Another small compound targeting IBAT
Another small compound targeting IBAT has been evaluated in Phase I clinical trial (EudraCT 2013-001175-21) . The oral administration of A4250 to healthy subjects did not give rise to any serious adverse events, was well tolerated and had a similar safety profile as elobixibat; however, it caused abdominal discomfort, nausea and mild diarrhea. It induced substantial effects on the synthesis of BAs and plasma and fecal BAs levels due to decreased ileal FXR-dependent FGF19 secretion. The local, rather than systemic exposure to A4250 makes it a promising candidate for further research regarding BA-related pathologies . Up to now, the compound was evaluated only in cholestatic liver diseases (ClinicalTrials.gov Identifier: NCT02630875).
Rifaximin is an antibiotic used to treat bacterial infections in the subsets with IBS-D , , . Nevertheless, due to the drug’s low solubility in the aqueous environment of the colon and thereby a low bioavailability, it has minimal effect on colonic flora. To increase its solubility and hamper the spread of microbial invasion more effectively, Darkoh et al. suggested simultaneous administration of BAs and rifaximin . In effect, the rifaximin-BA mixture improved the effectiveness of the anti-diarrheal therapy by disrupting the bacterial cell membrane and facilitating the drug entry into the cytoplasm faster than the treatment based only on the administration of rifaximin. Increasing concentrations of BAs increased rifaximin solubility and caused a marked antimicrobial effect. So far, the effect of the proposed antibiotic-BA combination has been evaluated in vitro, however, such delivery holds potential in delivering the antibiotic to a wider area of the bowel and gives potential to improve the efficacy of other hydrophobic 63 7 in the future .
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Introduction Metabolic syndrome-related diseases are major obstacles for the health systems worldwide. According to the World Health Organization (WHO) the prevalence of obesity has more than doubled between 1980 and 2014 with an overall 13% of the world's adult population being obese in 2014. The occurrence of overweight and obesity is not only an issue in high-income countries but also in urban settings of middle- and low-income countries, linking it globally to more deaths than underweight. The main cause for the increased occurrence of overweight and obesity lies in the enhanced consumption of energy-dense, high-fat foods and an increase in sedentary lifestyles, resulting in an imbalance between energy consumption and expenditure. Overweight and obesity can be seen as gateway conditions facilitating the development of more serious diseases, including diabetes and cardiovascular diseases (WHO, 2016). Nuclear receptors are ligand-activated transcription factors that regulate target gene expression in a wide variety of physiological pathways such as metabolic processes (Degirolamo et al., 2015; Gronemeyer et al., 2004; Mangelsdorf and Evans, 1995). Nuclear receptors involved in metabolism are classified as type 2 nuclear receptors, which are located in the nucleus regardless of ligand binding. With no ligand present, they are bound to the response elements (REs) of target genes together with corepressors. Upon ligand binding, conformational changes lead to the dissociation of these corepressors and to their exchange with coactivators, leading to the initiation of target gene expression (Mangelsdorf and Evans, 1995). Fig. 1 depicts the structural organisation of nuclear receptors. Most type 2 nuclear receptors form heterodimers with the retinoid X receptors (RXRs, NR2B1/NR2B2/NR2B3) (Sever and Glass, 2013). Type 2 nuclear receptors for the regulation of metabolic processes include the liver X receptors [LXRα (NR1H3) and LXRβ (NR1H2)], the farnesoid X receptor (FXR, NR1H4), the peroxisome proliferator-activated receptors (PPARs, NR1C1/NR1C2/NR1C3), and the RXRs. Ligands for these receptors include fatty acids, oxysterols and bile acids as well as rexinoids, pointing to their relevance in the regulation of metabolic pathways (Chawla et al., 2001; Janowski et al., 1996; Keller et al., 1993; Parks et al., 1999) (Fig. 2).