Hot-melt extrudability of amorphous solid dispersions of flubendazole-copovidone: An exploratory study of the effect of drug loading and the balance of adjuvants on extrudability and dissolution.

The FDA-approved anthelmintic flubendazole has shown potential to be repositioned to treat cancer and dry macular degeneration; however, its poor water solubility limits its use. Amorphous solid dispersions may overcome this challenge, but the balance of excipients may impact the preparation method and drug release. The purpose of this study was to evaluate the influence of adjuvants and drug loading on the development of an amorphous solid dispersion of flubendazole-copovidone by hot-melt extrusion. The drug, copovidone, and adjuvants (magnesium stearate and hydroxypropyl cellulose) mixtures were statistically designed, and the process was performed in a twin-screw extruder. The study showed that flubendazole and copovidone mixtures were highly extrudable, except when drug loading was high (>40%). Furthermore, magnesium stearate positively impacted the extrusion and was more effective than hydroxypropyl cellulose. The extruded materials were evaluated by modulated differential scanning calorimetry and X-ray powder diffraction, obtaining positive amorphization and physical stability results. Pair distribution function analysis indicated the presence of drug-rich domains with medium-range order structure and no evidence of polymer-drug interaction. All extrudates presented faster dissolution (HCl, pH 1.2) than pure flubendazole, and both adjuvants had a notable influence on the dissolution rate. In conclusion, hot-melt extrusion may be a viable option to obtain stable flubendazole:copovidone amorphous dispersions.

Impact of Tb3+ ion concentration on the morphology, structure and photoluminescence of Gd2 O2 SO4 :Tb3+ phosphor obtained using thermal decomposition of sulfate hydrate.

Gadolinium oxysulfate doped with terbium (Gd2 O2 SO4 :Tb3+ ; 0.1, 1.0, and 10.0 mol%) materials were obtained using thermal decomposition from sulfate hydrate under a dynamic air atmosphere and between 1320-1400 K. The materials were characterized using Fourier transform infrared spectroscopy, thermogravimetric/derivative thermogravimetric investigations and X-ray powder diffraction patterns. The Tb2 O2 SO4 compound was obtained at 1300 K and was used to compare thermal stability and photoluminescence behaviour with that of Gd2 O2 SO4 :Tb3+ (0.1, 1.0, and 10.0 mol%). Magnetic susceptibility measurements indicated the presence of 15% Tb4+ phases within Tb2 O2 SO4 . The materials were excited at 377 nm and displayed green narrow lines with the strongest emission peak at 545.5 nm due to the 5 D4 →7 F5 transition of Tb3+ ions. Brightness of terbium-activated gadolinium oxysulfate phosphors was enhanced with increase in the concentration of Tb3+ . Detailed analysis of spectroscopic properties of materials under investigations revealed efficient Gd2 O2 SO4 to Tb3+ and Tb3+ to Tb3+ energy transfers. Increase in dopant concentration led to the enhancement of 5 D4 →7 FJ emission intensity and reduction of 5 D3 →7 FJ emission intensity via cross-relaxation mechanisms. Distribution of particle size was increased by controlling dopant concentration in the host lattice. Obtained results confirmed that these materials could be applied potentially in field emission display devices and light-emitting diodes.

Simultaneous pollinator occurence (Hymenoptera, Agaoninae) in a threatened species: Ficus mexiae Standley (Moraceae).

In Brazil, Ficus mexiae is classified as Vulnerable under IUCN criteria, and to date there is only one report on pollinator activity for this species. Is not unusual to find cases where more than one species of wasp simultaneously occurs on and pollinates the same fig. In this study we present evidence that two Pegoscapus wasp species contribute to the pollination of F. mexiae and relationship between pollinators maybe competitive. These results indicate that the F. mexiae population represent an important element in the complex dynamics of maintaining diversity in neotropical Ficus spp.

Synergistic effects of nelfinavir and bortezomib on proteotoxic death of NSCLC and multiple myeloma cells.

Exploiting protein homeostasis is a new therapeutic approach in cancer. Nelfinavir (NFV) is an HIV protease inhibitor that induces endoplasmic reticulum (ER) stress in cancer cells. Under conditions of ER stress, misfolded proteins are transported from the ER back to the cytosol for subsequent degradation by the ubiquitin-proteasome system. Bortezomib (BZ) is a proteasome inhibitor and interferes with degradation of misfolded proteins. Here, we show that NFV and BZ enhance proteotoxicity in non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells. The combination synergistically inhibited cell proliferation and induced cell death. Activating transcription factor (ATF)3 and CCAAT-enhancer binding protein homologous protein (CHOP), markers of ER stress, were rapidly increased, and their siRNA-mediated knockdown inhibited cell death. Knockdown of double-stranded RNA activated protein kinase-like ER kinase, a signal transducer in ER stress, significantly decreased apoptosis. Pretreatment with the protein synthesis inhibitor, cycloheximide, decreased levels of ubiquitinated proteins, ATF3, CHOP, and the overall total cell death, suggesting that inhibition of protein synthesis increases cell survival by relieving proteotoxic stress. The NFV/BZ combination inhibited the growth of NSCLC xenografts, which correlated with the induction of markers of ER stress and apoptosis. Collectively, these data show that NFV and BZ enhance proteotoxicity in NSCLC and MM cells, and suggest that this combination could tip the precarious balance of protein homeostasis in cancer cells for therapeutic gain.

S-adenosylmethionine: studies on chemical and enzymatic synthesis.

Several methods for the chemical and enzymatic synthesis of (-)-S-adenosylmethionine (AdoMet) are described and compared. Studies on the effects of solvents, pH, methylating reagents, and KI on the coupling of sodium homocysteine thiolate and 5'-chloro-5'-deoxyadenosine led to an improved procedure for the synthesis of (+/-)-AdoMet. The use of trimethylsulfonium iodide as a methylating agent under acidic conditions results in a higher content of the desired (-)-epimer than does the use of CH3I. The enzymatic synthesis of (-)-AdoMet using AdoMet synthetase from an over-producing strain of Escherichia coli is demonstrated and the effect of product inhibition on preparative-scale synthesis is illustrated. A new HPLC technique for separation of the epimeric mixture of AdoMet, which allows small-scale preparation of optically pure AdoMet from the enzyme product, has been developed. With this HPLC technique, evidence that (-)-AdoMet is the sole epimer formed by the enzyme has been shown.