ENANTIOMERIC SEPARATION OF ETODOLAC IN A BULK DRUG SUBSTANCE BY REVERSE-PHASE CHIRAL LIQUID CHROMATOGRAPHY METHOD

Objective: To develop novel, simple and rapid enantiomeric separation of Etodolac by reverse-phase high-performance liquid chromatographic method as per ICH guidelines.Methods: The R-isomer and S-isomer were baseline resolved on a CHIRAL-AGP, (100 x 4.0 mm i. d, 5 mm) column using a mobile phase system containing 0.1 M sodium dihydrogen phosphate dihydrate pH 4.0 buffer: Isopropanol (85:15 v/v.) at detector wavelength 225 nm and column temperature 25 °C. The chromatographic resolutions between R-isomer and S-isomer were found three. The developed method was extensively validated according to ICH guidelines.Results: Good linearity was observed for R-isomer over the concentration range of 300–3000 ng/ml, with the linear regression (Correlation coefficient R = 0.999) and proved to be robust. The limit of detection and limit of quantification of R-isomer was found to be 300 and 900 ng/ml, respectively for 10 ml injection volume. The percentage recovery of R-isomer was ranged from 98.0 to 102.0 in bulk drug samples of Etodolac. Etodolac sample solution and mobile phase were found to be stable for at least 48 hours. The proposed method was found to be suitable and accurate for the quantitative determination of R-isomer in bulk drugs.Conclusion: A novel, simple and rapid enantiomeric separation of Etodolac by reverse-phase high-performance liquid chromatographic method was developed and validated as per ICH guidelines. The developed method can be used for the quantitative determination R-isomer in bulk drug materials in pharmaceutical industry.Â

SEPARATION AND DETERMINATION OF THE S-ISOMER OF (10-CAMPHORSULFONYL) OXAZIRIDINE IN A BULK DRUG SUBSTANCE BY NORMAL-PHASE LIQUID CHROMATOGRAPHY

Objective: To develop novel, simple and accurate enantiomeric separation of (10-Camphorsulfonyl) oxaziridine by normal-phase high-performance liquid chromatographic method as per ICH guidelines.Methods: The S-isomer and R-isomer of (10-Camphorsulfonyl) oxaziridine were baseline resolved on a Chiralcel OD-H (250 x 4.0 mm i. d, 5 mm) column using a mobile phase system containing n-Hexane: ethanol: trifluoroacetic acid (90:10:0.1 v/v/v.) at detector wavelength 210 nm and column temperature 30 °C. The chromatographic resolutions between S-isomer and R-isomer were found three. The developed method was extensively validated according to ICH guidelines.Results: Good linearity was observed for S-isomer over the concentration range of 900–9000 ng/ml, with the linear regression (Correlation coefficient R = 0.999) and proved to be robust. The limit of detection and limit of quantification of S-isomer was found to be 400 and 900 ng/ml, respectively for 20 ml injection volume. The percentage recovery of S-isomer was ranged from 97.0 to 102.0 in bulk drug samples of (10-Camphorsulfonyl) oxaziridine. (10-Camphorsulfonyl) oxaziridine sample solution and mobile, phase was found to be stable for at least 48 hours. The proposed method was found to be suitable and accurate for the quantitative determination of S-isomer in bulk drugs.Conclusion: A novel, simple and accurate normal phase LC method was described for the enantiomeric separation of 10-Camphorsulfonyl Oxaziridine is precise and specific.Â

Field Measurements of Terrestrial and Martian Dust Devils

Surface-based measurements of terrestrial and martian dust devils/convective vortices provided from mobile and stationary platforms are discussed. Imaging of terrestrial dust devils has quantified their rotational and vertical wind speeds, translation speeds, dimensions, dust load, and frequency of occurrence. Imaging of martian dust devils has provided translation speeds and constraints on dimensions, but only limited constraints on vertical motion within a vortex. The longer mission durations on Mars afforded by long operating robotic landers and rovers have provided statistical quantification of vortex occurrence (time-of-sol, and recently seasonal) that has until recently not been a primary outcome of more temporally limited terrestrial dust devil measurement campaigns. Terrestrial measurement campaigns have included a more extensive range of measured vortex parameters (pressure, wind, morphology, etc.) than have martian opportunities, with electric field and direct measure of dust abundance not yet obtained on Mars. No martian robotic mission has yet provided contemporaneous high frequency wind and pressure measurements. Comparison of measured terrestrial and martian dust devil characteristics suggests that martian dust devils are larger and possess faster maximum rotational wind speeds, that the absolute magnitude of the pressure deficit within a terrestrial dust devil is an order of magnitude greater than a martian dust devil, and that the time-of-day variation in vortex frequency is similar. Recent terrestrial investigations have demonstrated the presence of diagnostic dust devil signals within seismic and infrasound measurements; an upcoming Mars robotic mission will obtain similar measurement types

Dust Devil Tracks

Dust devils that leave dark- or light-toned tracks are common on Mars and they can also be found on the Earth’s surface. Dust devil tracks (hereinafter DDTs) are ephemeral surface features with mostly sub-annual lifetimes. Regarding their size, DDT widths can range between ∼1 m and ∼1 km, depending on the diameter of dust devil that created the track, and DDT lengths range from a few tens of meters to several kilometers, limited by the duration and horizontal ground speed of dust devils. DDTs can be classified into three main types based on their morphology and albedo in contrast to their surroundings; all are found on both planets: (a) dark continuous DDTs, (b) dark cycloidal DDTs, and (c) bright DDTs. Dark continuous DDTs are the most common type on Mars. They are characterized by their relatively homogenous and continuous low albedo surface tracks. Based on terrestrial and martian in situ studies, these DDTs most likely form when surficial dust layers are removed to expose larger-grained substrate material (coarse sands of ≥500 μm in diameter). The exposure of larger-grained materials changes the photometric properties of the surface; hence leading to lower albedo tracks because grain size is photometrically inversely proportional to the surface reflectance. However, although not observed so far, compositional differences (i.e., color differences) might also lead to albedo contrasts when dust is removed to expose substrate materials with mineralogical differences. For dark continuous DDTs, albedo drop measurements are around 2.5 % in the wavelength range of 550–850 nm on Mars and around 0.5 % in the wavelength range from 300–1100 nm on Earth. The removal of an equivalent layer thickness around 1 μm is sufficient for the formation of visible dark continuous DDTs on Mars and Earth. The next type of DDTs, dark cycloidal DDTs, are characterized by their low albedo pattern of overlapping scallops. Terrestrial in situ studies imply that they are formed when sand-sized material that is eroded from the outer vortex area of a dust devil is redeposited in annular patterns in the central vortex region. This type of DDT can also be found in on Mars in orbital image data, and although in situ studies are lacking, terrestrial analog studies, laboratory work, and numerical modeling suggest they have the same formation mechanism as those on Earth. Finally, bright DDTs are characterized by their continuous track pattern and high albedo compared to their undisturbed surroundings. They are found on both planets, but to date they have only been analyzed in situ on Earth. Here, the destruction of aggregates of dust, silt and sand by dust devils leads to smooth surfaces in contrast to the undisturbed rough surfaces surrounding the track. The resulting change in photometric properties occurs because the smoother surfaces have a higher reflectance compared to the surrounding rough surface, leading to bright DDTs. On Mars, the destruction of surficial dust-aggregates may also lead to bright DDTs. However, higher reflective surfaces may be produced by other formation mechanisms, such as dust compaction by passing dust devils, as this may also cause changes in photometric properties. On Mars, DDTs in general are found at all elevations and on a global scale, except on the permanent polar caps. DDT maximum areal densities occur during spring and summer in both hemispheres produced by an increase in dust devil activity caused by maximum insolation. Regionally, dust devil densities vary spatially likely controlled by changes in dust cover thicknesses and substrate materials. This variability makes it difficult to infer dust devil activity from DDT frequencies. Furthermore, only a fraction of dust devils leave tracks. However, DDTs can be used as proxies for dust devil lifetimes and wind directions and speeds, and they can also be used to predict lander or rover solar panel clearing events. Overall, the high DDT frequency in many areas on Mars leads to drastic albedo changes that affect large-scale weather patterns

Evaluation of effects of porcelain firing on the marginal fit changes of porcelain–fused-to -metal crown fabricated utilizing two different margin designs and two commercially available base metal alloys

Aim: To find the marginal fit of the porcelain fused to metal crowns by two different margin designs (shoulder and chamfer) and two commercially available base metal alloys.Material and Methods: Tooth preparation of first central incisor for porcelain-fused-to-metal crown with shoulder margin and second incisor for porcelain-fused-to-metal crown with chamfer margin was done. Wax pattern of the same was prepared. Impression of both prepared ivorine incisors was made by light body impression material and poured with pattern resin. Both the patterns were invested and casted with cobalt chromium alloy for making master dies. Two wax patterns of unprepared central incisors were fabricated, one with shoulder margin and another with chamfer margin. These patterns were then cut back to the size of the coping. Four rings were invested. In each ring ten patterns, five with shoulder margin and five with deep chamfer margin were sprued together to ensure that each group would pass through the same investing and casting procedure, followed by ceramic firing and measurement.Results: Marginal fit change or marginal discrepancy (before and after firing) between the groups was highly significant.Conclusions: Veneered crowns exhibited highly significant marginal distortion than non- veneered copings after porcelain firing. Shoulder margin is better in minimizing marginal discrepancy compared to deep chamfer margin. Marginal discrepancy is less when cerabond base metal alloy is used with shoulder margin as compared to commend base metal alloy used for shoulder margin

Spray washes of organic acids to decontaminate pork carcass tissues in India

Medical and commercial requirements to extend safe, high quality shelf life of food, have focussed attention on decontamination systems. Organic acid sprays of acetic, propionic and lactic at 3Kg/cm\u27 pressure and 1%, 2% and 3% concentrations, individually and in combination, were used to decontaminate pork samples. It was observed that out of 3 acids lactic acid at 2% was found to reduce the total viable count (TVC) by 0.07 log units whereas the combination treatment of 3% acetic and propionic acids resulted in 0.09 log unit reduction of TVC without affecting the color and odour score. The shelf life, on analysis, was sound to almost double at refrigeration storage as compared to control. Thus, 2 % lactic acid and 3% acetic + propionic acids offer scope for reduction in microflora and suppression of pathogen proliferation on pork samples during refrigeration storage and transport, thereby improving meat quality and shelf life

A simple method of estimating folic acid absorption (a modified faecal excretion method)

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Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long-Term Treatment Response in Rheumatoid Arthritis

Objective: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.  Methods: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.  Results: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.  Conclusion: Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months

Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11

The ATP-dependent degradation of polyubiquitylated proteins by the 26S proteasome is essential for the maintenance of proteome stability and the regulation of a plethora of cellular processes. Degradation of substrates is preceded by the removal of polyubiquitin moieties through the isopeptidase activity of the subunit Rpn11. Here we describe three crystal structures of the heterodimer of the Mpr1-Pad1-N-terminal domains of Rpn8 and Rpn11, crystallized as a fusion protein in complex with a nanobody. This fusion protein exhibits modest deubiquitylation activity toward a model substrate. Full activation requires incorporation of Rpn11 into the 26S proteasome and is dependent on ATP hydrolysis, suggesting that substrate processing and polyubiquitin removal are coupled. Based on our structures, we propose that premature activation is prevented by the combined effects of low intrinsic ubiquitin affinity, an insertion segment acting as a physical barrier across the substrate access channel, and a conformationally unstable catalytic loop in Rpn11. The docking of the structure into the proteasome EM density revealed contacts of Rpn11 with ATPase subunits, which likely stabilize the active conformation and boost the affinity for the proximal ubiquitin moiety. The narrow space around the Rpn11 active site at the entrance to the ATPase ring pore is likely to prevent erroneous deubiquitylation of folded proteins