An oral lipidic native testosterone formulation that is absorbed independent of food

Context: There is no licensed oral Native Testosterone (NT) because of challenges in formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. Objective: To develop an oral NT formulation. Design and Methods: A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40mg per capsule was designed with 2 years stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men. Results: In dogs, 40mg NT was well absorbed under fasted conditions whereas 40mg TU required a high fat meal: for NT the mean fed / fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/l (769 vs 882 ng/dl), AUC0-10h 87 vs 88.6 h*nmol/l. NT (fed state) showed a testosterone AUC increase of 45% between 120mg and 200mg and NT 200mg gave a similar mean AUC0-10h to TU 80mg: 87 vs. 64.8 h*nmol/l. Serum TU levels were variable and on a molar basis were ~10-fold higher than serum testosterone levels after TU 80mg fed. The DHT:testosterone AUC0-10h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT. Conclusion: This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independent of food and a lower risk of supraphysiological DHT levels.

Influences of C5 esters addition on anti-knock and auto-ignition tendency of a gasoline surrogate fuel

The research octane numbers and auto-ignition characteristics of a toluene primary reference fuel (TPRF), when blended with three C5 esters, γ-valerolactone (GVL), methyl butanoate (MB), and methyl crotonate (MC), were investigated on a cooperative fuel research (CFR) engine and a constant volume combustion chamber (CVCC). In fuel preparation, ethanol was used to improve the miscibility, and the total additive comprised 1/3 ethanol and 2/3 GVL/MB/MC on a molar basis. The experimental results first reveal that the addition of the three series of additives boost fuel octane rating, and their boosting effects rank as MB > GVL ∼ MC when fuels are blended on a molar basis. In contrast, the auto-ignition tendency of the three series of fuel blends, when blended on the molar basis, ranks as the MC blends > the GVL blends> the MB blends. Different from the similar reactivities observed for the MC blends and the GVL blends in the RON tests, the MC blends exhibit higher auto-ignition propensity than the GVL blends, probably because the higher enthalpy of vaporization of GVL causes a more significant cooling effect. Finally, different from the literature studies that reported similar reactivities for pure MB and MC, in this study MB shows lower reactivity than MC when blending with the TPRF gasoline surrogate.

Energy and exergy optimization of oxidative steam reforming of acetone–butanol–ethanol–water mixture as a renewable source for H2 production via thermodynamic modeling

Acetone–butanol–ethanol–water mixture is obtained by fermentation of biomass namely, corncob, wheat straw, sugarbeets, sugarcane, etc. For using the individual components, one alternative is to separate the mixture by distillation, which is costly and energy intensive operation. This paper proposes its other use in available conditions to produce hydrogen fuel by oxidative steam reforming process. For the proposed process, thermodynamic equilibrium modeling has been performed by using non-stoichiometric approach of Gibbs free energy minimization. The compositions of acetone, butanol and ethanol in mixture are 0.33:0.52:0.15 on molar basis. The influence of pressure (1–10 atm), temperature (573–1473 K), steam to ABE mixture molar feed ratio (F ABE = 5.5–8.5), and oxygen to ABE mixture molar feed ratio (F OABE = 0.25–1) have been tested by simulations on the yield of products (at equilibrium) namely, H2, CH4, CO2, CO, and carbon as solid. The optimum conditions for maximum production of desired H2, minimization of undesired CH4, and elimination of carbon (solid) formation are T = 973 K, P = 1 atm, F ABE = 8.5, and F OABE = 0.25. Under same operating conditions, the maximum generation of H2 is 7.51 on molar basis with negligible carbon formation. The total energy requirement for the process (295.73 kJ/mol), the energy required/mol of hydrogen (39.37 kJ), and thermal efficiency (68.09%) of the reformer have been obtained at same operating conditions. The exergy analysis has also been investigated to measure the work potential of the energy implied in the reforming process.

New data on the metabolism of chloromethylisothiazolinone and methylisothiazolinone in human volunteers after oral dosage: excretion kinetics of a urinary mercapturic acid metabolite (“M-12”)

Methylisothiazolinone (MI) as well as the mixture of chloromethylisothiazolinone/methylisothiazolinone [MCI/MI (3:1)] are biocides that are used in a variety of products of every-day life. Due to the skin sensitizing properties of these biocides, their use has come under scrutiny. We have previously examined the human metabolism of MI and MCI after oral dosage of isotope-labelled analogues in human volunteers and confirmed N-methylmalonamic acid to be a major, but presumably unspecific human urinary metabolite. In the present study, we have investigated the urinary kinetics of a mercapturic acid metabolite of MI and MCI using the same set of samples. Four human volunteers received 2 mg of isotopically labelled MI and MCI separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h and were examined for the content of the (labelled) 3-mercapturic acid conjugate of 3-thiomethyl-N-methyl-propionamide (“M-12”), a known metabolite in rats. On a molar basis, M-12 represented 7.1% (3.0–10.1%) of the dose excreted in urine after dosage of MI. Excretion of this mercapturate was fast with a mean half-life of 3.6 h. Surprisingly, for MCI the mercapturate M-12 represented only 0.13% of the dose excreted in urine. Thus, this biomarker is highly specific for exposures to MI and might be used to distinguish between different exposure patterns of these biocides [use of MI or MCI/MI (3:1)] in the general population.

Accretion of fast-spread lower oceanic crust: drill core GT1 from the ICDP Oman Drilling Project

<p>The Sumail Ophiolite at the northeastern coast of the Sultanate of Oman provides an ideal field laboratory for studies on fast-spread oceanic crust on land. Based on numerous campaigns in the past, the Oman Drilling Project (OmanDP) of the International Continental Scientific Drilling Program (ICDP) obtained nine 300 to 400 m long drill cores covering sections from the upper mantle to the dyke/gabbro transition zone. Drill core GT1 is located in the layered gabbros between ~1200 and ~800 m above the Moho transition zone (m.a.M.) and comprises of modally layered gabbro with cm-scale coherent bands of troctolite, anorthosite, and wehrlite. We prepared thin-sections with a small average spacing of <2 m and analyzed them by petrological, microstructural and geochemical methods. Clinopyroxene reveals Mg# (where Mg# = Mg/Mg+Fe x 100; molar basis) between 74 and 86, with some heavily altered olivine relicts between 70 and 83, and Ca# (where Ca# = Ca/Ca+Na x 100; molar basis) of plagioclase range from 68 to 87. The plots of these data show clear and consistently decreasing trends from the base of the drill core up section to a crustal height of 1070 m.a.M. where all fractionation indices show significant minima. Above 1070 m.a.M., the indices increase to their maxima. Clinopyroxene shows core/rim zonation in Mg# and TiO<sub>2</sub> content with more primitive core compositions. However, distinct zonation is only observed above the minima mentioned above. Besides this general fractionation trend from the core base to 1070 m.a.M., individual fractionation trends on the scale of several decameters can be defined along the core (e.g., 820 to 895, 890 to 970, and 1085 to 1110 m.a.M.). As a quantifier of the plagioclase fabric symmetry, we used the BA index which ranges from 0 for a purely foliated to 1 for a purely lineated fabric. We found that the rock fabric changes parallel the observed fractionation trend with significant lineation at the base of the core and evolving towards almost purely foliated fabrics up section to 1070 m.a.M., indicating either an intense compaction or weaker shearing, or both at 1070 m.a.M. A possible scenario creating the observed trends is an evolved melt entering the more primitive crystal mush at 1070 m.a.M.  and crystallizing primary phases with significantly more evolved compositions. In such an environment, where the liquid/solid ratio is increased, minerals may be more sensitive to compaction and less affected by shearing which is possibly induced by convection of the upper mantle. Magmatic deformation would therefore lead to a strong foliation with only a limited lineation component. Moreover, we interpret the observed decameter-scale fractionation trends, also being accompanied by slight changes in the fabric, as results of individual magma reservoirs crystallizing in-situ and leading to the accretion of the lower gabbros in Oman (e.g., [1]).</p><p> </p><p>[1] Kelemen, P. B., Koga, K., & Shimizu, N. (1997). Geochemistry of gabbro sills in the crust-mantle transition zone of the Oman ophiolite: Implications for the origin of the oceanic lower crust. Earth and Planetary Science Letters, 146(3-4), 475-488.</p>

Coupling Chlorin e6 to the surface of Nanoscale Gas Vesicles strongly enhances their intracellular delivery and photodynamic killing of cancer cells

Protein-based nanobubbles such as halophilic archaeabacterial gas vesicles (GVs) represent a new class of stable, homogeneous nanoparticles with acoustic properties that allow them to be visualized by ultrasound (US) waves. To design GVs as theranostic agents, we modified them to respond to light, with a view to locally generate reactive oxygen species that can kill cancer cells. Specifically, up to 60,000 photoreactive chlorin e6 (Ce6) molecules were chemically attached to lysine ε-amino groups present on the surface of each purified Halobacterium sp. NRC-1 GV. The resulting fluorescent NRC-1 Ce6-GVs have dimensions comparable to that of native GVs and were efficiently taken up by human breast [MCF-7] and human hypopharyngeal [FaDu-GFP] cancer cells as monitored by confocal microscopy and flow cytometry. When exposed to light, internalized Ce6-GVs were 200-fold more effective on a molar basis than free Ce6 at killing cells. These results demonstrate the potential of Ce6-GVs as novel and promising nanomaterials for image-guided photodynamic therapy.

Light-Activated Nanoscale Gas Vesicles Selectively Kill Tumor Cells

Protein-based nanobubbles such as halophilic archaeabacterial gas vesicles (GVs) represent a new class of stable, homogeneous nanoparticles with acoustic properties that allow them to be visualized by ultrasound (US) waves. To design GVs as theranostic agents, we modified them to respond to light, with a view to locally generate reactive oxygen species that can kill cancer cells. Specifically, up to 60,000 photoreactive chlorin e6 (Ce6) molecules were chemically attached to lysine ε-amino groups present on the surface of each purified Halobacterium sp. NRC-1 GV. The resulting fluorescent NRC-1 Ce6-GVs have dimensions comparable to that of native GVs and were efficiently taken up by human breast [MCF-7] and human hypopharyngeal [FaDu-GFP] cancer cells as monitored by confocal microscopy and flow cytometry. When exposed to light, internalized Ce6-GVs were 200-fold more effective on a molar basis than free Ce6 at killing cells. These results demonstrate the potential of Ce6-GVs as novel and promising nanomaterials for image-guided photodynamic therapy.

119 Bioavailability of L-Methionine in comparison to DL-Methionine for nitrogen retention of weaned and growing pigs

Two nitrogen (N) balance studies were conducted to compare the relative bioavailability (RBV) of L-Met with DL-Met as Met sources in young pigs. In each experiment, 42 barrows (PIC; initial BW in Exp. 1: 10.7 kg and Exp. 2: 20.5 kg) were allotted to 7 experimental diets with 6 pigs per treatment. The basal diets (diet 1) were formulated based on corn and soybean meal being deficient in Met, but adequate for the other AA (Exp. 1: 0.24% standardized ileal digestible [SID] Met; 0.53% SID Met + Cys; 1.30% SID Lys; Exp 2: 0.23% SID Met; 0.47% SID Met + Cys; 1.15% SID Lys). Three graded levels of DL-Met and L-Met (0.03, 0.06 and 0.09%) were supplemented to the basal diet on top to create diets 2 to 7 for both studies. In Exp.1, N retention (% of N absorbed) increased linearly (P < 0.05) with supplementation with both Met sources. The slope-ratio regression estimated the RBV of 106% [95% confidence interval (CI): 39 to 173%] for N retention (% of absorbed) on an equi-molar basis. In Exp. 2, N retained (g/d), N retention (% of N intake and % of N absorbed) increased linearly (P < 0.05) by supplementing with both Met sources. There was no effect of Met sources on all N balance parameters in both studies. The slope-ratio estimated the RBV of 89% (95% CI: -28 to 206%) for N retained (g/d), 95% (95% CI: 13 to 177%) for N retention (% of N intake) and 94% (95% CI: 20 to 167%) for N retention (% of N absorbed), respectively on an equi-molar basis. In conclusion, the 95% CI for the RBV of L-Met covers 100%, indicating the RBV of L-Met is not different from that of DL-Met as a Met source for weaned and growing pigs.

Simultaneous adsorption of Cd2+ , Ni2+ and Pb2+ on peat

The aim of the present work was to investigate iflocally available untreated peat could beused as filter material for the removal of heavy metals from leachate. The aqueoussolutions containing Cd2+, Ni2+ and Pb2+ ions in single-metal and multi-metal solutionswere used to study the adsorption of metals on peat. The peat was obtained fromSouthern Estonia. The decomposition rate of the peat was H6-H7 on the von Post scale.In order to assess the adsorption mechanism, the amounts of Ca2+ and Mg2+ ions desorbedfrom untreated peat were measured and compared to the adsorption efficiency of Cd2+,Ni2+ and Pb2+ ions from solution on the peat. The desorption of other cations, such asAl3+, K+, Na+, Fe3+, Zn2+ etc. were negligible during all experiments. Adsorption batchisotherm studies were carried out by using IO experimental series with the initialconcentration of 10 - 300 mg/I. The samples were analyzed by using the axial ICP-AES.Results of the single- as well as multi-metal adsorptions show that peat can be effectivelyused. Adsorption of metals on molar basis was found in the indicated order: Pb2+ > Cd2+> Ni2+. The removal of single metal ions from ternary-metal solution was less than itsremoval from single-metal solution. However, the total adsorption capacity of metalsfrom multi-metal solution to peat increased. The Langmuir isotherm equation constantswere calculated and isotherms were drawn by using the program of calculating hyperbolefunctions. Correlations for Ni2+ and Cd2+ with the Langmuir isotherm equation was foundto be good, whereas for Pb2+ the plot (amount absorbed vs. the equilibrium aqueousconcentration) was linear.

Cross-reactivity of commercial and non-commercial deoxynivalenol-antibodies to emerging trichothecenes and common deoxynivalenol-derivatives

Immunoassay based techniques are an important and fast option for the detection and quantification of mycotoxins. They are frequently used as on-site screening tools in grain elevators, storage and production facilities. However, accurate quantification may be hampered by the co-recognition of structurally related metabolites by the used antibodies. Therefore, it is crucial to assess their cross-reactivity to avoid misinterpretation of the results. Several immunoassays for the determination of deoxynivalenol (DON) are commercially available. Recently, novel trichothecene mycotoxins with structures similar to DON, the NX-toxins (NX-2, NX-3 and NX-4), were discovered, which can potentially co-occur with DON in cereals. So far, no data about the cross-reactivity of those toxins with DON-antibodies are available. The aim of this study was to assess the cross-reactivities of NX-toxins and some other DON-related metabolites with DON-antibodies in buffer solutions. Six commercially available enzyme-linked immunosorbent assays (ELISAs) and two previously developed DON-antibodies (Mab#1 and Mab#22) were tested. Cross-reactivity with NX-metabolites was not observed for any of the ELISA-kits nor Mab#22, whereas Mab#1 reacted moderately against NX-3 and NX-4 (cross-reactivity based on a molar basis of 14 and 30%, respectively). Modifications at position C-3 (3-acetyl-DON and DON-3-glucoside) led to moderate or high cross-reactivity with Mab#22 and the commercial ELISA-kits, whereas these compounds were not recognised by Mab#1. Similar to NX-metabolites, 15-acetyl-DON interacted only weakly with Mab#22 and the commercial ELISA-kits, but strongly with Mab#1. The results demonstrate the importance of proper antibody characterisation. If NX-metabolites prove to be widely distributed and reach significant levels, the development of specific antibodies targeting these novel metabolites might become necessary.