Synthesis of carbazole based α-aminophosphonate derivatives: design, molecular docking and in vitro cholinesterase activity.

A series of novel carbazole based α-aminophosphonate derivatives were synthesized under solvent-free condition, characterized and evaluated for their cholinesterase inhibition, enzyme kinetic inhibition, in-vitro cell viability using N2a cells, neuroprotective studies against H2O2-induced stress using N2a cells and antioxidant studies using DPPH radical activity. Test compounds displayed better AChE activity (0.475 to 7.781 µM) than BuChE (3.306 to 21.32 µM). Compound 4j was most potent derivative against AChE as well as BuChE with IC50=0.475 ± 0.12 µM and IC50=3.306 ± 0.21 µM respectively. Kinetic inhibition studies indicate that compound 4j exhibits mixed type inhibition against both enzymes which was supported by molecular docking studies. Cell viability studies showed that compounds did not induce any cytotoxic effect against N2a cells using MTT assay. Also, compound 4j, 4 s and 4r were subjected to H2O2-induced stress using N2a cells and were found to be protective in nature. ADME predictions were carried out to understand the pharmacokinetics behaviour.Communicated by Ramaswamy H. Sarma.

Planetary albedo decline over Northwest India contributing to near surface warming.

The increase in frequency and severity of heat waves during the pre-monsoon season (March-May) over Northwest India in recent decades is alarming. This study investigates the causative mechanism for warming through the forcing induced by planetary albedo changes over Northwest India, a hotspot for land-cover change. We use satellite-measured planetary albedo (α) and satellite-derived land-use-land-cover (LULC) data to estimate the impact of LULC changes from 2001 to 2018 on α and the associated radiative forcing. Over Northwest India, significant area under native land-cover, viz., barren, shrub and grass-lands, has been converted to cropland. The associated land-cover-induced changes have perturbed the radiation-budget by modifying the absorption of shortwave radiation, thereby contributing to the pronounced reduction of α as observed over this region. The diurnal-mean α has decreased by 0.016 ± 0.001 from 2001 to 2018 during pre-monsoon season which dominates α-decrease during the annual cycle over this region and contributes to the overall decreasing trend over India. Conversion of barren and shrub-lands to cropland is observed to be the greatest contributor to the α-decrease as compared to other land-cover changes. The radiative forcing due to decline in diurnal-mean α over Northwest India from 2001 to 2018 is highest during pre-monsoon at 5.99 ± 0.34 W/m2. This α-induced forcing averaged over the global land surface (0.02 W/m2) is equivalent to the corresponding direct forcing from rise in atmospheric methane concentrations during this period. We find an enhancement in near-surface heating to be associated with change in α; the decreasing trend in α during pre-monsoon has substantially enhanced near-surface extreme effective temperatures by 3.15 ± 2.61 K thus far and may further lead to more extreme heatwaves in future. Further, our findings highlight a decreasing (warming) and increasing (cooling) trend in clear-sky planetary albedo respectively over Northwest India and coastal regions, suggesting that sudden climate change could occur if one forcing dominates over the other.

Intra-seasonal contrasting trends in clouds due to warming induced circulation changes.

Quantification of long term changes in cloud distribution and properties is critical for the proper assessment of future climate. We show contrasting trends in cloud properties and cloud radiative effects over Northwest Indian Ocean (NWIO) in south Asian summer monsoon. Cloud top height (CTH) decreases in June (- 69 ± 3 myr-1) and July (- 44 ± 3 myr-1), whereas it increases in August (106 ± 2 myr-1) and September (37 ± 1 myr-1). These contrasting trends are investigated to be due to the changes in upper tropospheric winds and atmospheric circulation pattern. Strengthening of upper tropospheric easterlies and changes in vertical wind dampen the vertical development of clouds in June and July. In contrast, weakening of upper tropospheric winds over NWIO and strengthening of updraft favour the vertical growth of clouds in August. Further, changes in horizontal winds at 450-350 hPa and strengthening of Indian Ocean Walker cell favour the westward spread of high level clouds, contributing to the increase in CTH over NWIO in August. Decrease of cloud cover and altitude in June and July and increase of the same in subsequent months would affect the monsoon rainfall over the Indian region. Proper representation of these intra-seasonal contrasting trends of clouds in climate models is important for the better prediction of regional weather.

CCN concentrations and BC warming influenced by maritime ship emitted aerosol plumes over southern Bay of Bengal.

Significant quantities of carbon soot aerosols are emitted into pristine parts of the atmosphere by marine shipping. Soot impacts the radiative balance of the Earth-atmosphere system by absorbing solar-terrestrial radiation and modifies the microphysical properties of clouds. Here we examined the impact of black carbon (BC) on net warming during monsoon season over southern Bay-of-Bengal, using surface and satellite measurements of aerosol plumes from shipping. Shipping plumes had enhanced the BC concentrations by a factor of four around the shipping lane and exerted a strong positive influence on net warming. Compiling all the data, we show that BC atmospheric heating rates for relatively-clean and polluted-shipping corridor locations to be 0.06 and 0.16 K/day respectively within the surface layer. Emissions from maritime ships had directly heated the lower troposphere by two-and-half times and created a gradient of around 0.1 K/day on either side of the shipping corridor. Furthermore, we show that ship emitted aerosol plumes were responsible for increase in the concentration of cloud condensation nuclei (CCN) by an order of magnitude that of clean air. The effects seen here may have significant impact on the monsoonal activity over Bay-of-Bengal and implications for climate change mitigation strategies.

Synergistic Chemotherapeutic Activity of Curcumin Bearing Methoxypolyethylene Glycol-g-Linoleic Acid Based Micelles on Breast Cancer Cells.

Although curcumin (Cur), has been poised to be an anticancer boon for quite some, its progress from bench to bed has been strained due to various pharmaceutical hurdles. Consequently curcumin has been entrapped in methoxy poly ethylene glycol and linoleic acid conjugated polymeric micelles (PMs) to not only tackle the routine issues but to also provide a synergetic effect against MCF-7 breast cancer cells. Optimized PMs of Cur had size 186.53 ± 12.10 nm with polydispersity index 0.143 ± 0.031 and zeta potential -30.1 ± 3.2 mV. Developed formulation (Mpeg-Cla-Cur PMs) was hemocompatible and had high cytotoxicity (IC50 55.80 ± 4.63 µ/mL) against MCF-7 cells in comparison to pure Cur suspension (IC50 75.05 ± 5.75 µg/mL). As postulated cell cycle arrest and apoptosis studies revealed synergetic effect of Mpeg-Cla-Cur PMs with higher cell population in G1 phase in addition to high apoptosis of MCF-7 cells as compared to pure Cur suspension and con- trol group. Pharmacokinetic studies also show PMs enhanced MRT and T1/2 of Cur indicating its longer retention time in body. Mpeg-Cla-Cur PMs might become as an excellent chemotherapeutic alternative candidate for treatment of breast cancer with higher commercial value.

Age- and Sex-related Prevalence and Drug Utilization Pattern in the Management of Type 2 Diabetes Mellitus and its Comorbidity with Cardiovascular Diseases: A Comparative Study.

A cross-sectional study of 250 cases of type 2 diabetes management was conducted in a governmental tertiary care hospital of urban south India to determine the comparative prevalence of type 2 diabetes and its comorbidity with cardiovascular diseases in diabetic population, core drug use indicators and drug utilization pattern in the management of diabetics entirely and with cardiovascular diseases. Highest prevalent age group for type 2 diabetes/cardiovascular diseases (greater incidence in female than male) was 51-60 years. The 62.8% prevalence of cardiovascular diseases in the diabetic population ascertained in the study could provide an evidence-based rationale for the World Health Organization guidelines for the management of hypertension in type 2 diabetics. Incidence of polypharmacy (6.06, the mean number of total drug products prescribed); 59.26% of encounters prescribed antibiotics; 17.6 and 18.5 min of average consultation and dispensing time, respectively; 100% of drugs actually dispensed and adequately labeled; 81.26% of patients having knowledge of correct dosage and average drug cost of Indian Rupees 145.54 per prescription were the core drug use indicators found mainly. Moreover, drugs prescribed from the Essential Drug List were more than 90% and thereby indicated the drug use in this set-up quite rational. Around 71.09% of cardiovascular agents prescribed by generic name revealed the cost effective medical care. Among the agents in type 2 diabetes management, Actrapid(®) (35.43%) was the highest. Among the cardiovascular agents prescribed, lasix (19.37%) was the highest. Cardiovascular agents prescribed orally by 76.48% signified the good prescription habit indicating the improved patients' adherence to the treatment. The present study emphasizes the need of early detection of hypertension as a preliminary diagnostic parameter of cardiovascular diseases in diabetics and appropriate management through concomitant therapy of cardiovascular drugs to minimize the risks of death.

Evaluation of a multiplex PCR assay for concurrent detection of four major mycotoxigenic fungi from foods.

AIM: To develop and evaluate a multiplex polymerase chain reaction assay (mPCR) for the concurrent detection of four major mycotoxin metabolic pathway genes, viz. nor1 (aflatoxin), Tri6 (trichothecene), FUM13 (fumonisin) and otanps (ochratoxin A). METHODS AND RESULTS: A mPCR assay with competitive internal amplification control, employing specific primers for each of the aforementioned four genes, was optimized and validated using 10 reference strains and 60 pure culture isolates. The standardized mPCR assay detected all four mycotoxin metabolic genes in artificially contaminated maize samples with a sensitivity of 2 × 10(3) CFU g(-1) for nor1-positive Aspergillus strains, Tri6 and FUM13-positive Fusarium strains and 2 × 10(4) CFU g(-1) for otanps-positive Penicillium strains. When the developed mPCR assay was applied to 40 natural foods, 35% (14 of 40) of the samples were contaminated with either one or more mycotoxins. The mPCR results were further evaluated with high-performance liquid chromatography (HPLC), and in general, both the methods provided unequivocal results. CONCLUSION: The current mPCR assay is a rapid and reliable tool for simultaneous specific and sensitive detection of aflatoxigenic Aspergillus strains, trichothecene- and fumonisin-producing Fusarium strains, and ochratoxigenic Penicillium species from naturally contaminated foods. SIGNIFICANCE AND IMPACT OF THE STUDY: This mPCR assay could be a supplementary strategy to current conventional mycotoxin analytical techniques such as thin-layer chromatography (TLC), high performance thin layer chromatography, HPLC, etc., and a reliable tool for high-throughput monitoring of major mycotoxin-producing fungi during the processing steps of food and feed commodities.

Dissolution behavior of ß-cyclodextrin molecular inclusion complexes of aceclofenac.

The objective of the present investigation was to study the effect of ß-cyclodextrin (ß-CD) on the in vitro dissolution of aceclofenac (AF) from molecular inclusion complexes. Aceclofenac molecular inclusion complexes in 1:1 and 1:2 M ratio were prepared using a kneading method. The in vitro dissolution of pure drug, physical mixtures, and cyclodextrin inclusion complexes was carried out. Molecular inclusion complexes of AF with ß-CD showed a considerable increase in the dissolution rate in comparison with the physical mixture and pure drug in 0.1 N HCl, pH 1.2, and phosphate buffer, pH 7.4. Inclusion complexes with a 1:2 M ratio showed the maximum dissolution rate in comparison to other ratios. Fourier transform infrared spectroscopy and differential scanning calorimetry studies indicated no interaction between AF and ß-CD in complexes in solid state. Molecular modeling results indicated the relative energetic stability of the ß-CD dimer-AF complex as compared to ß-CD monomer-AF. Dissolution enhancement was attributed to the formation of water soluble inclusion complexes with ß-CD. The in vitro release from all the formulations was best described by first-order kinetics (R(2) = 0.9826 and 0.9938 in 0.1 N HCl and phosphate buffer, respectively) followed by the Higuchi release model (R(2) = 0.9542 and 0.9686 in 0.1 N HCl and phosphate buffer, respectively). In conclusion, the dissolution of AF can be enhanced by the use of a hydrophilic carrier like ß-CD.

Comparative Investigation on in vitro release of extemporaneously prepared norfloxacin semisolid formulations with marketed silver sulfadiazine 1% cream, USP using model independent approach

ObjectiveIn an attempt for better treatment of bacterial infections, various semisolid formulations containing 5%w/w of norfloxacin were prepared and evaluated for in vitro drug release and in vitro skin permeabilityusing dialysis membrane and rat abdominal skin respectively. The in vitro diffusion and permeationprofile of the prepared formulation was compared with marketed silver sulfadiazine cream 1%, USPusing model independent approach.MethodsVarious semisolid formulations were prepared with different dermatological bases usingstandard procedures. In vitro diffusion and permeation studies were carried out using Keshary-Chein(KC) type diffusion cell using dialysis membrane and rat abdominal skin respectively.ResultsThe f1 lower than 15 and f2 higher than 50 indicated similarities in the in vitro diffusion andpermeation profiles of the extemporaneously prepared selected semisolid formulations and marketedsilver sulfadiazine 1% cream, USP.ConclusionAmongst all the semisolid formulations prepared, carbopol gel base was found to be most suitabledermatological base for norfloxacin, the results obtained for in vitro diffusion, and in vitro skinpermeation studies are comparable with that of marketed silver sulphadiazine 1% cream, USP(AU)

Preparation and evaluation of transdermal plasters containing norfloxacin: a novel treatment for burn wound healing.

OBJECTIVE: In an attempt for better treatment of bacterial infections and burn wounds, plaster formulations containing different concentrations of norfloxacin were prepared using polymers like polyvinylpyrrolidone and polyvinyl alcohol and evaluated for physicochemical parameters, in vitro drug release, antimicrobial activity, and burn wound healing properties. The prepared formulations were compared with silver sulfadiazine cream 1%, USP. METHODS: Plaster formulations containing different concentrations of norfloxacin were prepared by solvent casting method using combination of polymers like polyvinylpyrrolidone and polyvinyl alcohol. These plasters were characterized for drug content, thickness, percentage elongation, tensile strength, in vitro drug release properties, and antimicrobial activity against various strains of aerobic and anaerobic microorganisms. The wound healing property was evaluated by histopathological examination and by measuring the wound contraction. RESULTS: The in vitro release and in vitro skin permeation followed the first-order kinetics followed by diffusion as dominant release mechanism. In spite of the significant antimicrobial and wound healing effects produced by plasters, the observed values were less than the values obtained with silver sulfadiazine 1% cream (P < .05). Various histopathological changes observed during the study period (days 1, 4, 8, and 12) also supported the wound healing process. CONCLUSION: Based on the observed in vitro performances along with antimicrobial and wound healing effects, the 5% norfloxacin transdermal plasters could be employed as an alternative to commercial silver sulfadiazine 1% cream.

Simultaneous observations of aerosol-cloud-albedo interactions with three stacked unmanned aerial vehicles.

Aerosol impacts on climate change are still poorly understood, in part, because the few observations and methods for detecting their effects are not well established. For the first time, the enhancement in cloud albedo is directly measured on a cloud-by-cloud basis and linked to increasing aerosol concentrations by using multiple autonomous unmanned aerial vehicles to simultaneously observe the cloud microphysics, vertical aerosol distribution, and associated solar radiative fluxes. In the presence of long-range transport of dust and anthropogenic pollution, the trade cumuli have higher droplet concentrations and are on average brighter. Our observations suggest a higher sensitivity of radiative forcing by trade cumuli to increases in cloud droplet concentrations than previously reported owing to a constrained droplet radius such that increases in droplet concentrations also increase cloud liquid water content. This aerosol-cloud forcing efficiency is as much as -60 W m(-2) per 100% percent cloud fraction for a doubling of droplet concentrations and associated increase of liquid water content. Finally, we develop a strategy for detecting aerosol-cloud interactions based on a nondimensional scaling analysis that relates the contribution of single clouds to albedo measurements and illustrates the significance of characterizing cloud morphology in resolving radiometric measurements. This study demonstrates that aerosol-cloud-albedo interactions can be directly observed by simultaneous observations below, in, and above the clouds.

Synthesis and biological evaluation of delavayin-C.

The synthesis of a cyclic heptapeptide, delavayin-C, cyclo(gly-tyr-tyr-tyr-pro-val-pro) is described. The structure of this compound was established on the basis of analytical IR, (1)H NMR and FAB mass spectral data. The antibacterial and antifungal activities of this peptide are also described.

Investigation of enhancement of solubility of norfloxacin beta-cyclodextrin in presence of acidic solubilizing additives.

The present study is aimed at improving the solubility of a poorly water-soluble drug, norfloxacin by incorporating solubilizing additives such as ascorbic acid and citric acid into the beta-cyclodextrin complexes. Norfloxacin, being amphoteric in nature, exhibits a higher solubility at pH below 4 and above 8. Addition of substances like ascorbic acid and citric acid in beta-cyclodextrin complexes reduces the pH of the immediate microenvironment of the drug below pH 4. In the present work, beta-cyclodextrin complexes of norfloxacin were prepared along with solubilizing additives such as citric acid and ascorbic acid in various proportion and the dissolution profile was performed in both HCl buffer, pH 1.2 and phosphate buffer, pH 7.4. The results have shown an enhanced dissolution rate in both media. DSC and IR spectral studies performed on the solid complexes have shown that there is no interaction of the drug with the additives and beta-cyclodextrin. Disc diffusion studies have shown larger diameters of zone of inhibition indicating a greater diffusivity of the drug into the agar medium.

Synthesis and biological activity of a novel series of 4-[2'-(6'-nitro)benzimidazolyl]benzoyl amino acids and peptides.

A series of new 4-[2'-(6'-nitro)benzimidazolyl]benzoyl amino acids and peptides have been synthesized by coupling the 4-[2'-(6'-nitro)benzimidazolyl]benzoic acid with amino acid methyl esters/dipeptides using DCC as the coupling agent. All the synthesized compounds were found to exhibit potent anthelmintic activity along with moderate antimicrobial activity.

Detection of influenza virus induced DNA damage by comet assay.

Influenza virus A2/HK/68 is known to be a biological mutagen and teratogen. Reports are available implicating influenza virus as a causative agent of chromosomal aberrations in cells in culture and also in circulating leukocytes of humans. Also, an increased incidence of abortions, prenatal mortality and congenital abnormalities during the periods of epidemics has also been reported. In view of these reports, it would be worthwhile to screen persons especially pregnant women exposed to influenza virus for possible DNA damage. The present study reports the use of Comet assay to measure influenza virus induced DNA damage. We have carried out in vitro infection experiments using human leukocytes. Our results clearly indicate that influenza virus A2/HK/68 induces DNA damage in leukocytes right from 2-h post-infection. Maximum damage was observed at 24-h post-infection. However, at 48-h post-infection, a slight decrease was observed which can be attributed to the DNA repair occurring in the cells. Thereafter, irreparable damage was noticed. Cell viability results have shown lack of cytotoxicity till 72-h post-infection. However, significant cytotoxicity was observed only at 96-h post-infection. The occurrence of DNA damage without cell death may result in chromosomal aberrations or mutations. Therefore, it is most advisable to get screened for the possible DNA damage especially persons frequently infected with influenza and pregnant women.