Surface geochemical data evaluation and integration with geophysical observations for hydrocarbon prospecting, Tapti graben, Deccan Syneclise, India

The Deccan Syneclise is considered to have significant hydrocarbon potential. However, significant hydrocarbon discoveries, particularly for Mesozoic sequences, have not been established through conventional exploration due to the thick basalt cover over Mesozoic sedimentary rocks. In this study, near-surface geochemical data are used to understand the petroleum system and also investigate type of source for hydrocarbons generation of the study area. Soil samples were collected from favorable areas identified by integrated geophysical studies. The compositional and isotopic signatures of adsorbed gaseous hydrocarbons (methane through butane) were used as surface indicators of petroleum micro-seepages. An analysis of 75 near-surface soil-gas samples was carried out for light hydrocarbons (C1–C4) and their carbon isotopes from the western part of Tapti graben, Deccan Syneclise, India. The geochemical results reveal sites or clusters of sites containing anomalously high concentrations of light hydrocarbon gases. High concentrations of adsorbed thermogenic methane (C1 = 518 ppb) and ethane plus higher hydrocarbons (ΣC2+ = 977 ppb) were observed. Statistical analysis shows that samples from 13% of the samples contain anomalously high concentrations of light hydrocarbons in the soil-gas constituents. This seepage suggests largest magnitude of soil gas anomalies might be generated/source from Mesozoic sedimentary rocks, beneath Deccan Traps. The carbon isotopic composition of methane, ethane and propane ranges are from −22.5‰ to −30.2‰ PDB, −18.0‰ to 27.1‰ PDB and 16.9‰–32.1‰ PDB respectively, which are in thermogenic source. Surface soil sample represents the intersection of a migration conduit from the deep subsurface to the surface connected to sub-trappean Mesozoic sedimentary rocks. Prominent hydrocarbon concentrations were associated with dykes, lineaments and presented on thinner basaltic cover in the study area, which probably acts as channel for the micro-seepage of hydrocarbons

Experimental and Theoretical Investigations of Porous Structure Formation in Electrospun Fibers

The development of internal microstructure in electrospun fibers has been investigated both experimentally and theoretically. Various morphologies such as tubes, beads, and porous structures have been observed experimentally during electrospinning from amorphous polymer solutions such as poly(methyl methacrylate)/methylene chloride and poly(styrene)/tetrahydrofuran. The dynamics of electrospinning is modeled based on multiple virtual strands of beads connected by Maxwell\u27s elements in a cylindrical coordinate system. Concurrently, spatiotemporal growth of the porous structure is calculated in the framework of Cahn−Hilliard time-evolution equation under the quasi steady state assumption coupled with the solvent evaporation rate equation. The coarse-grain simulation reveals the real-time formation of pores along the spinline of the electrospun fiber as the concentration traverses across the phase diagram of the amorphous polymer solution

Effect of hepatic impairment on pharmacokinetics, safety, and tolerability of lemborexant

Abstract Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open‐label, parallel‐group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child–Pugh class A) or moderate (Child–Pugh class B) HI and healthy age‐, sex‐, and body mass index (BMI)‐matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax] and area under the curve extrapolated to infinity [AUC0‐inf]) increased by ~58% (Cmax) and ~25% (AUC0‐inf) in subjects with mild HI and ~22% (Cmax) and ~54% (AUC0‐inf) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060–0.065). All treatment‐emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups

Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant

Abstract The primary aim of this study was to examine the effect of severe renal impairment (SRI) on the pharmacokinetics of lemborexant, a dual orexin receptor antagonist indicated for the treatment of insomnia. A phase 1 multicenter, single‐dose, open‐label, parallel‐group study was conducted in subjects with SRI not requiring dialysis (estimated glomerular filtration rate 15–29 ml/min/1.73 m2; n = 8) compared with demographically matched healthy subjects with normal renal function (n = 8). Plasma levels of lemborexant and its metabolites were measured over 240 h following a single oral 10‐mg dose administered in the morning. Relative to subjects with normal renal function, lemborexant maximum plasma concentration (Cmax) was similar, whereas area under the plasma concentration–time curve from zero to time of last quantifiable concentration (AUC(0‐t)) and AUC from zero to infinity (AUC(0‐inf)) were about 1.5‐fold higher in subjects with SRI. The geometric mean ratios (90% confidence interval) were 104.8 (77.4–142.0), 150.5 (113.2–200.3), and 149.8 (113.1–198.6) for Cmax, AUC(0‐t), and AUC(0‐inf), respectively. In both groups, the median lemborexant time to Cmax (tmax) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax was reduced ~20% and exposure (AUC(0‐t) and AUC(0‐inf)) was ~1.4‐ to 1.5‐fold higher in subjects with SRI versus healthy subjects; tmax was delayed ~1.5–2 h for M4 and M10. All treatment‐emergent adverse events were mild or moderate. Lemborexant pharmacokinetics were not sufficiently altered to warrant a dose adjustment for subjects with renal impairment

Not Available

Not AvailableA130-day culture experiment was performed to compare the effects of rearing Litopenaeus vannamei in a biofloc system and conventional autotrophic system, supplemented with diets having graded protein levels on growth performance, non-specific immune response and immunomodulatory activity. The experiment groups consisted of four protein-level treatments with four replicates each, and was performed in 16 experimental units (7.5- Tcapacity) stocked with juvenile L. vannamei (initial average weight 1.48 ± 0.4 g) at a density of 150 juvenile shrimps /m3. Biofloc-based groups fed with supplementary feed containing varying levels of crude protein (CP) BFT40 (40% CP), BFT32 (32% CP) and BFT24 (24% CP), and a control group (CP 40%), were maintained in an autotrophic system. At the end of the experimental period, there was an improvement of 32.6–52.6% in terms of productivity, 22–27.6% average body weight; 8.7–19.6% survival rate and 10–31% feed conversion ratio (FCR) in shrimp maintained in biofloc systems as compared to control. Similarly, the protein efficiency ratio (PER) in biofloc treatment groups was32 to 83% higher than control. The shrimp also showed higher resistance to disease in the biofloc treatment when challenged with pathogenic Vibrio parahaemolyticus, as survival of juveniles was significantly higher (p < 0.05) in the biofloc treatments than in the control group. The total hemocyte count and proPhenoloxidase activity were significantly increased in the biofloc treatments when compared to control. The mRNA profiling of important immune genes in the shrimps showed higher levels of expression in the 32 and 40% CP feed treatments. Superoxide dismutase (SOD) mRNA transcript levels were highly up-regulated in the BFT40 treatment (7-fold), moderately upregulated in the BFT32 treatment (2-fold), and downregulated in the BFT24 treatment (0.9-fold). Transcription of antimicrobial peptides like crustin showed significant up-regulation in BFT40 (10.31-fold) followed by BFT32 (6.11-fold) and BFT24 (1.07-fold). Likewise, other immune genes, such as MnSOD, hemocyanin, proPhenoloxidase (proPO), peroxinectin (PX) and serine protease (SP) showed similar trends, indicating immunomodulation in the biofloc groups. We concluded that the biofloc system has the potential to improve growth performance, immune response and disease resistance in Pacific white shrimp in spite of the low-protein supplemented dietNot Availabl

First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE2-receptor E-type 4 (EP4), in patients with advanced cancers

Background E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.Methods This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment.Results No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses.Conclusions In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting.Trial registration number NCT02540291

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 1

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation

Optimization of PDGFR inhibitors for duration of action, as an inhaled therapy for lung remodeling in pulmonary arterial hypertension

: A series of potent dual PDGFR/cKIT inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after it dosing. Compound 25 shows 24 hour occupancy of the PDGFR kinase domain, after a single it dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro: in vivo correlations which link duration of action in vivo with low permeability and high basicity, and demonstrate that nonspecific binding to lung tissue increases with lipophilicity