Therapeutic drug monitoring (TDM) is the clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patient's bloodstream, thereby optimizing individual dosage regimens. It is unnecessary to employ TDM for the majority of medications, and it is used mainly for monitoring drugs with narrow therapeutic ranges, drugs with marked pharmacokinetic variability, medications for which target concentrations are difficult to monitor, and drugs known to cause therapeutic and adverse effects. The process of TDM is predicated on the assumption that there is a definable relationship between dose and plasma or blood drug concentration, and between concentration and therapeutic effects. TDM begins when the drug is first prescribed, and involves determining an initial dosage regimen appropriate for the clinical condition and such patient characteristics as age, weight, organ function, and concomitant drug therapy. When interpreting concentration measurements, factors that need to be considered include the sampling time in relation to drug dose, dosage history, patient response, and the desired medicinal targets. The goal of TDM is to use appropriate concentrations of difficult-to-manage medications to optimize clinical outcomes in patients in various clinical situations.

Bacteroides fragilis produces an approximately 20-kDa heat-labile toxin (B. fragilis enterotoxin, BFT) which is known to be associated with diarrhea. To determine whether cyclooxygenase (COX)-2, via NF-jB activation, can contribute to BFT-induced diarrhea, the relationship between COX-2 expression and fluid secretion in BFT-stimulated human intestinal epithelial cells was examined. BFT stimulation increased the expression of COX-2, but not COX-1, in human intestinal epithelial cells. Suppression of the NF-jB signal significantly decreased COX-2 expression in response to BFT stimulation. Prostaglandin E 2 (PGE 2 ) levels were increased in parallel with COX-2 expression, and, conversely, PGE 2 production was significantly inhibited when COX-2 or NF-jB activities were suppressed using COX-2 small interfering RNA (siRNA), p65 NF-jB subunit siRNA, or a retrovirus encoding the IjBa superrepressor. In addition, a selective COX-2 inhibitor, NS-398, significantly inhibited the increased cAMP level induced by BFT stimulation. Furthermore, a selective COX-2 inhibitor prevented BFTinduced PGE 2 production and ileal fluid secretion in a mouse ileal loop model. These results suggest that the secretory response to BFT stimulation may be mediated by the production of PGE 2 , through NF-jB activation and the up-regulation of COX-2 in intestinal epithelial cells. IntroductionEnterotoxigenic Bacteroides fragilis (ETBF) has been shown to be associated with non-invasive diarrheal diseases in animals and young children [1][2][3][4][5], and B. fragilis enterotoxin (BFT), an approximately 20-kDa heat-labile metalloprotease, is regarded as a virulence factor for this diarrheal disease. BFT stimulates NF-jB activation and IL-8 secretion [6][7][8][9], which is predicted to lead to mucosal transmigration of neutrophils with release of prostaglandins (PG). In addition, animal loop experiments and gnotobiotic piglet infection indicate that BFT is proinflammatory and BFT stimulates a brief chloride current and a loss of barrier function in vitro [3,10], suggesting that these findings are potential mechanisms accounting for ETBF-induced diarrhea. Several studies have shown that secretion of PG from intestinal mucosal epithelial cells is closely associated with diarrheal diseases [11,12], and administration of PG analogues, such as PGE 2 , causes increased fluid secretion in human subjects [13,14]. In addition, the roles of PG in the secretory response to cholera toxin and enterotoxigenic Escherichia coli have been demonstrated [15][16][17]. These results suggest the hypothesis that the diarrhea associated with ETBF may be PG-derived. PGE 2 is a metabolite of arachidonic acid and is synthesized by cyclooxygenase (COX). There are two isoforms of this enzyme [18]: COX-1, which is constitutively expressed in crypt epithelial cells, and COX-2, which can be induced in a variety of cell types, including epithelial cells, macrophages and fibroblasts. COX-2 is induced by proinflammatory cytokines, lipopolysaccharide and infectious agents [19]. The expr...

Enterotoxigenic Bacteroides fragilis (ETBF) produces an approximately 20-kDa heat-labile enterotoxin (BFT) that plays an essential role in mucosal inflammation. Although spontaneous disappearance of ETBF infection is common, little information is available on regulated expression of antibacterial factors in response to BFT stimulation. This study investigates the role of BFT in human β-defensin 2 (hBD-2) induction from intestinal epithelial cells. Stimulation of HT-29 and Caco-2 intestinal epithelial cell lines with BFT resulted in the induction of hBD-2. Activation of a reporter gene for hBD-2 was dependent on the presence of NF-κB binding sites. In contrast, suppression of AP-1 did not affect hBD-2 expression in BFT-stimulated cells. Inhibition of p38 mitogen-activated protein kinase (MAPK) using SB203580 and small interfering RNA (siRNA) transfection resulted in a significant reduction in BFT-induced IκB kinase (IKK)/NF-κB activation and hBD-2 expression. Our results suggest that a pathway including p38 MAPK, IKK, and NF-κB activation is required for hBD-2 induction in intestinal epithelial cells exposed to BFT, and may be involved in the host defense following infection with ETBF.

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Exosomes are membranous vesicles of 30-150 nm in diameter that are derived from the exocytosis of the intraluminal vesicles of many cell types including immune cells, stem cells, cardiovascular cells and tumor cells. Exosomes participate in intercellular communication by delivering their contents to recipient cells, with or without direct contact between cells, and thereby influence physiological and pathological processes. They are present in various body fluids and contain proteins, nucleic acids, lipids, and microRNAs that can be transported to surrounding cells. Theragnosis is a concept in next-generation medicine that simultaneously combines accurate diagnostics with therapeutic effects. Molecular components in exosomes have been found to be related to certain diseases and treatment responses, indicating that they may have applications in diagnosis via molecular imaging and biomarker detection. In addition, recent studies have reported that exosomes have immunotherapeutic applications or can act as a drug delivery system for targeted therapies with drugs and biomolecules. In this review, we describe the formation, structure, and physiological roles of exosomes. We also discuss their roles in the pathogenesis and progression of diseases including neurodegenerative diseases, cardiovascular diseases, and cancer. The potential applications of exosomes for theragnostic purposes in various diseases are also discussed. This review summarizes the current knowledge about the physiological and pathological roles of exosomes as well as their diagnostic and therapeutic uses, including emerging exosome-based therapies that could not be applied until now.