under fasted state.


Subject(s)
Bile/metabolism , Celecoxib/pharmacokinetics , Fasting/metabolism , Gastrointestinal Tract/metabolism , Adult , Biological Availability , Diet, High-Fat/methods , Food , Food-Drug Interactions/physiology , Humans , Models, Biological , Solubility
2.
J Immunol ; 183(1): 613-20, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19535637

ABSTRACT

Multiple sclerosis (MS) is an autoimmune disease of the CNS characterized by disruption of the blood-brain barrier (BBB). This breach in CNS immune privilege allows undeterred trafficking of myelin-specific lymphocytes into the CNS where they induce demyelination. Although the mechanism of BBB compromise is not known, the chemokine CXCL12 has been implicated as a molecular component of the BBB whose pattern of expression is specifically altered during MS and which correlates with disease severity. The inflammatory cytokine IL-1beta has recently been shown to contribute not only to BBB permeability but also to the development of IL-17-driven autoimmune responses. Using experimental autoimmune encephalomyelitis, the rodent model of MS, we demonstrate that IL-1beta mediates pathologic relocation of CXCL12 during the induction phase of the disease, before the development of BBB disruption. We also show that CD4, CD8, and, surprisingly gammadelta T cells are all sources of IL-1beta. In addition, gammadelta T cells are also targets of this cytokine, contributing to IL-1beta-mediated production of IL-17. Finally, we show that the level of CNS IL-1R determines the clinical severity of experimental autoimmune encephalomyelitis. These data suggest that T cell-derived IL-1beta contributes to loss of immune privilege during CNS autoimmunity via pathologic alteration in the expression of CXCL12 at the BBB.


Subject(s)
Blood-Brain Barrier/immunology , Chemokine CXCL12/biosynthesis , Encephalomyelitis, Autoimmune, Experimental/immunology , Receptors, Interleukin-1/physiology , Severity of Illness Index , Signal Transduction/immunology , Spinal Cord/immunology , Spinal Cord/metabolism , Animals , Chemokine CXCL12/genetics , Chemokine CXCL12/metabolism , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Transport/genetics , Protein Transport/immunology , Receptors, Interleukin-1/deficiency , Receptors, Interleukin-1/genetics , Signal Transduction/genetics , Spinal Cord/pathology
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