- Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. [Journal Article]
- SRSci Rep 2017 Nov 10; 7(1):15307
- The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta vi...
The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection. 1280 FDA/EMA-approved drugs were screened to identify compounds that reduce uptake of taurocholic acid and lower Myrcludex B-binding in U2OS cells stably expressing human NTCP. HBV/HDV viral entry inhibition was studied in HepaRG cells. The four most potent inhibitors of human NTCP were rosiglitazone (IC505.1 µM), zafirlukast (IC506.5 µM), TRIAC (IC506.9 µM), and sulfasalazine (IC509.6 µM). Chicago sky blue 6B (IC507.1 µM) inhibited both NTCP and ASBT, a distinct though related bile acid transporter. Rosiglitazone, zafirlukast, TRIAC, sulfasalazine, and chicago sky blue 6B reduced HBV/HDV infection in HepaRG cells in a dose-dependent manner. Five out of 1280 clinically approved drugs were identified that inhibit NTCP-mediated bile acid uptake and HBV/HDV infection in vitro.
- Neuropsychiatric Events Associated with Leukotriene-Modifying Agents: A Systematic Review. [Review]
- DSDrug Saf 2017 Oct 26
- CONCLUSIONS: The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association.Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults.
- Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs. [Journal Article]
- EJEur J Pharm Sci 2018 Jan 01; 111:247-256
- Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal s...
Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique. In this study a design of experiment covering the full range from the lower limit of fasted to the upper limit of fed parameters and using a small number of experiments has been performed. The measured equilibrium solubility values are comparable with literature values for simulated fasted and fed intestinal fluids as well as human fasted and fed intestinal fluids. The equilibrium solubility data range is statistically equivalent to a combination of published fasted and fed design of experiment data in six (indomethacin, phenytoin, zafirlukast, carvedilol, fenofibrate and probucol) drugs with three (aprepitant, tadalafil and felodipine) drugs not equivalent. In addition the measured equilibrium solubility data sets were not normally distributed. Further studies will be required to determine the reasons for these results however it implies that a single solubility measurement without knowledge of the solubility distribution will be of limited value. The statistically significant media factors which promote equilibrium solubility (pH, sodium oleate and bile salt) were in agreement with published results but the number of determined significant factors and factor interactions was fewer in this study, lecithin for example did not influence solubility. This may be due to the reduction in statistical sensitivity from the lower number of experimental data points or the fact that using the full range will examine media parameters ratios that are not biorelevant. Overall the approach will provide an estimate of the solubility range and the most important media factors but will not be equivalent to larger scale focussed studies. Further investigations will be required to determine why some drugs do not produce equivalent DoE solubility distributions, for example combined fasted and fed DoE, but this simply may be due to the complexity and individuality of the interactions between a drug and the media components.
- Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments. [Journal Article]
- EJEur J Pharm Sci 2018 Jan 01; 111:311-319
- The composition of the human intestinal fluids varies both intra- and inter-individually. This will influence the solubility of orally administered drug compounds, and hence, the absorption and effic...
The composition of the human intestinal fluids varies both intra- and inter-individually. This will influence the solubility of orally administered drug compounds, and hence, the absorption and efficacy of compounds displaying solubility limited absorption. The purpose of this study was to assess the influence of simulated intestinal fluid (SIF) composition on the solubility of poorly soluble compounds. Using a Design of Experiments (DoE) approach, a set of 24 SIF was defined within the known compositions of human fasted state intestinal fluid. The SIF were composed of phospholipid, bile salt, and different pH, buffer capacities and osmolarities. On a small scale semi-robotic system, the solubility of 6 compounds (aprepitant, carvedilol, felodipine, fenofibrate, probucol, and zafirlukast) was determined in the 24 SIF. Compound specific models, describing key factors influencing the solubility of each compound, were identified. Although all models were different, the level of phospholipid and bile salt, the pH, and the interactions between these, had the biggest influences on solubility overall. Thus, a reduction of the DoE from five to three factors was possible (11-13 media), making DoE solubility studies feasible compared to single SIF solubility studies. Applying this DoE approach will lead to a better understanding of the impact of intestinal fluid composition on the solubility of a given drug compound.
- Influence of Physiological Gastrointestinal Surfactant Ratio on the Equilibrium Solubility of BCS Class II Drugs Investigated Using a Four Component Mixture Design. [Journal Article]
- MPMol Pharm 2017 Dec 04; 14(12):4132-4144
- The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced in...
The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced into dissolution testing including endogenous amphiphiles and digested lipids at physiological levels; however, in vivo individual variation exists in the concentrations of these components, which will alter drug absorption through an effect on solubility. The use of a factorial design of experiment and varying media by introducing different levels of bile, lecithin, and digested lipids has been previously reported, but here we investigate the solubility variation of poorly soluble drugs through more complex biorelevant amphiphile interactions. A four-component mixture design was conducted to understand the solubilization capacity and interactions of bile salt, lecithin, oleate, and monoglyceride with a constant total concentration (11.7 mM) but varying molar ratios. The equilibrium solubility of seven low solubility acidic (zafirlukast), basic (aprepitant, carvedilol), and neutral (fenofibrate, felodipine, griseofulvin, and spironolactone) drugs was investigated. Solubility results are comparable with literature values and also our own previously published design of experiment studies. Results indicate that solubilization is not a sum accumulation of individual amphiphile concentrations, but a drug specific effect through interactions of mixed amphiphile compositions with the drug. This is probably due to a combined interaction of drug characteristics; for example, lipophilicity, molecular shape, and ionization with amphiphile components, which can generate specific drug-micelle affinities. The proportion of each component can have a remarkable influence on solubility with, in some cases, the highest and lowest points close to each other. A single-point solubility measurement in a fixed composition simulated media or human intestinal fluid sample will therefore provide a value without knowledge of the surrounding solubility topography meaning that variability may be overlooked. This study has demonstrated how the amphiphile ratios influence drug solubility and highlights the importance of the envelope of physiological variation when simulating in vivo drug behavior.
- Validation of Dissolution Testing with Biorelevant Media: An OrBiTo Study. [Journal Article]
- MPMol Pharm 2017 Dec 04; 14(12):4192-4201
- Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Unt...
Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Until now, however, there have been few attempts to gauge the reproducibility of results obtained with these methods. The aim of this study was to determine the interlaboratory reproducibility of biorelevant dissolution testing, using the paddle apparatus (USP 2). Thirteen industrial and three academic laboratories participated in this study. All laboratories were provided with standard protocols for running the tests: dissolution in FaSSGF to simulate release in the stomach, dissolution in a single intestinal medium, FaSSIF, to simulate release in the small intestine, and a "transfer" (two-stage) protocol to simulate the concentration profile when conditions are changed from the gastric to the intestinal environment. The test products chosen were commercially available ibuprofen tablets and zafirlukast tablets. The biorelevant dissolution tests showed a high degree of reproducibility among the participating laboratories, even though several different batches of the commercially available medium preparation powder were used. Likewise, results were almost identicalbetween the commercial biorelevant media and those produced in-house. Comparing results to previous ring studies, including those performed with USP calibrator tablets or commercially available pharmaceutical products in a single medium, the results for the biorelevant studies were highly reproducible on an interlaboratory basis. Interlaboratory reproducibility with the two-stage test was also acceptable, although the variability was somewhat greater than with the single medium tests. Biorelevant dissolution testing is highly reproducible among laboratories and can be relied upon for cross-laboratory comparisons.
- Cysteinyl Leukotriene Receptor Antagonists Inhibit Migration, Invasion, and Expression of MMP-2/9 in Human Glioblastoma. [Journal Article]
- CMCell Mol Neurobiol 2017 Jun 09
- Glioblastoma is one of the most malignant and aggressive types of brain tumors. 5-lipoxygenase and cysteinyl leukotriene receptor 1 (CysLT1) play a role in human carcinogenesis. Leukotriene receptor ...
Glioblastoma is one of the most malignant and aggressive types of brain tumors. 5-lipoxygenase and cysteinyl leukotriene receptor 1 (CysLT1) play a role in human carcinogenesis. Leukotriene receptor antagonists (LTRAs), anti-asthmatic drugs with mild side effects, have anti-metastatic activity in epidermoid carcinoma, lung carcinoma, and colon cancers as well as neuroprotective effects. Herein, anti-migratory effects of two LTRAs, montelukast and zafirlukast, were investigated in glioblastoma cells. The level of CysLT1 in A172 cells was increased by 3.13 folds after IL-1β treatment. The median toxic concentration of LTRAs in A172, U373, and primary astrocytes ranged from 7.17 to 26.28 μM at 24-h post-exposure. Both LTRAs inhibited migration and invasion of glioma. Additionally, both drugs significantly inhibited the expression and activities of MMP-2 and MMP-9 in A172 and U373 glioblastoma cells and primary human astrocytes, suggesting that CysLT1 plays a role in migration and invasion of glioma, and LTRAs are potential drugs to reduce migration and invasion.
- An Innovative High-Throughput Screening Approach for Discovery of Small Molecules That Inhibit TNF Receptors. [Journal Article]
- SDSLAS Discov 2017; 22(8):950-961
- Tumor necrosis factor receptor 1 (TNFR1) is a transmembrane receptor that binds tumor necrosis factor or lymphotoxin-alpha and plays a critical role in regulating the inflammatory response. Upregulat...
Tumor necrosis factor receptor 1 (TNFR1) is a transmembrane receptor that binds tumor necrosis factor or lymphotoxin-alpha and plays a critical role in regulating the inflammatory response. Upregulation of these ligands is associated with inflammatory and autoimmune diseases. Current treatments reduce symptoms by sequestering free ligands, but this can cause adverse side effects by unintentionally inhibiting ligand binding to off-target receptors. Hence, there is a need for new small molecules that specifically target the receptors, rather than the ligands. Here, we developed a TNFR1 FRET biosensor expressed in living cells to screen compounds from the NIH Clinical Collection. We used an innovative high-throughput fluorescence lifetime screening platform that has exquisite spatial and temporal resolution to identify two small-molecule compounds, zafirlukast and triclabendazole, that inhibit the TNFR1-induced IκBα degradation and NF-κB activation. Biochemical and computational docking methods were used to show that zafirlukast disrupts the interactions between TNFR1 pre-ligand assembly domain (PLAD), whereas triclabendazole acts allosterically. Importantly, neither compound inhibits ligand binding, proving for the first time that it is possible to inhibit receptor activation by targeting TNF receptor-receptor interactions. This strategy should be generally applicable to other members of the TNFR superfamily, as well as to oligomeric receptors in general.
- Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1. [Journal Article]
- JPJ Pharm Sci 2017; 106(9):2483-2490
- To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library...
To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty-one and 10 drugs were found to inhibit and enhance 6-CF uptake by more than 50%, respectively. Effect of the 51 drugs on 6-CF uptake was positively correlated with that on PGE2uptake (r = 0.64, p < 0.001). Among those, 5 drugs not structurally related to prostaglandins, suramin, pranlukast, zafirlukast, olmesartan medoxomil, and losartan potassium, exhibited more than 90% PGE2uptake inhibition. Inhibitory affinity of suramin to OATP2A1 was the highest (IC50,2A1of 0.17 μM), and its IC50values to MRP4-mediated PGE2transport (IC50,MRP4) and PGE2synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC50,Syn) were 73.6 and 336.7 times higher than IC50,2A1, respectively. Moreover, structure-activity relationship study in 29 nonsteroidal anti-inflammatory drugs contained in the library displayed inhibitory activities of anthranilic acid derivatives, but enhancing effects of propionic acid derivatives. These results demonstrate that suramin is a potent selective inhibitor of OATP2A1, providing a comprehensive information about drugs in clinical use that interact with OATP2A1.
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- The leukotriene receptor antagonist montelukast and its possible role in the cardiovascular field. [Review]
- EJEur J Clin Pharmacol 2017; 73(7):799-809
- CONCLUSIONS: What it is known about leukotriene receptor antagonists? •Leukotriene receptor antagonist, such as montelukast and zafirlukast, is used in asthma, COPD, and allergic rhinitis. • Montelukast is the most prescribed CysLT1antagonist used in asthmatic patients. • Different in vivo animal studies have shown that leukotriene receptor antagonists can prevent the atherosclerosis progression, and have a protective role after cerebral ischemia. What we still need to know? • Today, there is a need for conducting clinical trials to assess the role of montelukast in reducing cardiovascular risk and to further understand the mechanism of action behind this effect.