P-glycoprotein inhibitors: synthesis and in vitro evaluation of a preactivated thiomer

Abstract

The aim of this study was to synthesize the preactivated thiomer poly(acrylic acid)-cyteine-2-mercaptonicotinic acid (PAA-Cys-2MNA) and to evaluate its P-glycoprotein (P-gp) inhibitory properties. The thiomer (PAA-Cys) was synthesized by covalent immobilization of thiol groups on poly(acrylic acid) (PAA) with a molecular mass of 250?kDa followed by immobilization of 2-mercaptonicotinic acid (2MNA) to thiol groups via disulfide bond formation resulting in PAA-Cys-2MNA. P-gp inhibitory effect of this preactivated thiomer was evaluated on Caco-2 cells. Transports of rhodamine 123 at 37?°C with and without verapamil and at 4?°C were performed to evaluate P-gp function of cells. In total, 1571.81?±?156.18?µmol thiol groups were immobilized per gram of polymer that were in the next step by 99.88% preactivated. The enhancement ratios of P_app calculated from the ratio between P_app of rhodamine 123 in the presence of P-gp inhibitors and P_app of rhodamine 123 alone were 2.36, 2.09, and 1.84-fold in the presence of PAA-Cys-2MNA, PAA-Cys, and PAA, respectively. Because of its pronounced P-gp inhibitory effect, PAA-Cys-2MNA could be considered as promising macromolecular P-gp inhibitor for various drug delivery systems.     

Decision tree induction based on minority entropy for the class imbalance problem

Most well-known classifiers can predict a balanced data set efficiently, but they misclassify an imbalanced data set. To overcome this problem, this research proposes a new impurity measure called minority entropy, which uses information from the minority class. It applies a local range of minority class instances on a selected numeric attribute with Shannon’s entropy. This range defines a subset of instances concentrating on the minority class to be constructed by decision tree induction. A decision tree algorithm using minority entropy shows improvement compared with the geometric mean and F-measure over C4.5, the distinct class-based splitting measure, asymmetric entropy, a top–down decision tree and Hellinger distance decision tree on 24 imbalanced data sets from the UCI repository.     

Evaluation of the impact of multivalent metal ions on the permeation behavior of Dolutegravir sodium

Interactions between active pharmaceutical ingredients (APIs) and polyvalent cations are an important factor within drug absorption in the gastrointestinal tract. Dolutegravir sodium, as a second-generation integrase stand transfer inhibitor for the treatment of HIV was investigated regarding chelation with Al³⁺, Ca²⁺, Fe³⁺, Mg²⁺ and Zn²⁺ ions at three different molar ratios. Furthermore, the influence of drug–ion chelates on the permeability of the drug across two intestinal membrane models was analyzed. For this purpose, Caco-2 monolayer model and Ussing chamber technique utilizing freshly excited rat intestinal mucosa were chosen and a buffer system without additional Mg²⁺ and Ca²⁺ ions was tested regarding cell detachment. The addition of polyvalent cations in an equal molar ratio to the drug solution decreased the dissolved drug by at least 11%. An increased multivalent cation concentration in a ratio of 1:10 afforded an API drop in the solution of at least 88% with the exception of Mg²⁺. In particular, Dolutegravir sodium was chelated with iron ions to nearly 100%. Overall, the higher the amount of metal ions in the solution, the lower was the detected amount of the drug. The permeation experiments across the Caco-2 monolayer and the rat intestinal mucosa pointed out that the addition of AlCl₃, CaCl₂ and ZnCl₂ in a molar ratio of 10:1 to the drug led to significantly decreased drug permeation. According to these results the co-administration of Al³⁺, Ca²⁺ or Zn²⁺ as well as of supplementary medications containing these polyvalent ions is in case of oral Dolutegravir delivery not recommended.     

Practical use of β-carotene-loaded nanoemulsion as a functional colorant in sausages made from goat meat surimi-like material

The potential applicability of β-carotene-loaded nanoemulsion (CNE) as a natural colorant in non-smoked sausage made from goat meat surimi-like material (GMS) was elucidated. The effect of CNE content (0–30 g 100 g⁻¹) on the physicochemical characteristic, oxidative stability and β-carotene remaining during cold storage (4 °C) was determined. The higher the CNE, the greater the a*, b* and redness index with the lower L*, and colour likeness score. CNE content had a little impact on the moisture content, a_w and pH of sausages over storage period. However, the expressible drip, breaking force and deformation were largely influenced by the CNE content. All CNE-containing sausages displayed a superior oxidative stability to control. Among CNE-incorporated samples, the lowest lipid oxidation and β-carotene degradation were noticeable in the sausage with 10 g 100 g⁻¹ CNE. Thus, the CNE at 10 g 100 g⁻¹ was a promising functional colorant for emulsion sausage made from GMS.     

Biochemical property and gel-forming ability of surimi-like material from goat meat

Biochemical and gel properties of surimi-like material from goat meat (SMGM) as affected by washing solutions including tap water, NaCl, sodium bicarbonate, aluminium sulphate and sodium pyrophosphate, with the same ionic strength of 0.15 for all salt solutions, were investigated. Three-cycle washing (cold solution/water/water; mince:solution ratio of 1:5; 10 min/cycle) was used. Washing solutions differently altered the pH, Ca²⁺-ATPase activity, reactive sulfhydryl, TCA-soluble peptide, total volatile base nitrogen (TVB-N), myoglobin, lipid and thiobarbituric acid reactive substances (TBARS) content of SMGM. Washing can eliminate undesirable lipid, myoglobin, TVB-N and TCA-soluble peptide from goat meat. SMGM washed with water and NaCl can form stable gels whereas SMGM washed with bicarbonate, pyrophosphate and aluminium sulphate formed very mushy gel/aggregate with high released water. SMGM gels particularly that washed with NaCl had higher breaking force, deformation and whiteness with lower TBARS content, species odour and expressible drip than unwashed mince. Therefore, SMGM can be optimally produced by washing with NaCl solution.     

A Molecular Dynamics investigation of the influence of framework flexibility on self-diffusivity of ethane in Zn(tbip) frameworks

Configurational-Bias Monte Carlo simulations of the adsorption isotherm of ethane in Zn(tbip) (H₂tbip = 5-tert-butyl isophthalic acid), a representative of metal-organic frameworks, show an inflection at a loading, q_i = 6 molecules per unit cell. This inflection causes the inverse thermodynamic factor, 1/Γ_i, to display a minimum at q_i = 6, along with a maximum at q_i ≈ 10. Molecular Dynamics (MD) simulations of the self-diffusivity D_i,self, taking account of the framework flexibility of Zn(tbip) show that the D_i,self − q_i dependence follows that of 1/Γ_i − q_i, with a minimum at q_i = 6. Remarkably, MD simulations assuming a rigid framework yield significantly lower values of the self-diffusivities, and show a monotonic decrease of D_i,self with q_i.     

Adsorption and diffusion of benzene in the nanoporous catalysts FAU, ZSM-5 and MCM-22: a molecular dynamics study

Molecular dynamics (MD) simulations of benzene in siliceous zeolites (FAU, ZSM-5, and MCM-22) were performed at loadings of 1, 2, 4, 8, and 16 molecules per supercell. The potential energy functions for these simulations were constructed in a semi-empirical way from existing potentials and experimental energetic data. The MD simulations were employed to analyze the dynamic properties of the benzene-zeolite systems. The adsorption energies of benzene/siliceous zeolite complexes increase with increasing loading number, due to the intermolecular attraction between benzene molecules. The self-diffusion coefficient of benzene in siliceous zeolites decreases with increasing loading due to the steric hindrance between the sorbates passing each other. From the zeolite-benzene radial distribution functions it was found that the benzene molecules are relatively far from each other, about 5.2A for siliceous FAU, 5.2A for siliceous ZSM-5, and 4.8A for siliceous MCM-22. In the case of FAU, the benzene molecules prefer to be adsorbed parallel to the surface of the sodalite cage above the six-membered-ring. In ZSM-5, we found a T-structure of the benzene molecules at loadings 2, 4, and 8 molecules per supercell. At loadings of 16 molecules per supercell, the molecules are lined up along the straight channel and their movement is highly correlated. For MCM-22 we found adjacent benzene molecules at a loading of 4 molecules with an orientation similar to the stacked conformation of benzene dimer in the gas phase.     

Reduction of offensive odor from natural rubber by odor‐reducing substances

A number of chemicals including carbon black, chitosan, benzalkonium chloride, sodium dodecyl sulfate, cyclodextrin, and zeolite13x were tested as odor‐reducing fillers. The rationale is based on the concept of using odor absorbents/adsorbents for which both physical adsorption and chemical adsorption play an important role in odor reduction. The fillers were incorporated into highly odorous natural rubber (STR20 and RSS5) by physical mixing prior to sulfur vulcanization. As identified by gas chromatography and gas chromatography/mass spectrometry, the unpleasant odor mainly originates from low molecular weight volatile fatty acids. The quantity of acetic acid, a representative of odor molecule, can be significantly reduced in the presence of chitosan and zeolite13x. Although carbon black and cyclodextrin exhibited a tendency to reduce the odor, they were not as effective as zeolite13x and chitosan. On the other hand, commercial surfactants such as benzalkonium chloride and sodium dodecyl sulfate cannot serve as odor‐reducing substances because of their limited thermal stability. An olfactometry test confirmed that chitosan and carbon black are good odor‐reducing agents. Chitosan and carbon black showed a reinforcing effect on vulcanized rubber, whereas the surfactant deteriorated the strength of the rubber composite. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 2253–2260, 2004     

Polypropylene/natural rubber thermoplastic elastomer: Effect of phenolic resin as a vulcanizing agent on mechanical properties and morphology

The aim of this study is to characterize thermoplastic elastomers (TPEs) from polypropylene and natural rubber with and without phenolic resin as a vulcanizing agent. The blends containing 40–60 wt % of polypropylene were mixed in an internal mixer and pressed with a compression molding machine. TPEs without rubber vulcanization, named as unvulcanized thermoplastic natural rubber (uTPNR) were compared to TPEs containing dynamic vulcanized rubber, referred as vulcanized thermoplastic natural rubber (vTPNR). The uTPNRs illustrated cocontinuous phase morphology, whereas the vTPNRs displayed dispersed phase of vulcanized natural rubber. Tensile properties, tear strength, thermal ageing resistance, ozone resistance, tension set, hardness and swelling test in toluene, IRM 903 oil and engine oil were carried out according to ASTM. It was found that tensile and tear strength, hardness and tension set of the uTPNRs increased with increasing polypropylene content. Dynamic vulcanization improved tensile strength, elongation at break, tension set and degree of swelling of the TPEs, whereas hardness and tear strength did not show significant change after dynamic vulcanization. The vTPNRs exhibited higher ozone resistance and swelling resistance than the uTPNRs. Reprocessability of the vTPNRs was investigated and showed that tensile strength decreased at 20 and 30% and elongation at break decreased at 13 and 27% for the first and the third reprocessing respectively. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009