Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study.

INTRODUCTION: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. METHODS: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. RESULTS: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. CONCLUSION: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Phase III Pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID 19 vaccine (Covaxin®).

One of the most preferable characteristics for a COVID-19 vaccine candidate is the ability to reduce transmission and infection of SARS-CoV-2, in addition to disease prevention. Unlike intramuscular vaccines, intranasal COVID-19 vaccines may offer this by generating mucosal immunity. In this open-label, randomised, multicentre, phase 3 clinical trial (CTRI/2022/02/40065; ClinicalTrials.gov: NCT05522335), healthy adults were randomised to receive two doses, 28 days apart, of either intranasal adenoviral vectored SARS-CoV-2 vaccine (BBV154) or licensed intramuscular vaccine, Covaxin®. Between April 16 and June 4, 2022, we enrolled 3160 subjects of whom, 2971 received 2 doses of BBV154 and 161 received Covaxin. On Day 42, 14 days after the second dose, BBV154 induced significant serum neutralization antibody titers against the ancestral (Wuhan) virus, which met the pre-defined superiority criterion for BBV154 over Covaxin®. Further, both vaccines showed cross protection against Omicron BA.5 variant. Salivary IgA titers were found to be higher in BBV154. In addition, extensive evaluation of T cell immunity revealed comparable responses in both cohorts due to prior infection. However, BBV154 showed significantly more ancestral specific IgA-secreting plasmablasts, post vaccination, whereas Covaxin recipients showed significant Omicron specific IgA-secreting plasmablasts only at day 42. Both vaccines were well tolerated. Overall reported solicited reactions were 6.9% and 25.5% and unsolicited reactions were 1.2% and 3.1% in BBV154 and Covaxin® participants respectively.

Design, Synthesis, and Characterization of [18F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates 8-10 featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound 6 in the cAMP GloSensor assays. Radiolabeling of compounds 8 and 9 (mG2P026) was achieved via Cu-mediated radiofluorination with satisfactory radiochemical yield, >5% (non-decay-corrected); high molar activity, >180 GBq/µmol; and excellent radiochemical purity, >98%. Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [18F]9 in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [18F]6. Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [18F]9. As a selective ligand, [18F]9 has the potential to be developed for translational studies.

Efficacy and Safety of Fluticasone Furoate and Oxymetazoline Nasal Spray: A Novel First Fixed Dose Combination for the Management of Allergic Rhinitis with Nasal Congestion.

Objective: To compare the efficacy and safety of a fixed dose combination of Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray 27.5/50 mcg (FDC) with Fluticasone Furoate Nasal Spray 27.5 mcg (Fluticasone) in the management of allergic rhinitis. Patients and Methods: A prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, comparative clinical study was conducted in patients with allergic rhinitis aged 18 years and above having moderate-to-severe nasal congestion. Results: A total of 250 patients were randomized (1:1) to receive either the FDC or Fluticasone alone in a dose of two sprays in each nostril once daily at night. There was a significantly (P<0.001) greater reduction in night-time Total Nasal Symptom Score with the FDC as compared to Fluticasone at all the time points starting from as early as day 3 and sustained till the end of treatment (Day 28) (Day 3: -3.1 vs -2.2; Day 7: -4.0 vs -3.4; Day 14: -5.7 vs -5.0; Day 28: -7.0 vs -6.4). A significantly greater number of patients (P<0.05) had complete relief in Nasal Congestion with the FDC (44.7%) as compared to Fluticasone (26.8%). Both the study medications were well tolerated by all the patients. The proportion of patients showing worsening of symptoms (rebound congestion/rhinitis medicamentosa) after stoppage of medication was similar in both groups (P>0.05). Conclusion: The FDC was superior to Fluticasone alone in relieving the nasal congestion and reduction of Total Nasal Symptom Score in allergic rhinitis patients with moderate-to-severe nasal congestion when administered once daily in the evening. Oxymetazoline when used along with the nasal steroid in a once daily dose does not cause rebound congestion and rhinitis medicamentosa even after long-term continuous use of 28 days.

Synthesis and Characterization of 5-(2-Fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/µmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.

Interrelationship of Indoor Particulate Matter and Respiratory Dust Depositions of Women in the Residence of Dhanbad City, India.

Women spend relatively more time in indoor environments in developing countries. Exposure to various indoor air pollutants leads them to higher health risks according to household air quality in which they reside. Particulate matter (PM) exposure with their exposure duration inside the household plays a significant role in women's respiratory problems. This study measured size-segregated particulate matter concentrations in 63 residences at different locations. Respiratory dust depositions (RDDs) for 118 women in their different respiratory regions like head airway (HD), tracheobronchial (TB), and alveolar (AL) regions for the three PM size fractions (PM10, PM2.5, and PM1) were investigated. For different positions like light exercise and the sitting condition, RDDs values found for AL region were 0.091 µgmin-1 (SD: 0.067, 0.012-0.408) and 0.028 µgmin-1 (SD: 0.021, 0.003-0.126) for PM10, 0.325 µgmin-1 (SD: 0.254, 0.053-1.521) and 0.183 µgmin-1 (SD: 0.143, 0.031-0.857) for PM2.5, 0.257 µgmin-1 (SD: 0.197, 0.043-1.04) and 0.057 µgmin-1 (SD: 0.044, 0.009-0.233) respectively for PM1 to females. RDDs values in the AL region significantly increase as PM10 (11%), PM2.5 (68%), and PM1 (21%), confirming that for women, the AL region is the most prominent affected zone by fine particles (PM2.5).

Assessment of Pollution and Health Risks of Heavy Metals in Particulate Matter and Road Dust Along the Road Network of Dhanbad, India.

BACKGROUND: The rise in particulate matter (PM) concentrations is a serious problem for the environment. Heavy metals associated with PM10, PM2.5, and road dust adversely affect human health. Different methods have been used to assess heavy metal contamination in PM10, PM2.5, and road dust and source apportionment of these heavy metals. These assessment tools utilize pollution indices and health risk assessment models. OBJECTIVES: The present study evaluates the total mass and average concentrations of heavy metals in PM10, PM2.5, and road dust along selected road networks in Dhanbad, India, analyzes the source apportionment of heavy metals, and assesses associated human health risks. METHODS: A total of 112 PM samples and 21 road dust samples were collected from six stations and one background site in Dhanbad, India from December 2015 to February 2016, and were analyzed for heavy metals (iron (Fe), lead (Pb), cadmium (Cd), nickel (Ni), copper (Cu), chromium (Cr), and zinc (Zn)) using atomic absorption spectrophotometry. Source apportionment was determined using principal component analysis. A health risk assessment of heavy metal concentrations in PM10, PM2.5, and road dust was also performed. RESULTS: The average mass concentration was found to be 229.54±118.40 µg m-3 for PM10 and 129.73 ±61.74 µg m-3 for PM2.5. The average concentration of heavy metals was found to be higher in PM2.5 than PM10. The pollution load index value of PM10 and PM2.5 road dust was found to be in the deteriorating category. Vehicles were the major source of pollution. The non-carcinogenic effects on children and adults were found to be within acceptable limits. The heavy metals present in PM and road dust posed a health risk in the order of road dust> PM10> and PM2.5. Particulate matter posed higher health risks than road dust due to particle size. CONCLUSIONS: The mass concentration analysis indicates serious PM10 and PM2.5 contamination in the study area. Vehicle traffic was the major source of heavy metals in PM10, PM2.5, and road dust. In terms of non-carcinogenic risks posed by heavy metals in the present study, children were more affected than adults. The carcinogenic risk posed by the heavy metals was negligible. COMPETING INTERESTS: The authors declare no competing financial interests.

Spatio-temporal variation of air pollutants around the coal mining areas of Jharia Coalfield, India.

Jharia Coalfield (JCF) is one of the oldest coalfields in the eastern part of India and falls under critically polluted areas as per CPCB/MoEFCC Notification. Therefore, a study of air pollution and its management is the demand of the day. This study had been undertaken to know the current status of JCF concerning air quality. Ambient air quality monitoring with reference to particulate matter (PM10 and PM2.5), SO2, NOx and trace elements had been conducted in the coal mining areas of JCF. The study area was divided into two groups, mainly fire and non-fire for the sampling of air. Principal component analysis (PCA) identified coal mine fire as a major source of air pollution in the mining areas of JCF. Air quality index (AQI) was calculated which revealed that the air quality index of coal mine fire-affected areas was nearly 1.5 times higher than that of the non-mine fire areas. Graphical abstract.

Evaluation of spatial and temporal heterogeneity of black carbon aerosol mass concentration over India using three year measurements from IMD BC observation network.

Extensive measurements of equivalent black carbon (EBC) aerosol mass concentration at fifteen stations of India Meteorological Department (IMD) BC observation network during the period 2016-2018 are used to study the spatial and temporal heterogeneity over India. The sampling sites represent different geographical region of India. Spatial distribution shows higher values of EBC over stations of north India and IGP. Highest annual mean EBC mass concentration during study period was reported at two mega cities New Delhi (13,575 ± 8401 ng/m3) followed by Kolkata (12,082 ± 6850 ng/m3) whereas lowest mean concentration was at Ranichauri (1737 ± 884 ng/m3) followed by Bhuj (2021 ± 1471 ng/m3). Stations located in coastal region of south India reported low concentration of EBC. In order to find out the quantitative contribution of biomass burning (EBCBB) and fossil fuel (EBCFF) in total mass concentration of EBC, source apportionment study has been carried out using Aethalometer model. The EBCFF is the dominant contributor to EBC mass concentration at all the sites in every season, while the highest seasonal biomass burning mass contribution (37%) was observed in the winter at a background site Ranichauri. Maximum concentration of EBCBB was observed at Srinagar (2671 ng/m3) where as EBCFF was maximum in Delhi (11,074 ng/m3). Seasonal and diurnal variation studies have also been carried out for all the stations. The EBC mass concentrations exhibited strong seasonality, with the highest values occurring in postmonsoon/winter and the lowest in monsoon season. The higher EBC concentration in postmonsoon/winter seasons was attributed to the increased use of fuel in seasonal emission sources, domestic heating and stagnant meteorological conditions, whereas the low levels in monsoon season were related to the precipitation scavenging. Maximum concentration of EBC (22,409 ± 10,510 ng/m3) was observed in winter season over Kolkata. Our study finds high spatial heterogeneity in EBC concentrations across the study area.

Pollution evaluation, spatial distribution, and source apportionment of trace metals around coal mines soil: the case study of eastern India.

The degradation of land by trace metals contamination around coal mining areas is a serious environmental issue, and therefore, it is necessary to have detailed information about the pollution caused by them and their sources. The objective of the work was to study the impact of trace metals (e.g., Cd, Co, Ni, Cr, Zn, Pb, and Cu) on the soil of Jharia coalfield to analyze their sources, contamination level, and their spatial distribution. The present values of the trace metals were compared by their natural background values which were then analyzed on the scale of the Potential Ecological Risk Index (PERI) and by Improved Nemerow Index (Lnm). The results of spatial distribution revealed that the majority of the soil in Jharia coalfield is moderately contaminated, a small portion of it is slightly contaminated, and altogether at moderate ecological risk due to trace metals. Multivariate statistical techniques including Principal component analysis, Cluster analysis, and Pearson's correlation evaluated that Cu, Ni, Zn, Co, and Cr in the soil samples had the same source which is coal mining; Pb and Cd were from multiple sources. The spatial distribution maps of trace metals present in the soil of Jharia coalfield were generated using Radial basis function an interpolation method.

Evaluation of change in biochar properties derived from different feedstock and pyrolysis temperature for environmental and agricultural application.

In recent years, the application of biochar has increased significantly for sustainable and efficient carbon sequestration, improving soil quality and enhancement of plant growth. The biochar is mostly made from agricultural residues and waste materials. The objective of this study was to assess the changes in physicochemical, surface morphology, and mineral composition of different biochars with varying pyrolysis temperature. Eighteen different types of biochars were prepared through pyrolysis of feedstock at four different temperatures (350 °C, 450 °C, 550 °C and 650 °C). The feedstock used for the preparation of biochar were organic waste materials such as pine saw dust, rice husk, food waste, poultry litter and paper sludge. Pyrolysis temperatures and feedstock types significantly influenced biochar properties. For instance, pH of poultry litter and paper sludge biochar has increased from 6.2 to 10.3, BET surface area of saw dust and rice husk increased from 3.39 to 443.79 m2 g-1 and 11.61 to 280.97 m2 g-1 while cation exchange capacity value decreased with the increase in temperature. Paper sludge and poultry litter had the highest ash content value (57.20 ± 0.02 and 44.10 ± 0.02) whereas saw dust, rice husk and food waste biochar have highest fixed carbon value (55.31 ± 0.15, 48.47 ± 0.31 and 58.85 ± 0.22) at 650 °C. Degree of aromaticity increased and polarity reduced significantly with pyrolysis temperature. Rice husk and saw dust biochar prepared at higher temperature were more stable among all and thus recalcitrant in nature. X-ray diffraction results revealed mineral like quartz in saw dust and poultry litter biochar, sylvite, potassium iodate, calcium sulfide in food waste biochar and calcium carbonate in paper sludge biochar. Scanning Electron Microscopy showed increase in number of pores as well as pore size specially for the saw dust, and rice husk biochar. This study suggested that biochar prepared at higher temperature (550 °C and 650 °C) are more suitable for carbon sequestration and agricultural purpose.

Comparative Analysis of the Conformation, Aggregation, Interaction, and Fibril Morphologies of Human α-, ß-, and γ-Synuclein Proteins.

The human synuclein (syn) family is comprised of α-, ß-, and γ-syn proteins. α-syn has the highest propensity for aggregation, and its aggregated forms accumulate in Lewy bodies (LB) and Lewy neurites, which are involved in Parkinson's disease (PD). ß- and γ-syn are absent in LB, and their exact role is still enigmatic. ß-syn does not form aggregates under physiological conditions (pH 7.4), while γ-syn is associated with neural and non-neural diseases like breast cancer. Because of their similar regional distribution in the brain, natively unfolded structure, and high degree of sequence homology, studying the effect of the environment on their conformation, interactions, fibrillation, and fibril morphologies has become important. Our studies show that high temperatures, low pH values, and high concentrations increase the rate of fibrillation of α- and γ-syn, while ß-syn forms fibrils only at low pH. Fibril morphologies are strongly dependent on the immediate environment of the proteins. The high molar ratio of ß-syn inhibits the fibrillation in α- and γ-syn. However, preformed seed fibrils of ß- and γ-syn do not affect fibrillation of α-syn. Surface plasmon resonance data show that interactions between α- and ß-syn, ß- and γ-syn, and α- and γ-syn are weak to moderate in nature and can be physiologically significant in counteracting several adverse conditions in the cells that trigger their aggregation. These studies could be helpful in understanding collective human synuclein behavior in various protein environments and in the modulation of the homeostasis between ß-syn and healthy versus corrupt α- and γ-syn that can potentially affect PD pathology.

Curcumin Pyrazole and its derivative (N-(3-Nitrophenylpyrazole) Curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of Wild type and Mutant α-Synuclein.

Accumulating evidence suggests that deposition of neurotoxic α-synuclein aggregates in the brain during the development of neurodegenerative diseases like Parkinson's disease can be curbed by anti-aggregation strategies that either disrupt or eliminate toxic aggregates. Curcumin, a dietary polyphenol exhibits anti-amyloid activity but the use of this polyphenol is limited owing to its instability. As chemical modifications in curcumin confiscate this limitation, such efforts are intensively performed to discover molecules with similar but enhanced stability and superior properties. This study focuses on the inhibitory effect of two stable analogs of curcumin viz. curcumin pyrazole and curcumin isoxazole and their derivatives against α-synuclein aggregation, fibrillization and toxicity. Employing biochemical, biophysical and cell based assays we discovered that curcumin pyrazole (3) and its derivative N-(3-Nitrophenylpyrazole) curcumin (15) exhibit remarkable potency in not only arresting fibrillization and disrupting preformed fibrils but also preventing formation of A11 conformation in the protein that imparts toxic effects. Compounds 3 and 15 also decreased neurotoxicity associated with fast aggregating A53T mutant form of α-synuclein. These two analogues of curcumin described here may therefore be useful therapeutic inhibitors for the treatment of α-synuclein amyloidosis and toxicity in Parkinson's disease and other synucleinopathies.

Modulation of human α-synuclein aggregation by a combined effect of calcium and dopamine.

Parkinson's disease is characterized by the deposition of aggregated α-syn and its familial mutants into Lewy bodies leading to death of dopaminergic neurons. α-syn is involved in Ca(II) and dopamine (DA) signaling and their adequate balance inside neuronal cytoplasm is essential for maintaining healthy dopaminergic neurons. We have probed the binding energetics of Ca(II) and DA to human α-syn and its familial mutants A30P, A53T and E46K using isothermal titration calorimetry and have investigated the conformational and aggregation aspects using circular dichroism and fluorescence spectroscopy. While binding of Ca(II) to α-syn and its familial mutants was observed to be endothermic in nature, interaction of DA with α-syn was not detectable. Ca(II) enhanced fibrillation of α-syn and its familial mutants while DA promoted the formation of oligomers. However, Ca(II) and DA together critically favored the formation of protofibrils that are more cytotoxic than the mature fibrils. Using fluorescently labeled cysteine mutant A90C, we have shown that different aggregating species of α-syn formed in the presence of Ca(II) and DA are internalized into the human neuroblastoma cells with different rates and are responsible for the differential cytotoxicity depending on their nature. The findings put together suggest that an interplay between the concentrations of Ca(II), DA and α-syn can critically regulate the formation of various aggregating species responsible for the survival of dopaminergic neurons. Modulating this balance leading to either complete suppression of α-syn aggregation or promoting the formation of mature fibrils could be used as a strategy for the development of drugs to cure Parkinson's disease.

Human spleen tyrosine kinase (Syk) recombinant expression systems for high-throughput assays.

Spleen tyrosine kinase (Syk) is an important non-receptor tyrosine kinase and its aberrant regulation is associated with a variety of allergic disorders and autoimmune diseases. To identify small molecule inhibitors of Syk in high-throughput assays, recombinant Syk protein is needed in bulk quantity. We studied the expression of recombinant human Syk in three heterologous systems: E. coli, baculovirus expression vector system (BEVS), and the cellular slime mold Dictyostelium discoideum (Dd). Syk activity was higher in the BEVS as compared to the Dd expression host, whereas in E. coli, no activity was observed under our assay conditions. Purified Syk kinase domain protein from BEVS showed concentration dependent inhibition with OXSI-2, a known Syk inhibitor. Molecular modeling and docking studies were performed to understand the binding mode and critical interactions of the inhibitor with catalytic domain of Syk. The BEVS generated Syk kinase domain showed stability upon multiple freeze-thaw cycles and exhibited significantly higher levels of tyrosine phosphorylation at pTyr(525)/Tyr(526) in the Syk activation loop. Based on our data, we conclude that BEVS is the ideal host to produce an active and stable enzyme, which can be successfully employed for screening of Syk inhibitors in a high-throughput system.

Air quality assessment along Dhanbad - Jharia road.

Road ambient air pollution status along Dhanbad - Jharia road is studied and presented in this article. The selection of this area is made considering the importance of the road in Dhanbad district and the nature of activities taking place along the road, which reflect that the portion of road upto Dhansar can be considered as having commercial areas on both sides and that from Dhansar to Jharia as having industrial areas on both sides. For the assessment of the ambient air quality along the road monitoring is done at the following five locations: Indian School of Mines (ISM), main gate; Bankmore; Dhansar police check post; Dhansar opencast project agent office and a residential house beside the Rajapur opencast project. The location of ISM, main gate is specially chosen as this represents a commercial shopping complexes and the situation can be compared with that at Bankmore. Monitoring of ambient air quality is done following the standard procedure prescribed in IS: 5182. In addition the concentration of lead, zinc, copper, iron, manganese, cadmium metals in SPM is also monitored. The ambient air quality is monitored in the months of September and November 1999, respectively, to represent monsoon and winter seasons. The SPM concentration observed at all the five locations in the winter season is more than the permissible limits for commercial and industrial areas. However, in the monsoon season, the SPM concentration is higher than the permissible limit at the two commercial locations, i.e., ISM gate and Bankmore, while it is less than the prescribed limit for industrial areas at the remaining three locations. At the ISM gate and Bankmore the SPM generation is mainly by vehicular traffic while at other three locations it was in addition due to mining and other activities.