A new normal with cataract surgery during COVID-19 pandemic.

Cataract is the second leading cause of preventable blindness on the globe. Several programs across the country have been running efficiently to increase the cataract surgical rates and decrease blindness due to cataract. The current COVID-19 pandemic has led to a complete halt of these programs and thus accumulating all the elective cataract procedures. At present with the better understanding of the safety precautions among the health care workers and general population the Government of India (GoI) has given clearance for functioning of eye care facilities. In order to facilitate smooth functioning of every clinic, in this paper, we prepared preferred practice pattern based on consensus discussions between leading ophthalmologists in India including representatives from major governmental and private institutions as well as the All India Ophthalmological Society leadership. These guidelines will be applicable to all practice settings including tertiary institutions, corporate and group practices and individual eye clinics. The guidelines include triage, use of personal protective equipment, precautions to be taken in the OPD and operating room as well for elective cataract screening and surgery. These guidelines have been prepared based on current situation but are expected to evolve over a period of time based on the ongoing pandemic and guidelines from GoI.

Access to 2,3-Fused Pyrroles via Visible Light Driven Coupling of α-Azidochalcones with 1/2-Naphthols, or 2-Hydroxy-1,4-Naphthoquinone.

α-Azidochalcones were coupled with 1/2-naphthols or 2-hydroxy-1,4-naphthoquinone using Ru(bpy)3(PF6)2 as a photocatalyst under blue LED light irradiation to yield 2,3-fused pyrroles in high yields (68-84%). The overall transformation involves photosensitized decomposition of α-azidochalcones into highly reactive 2 H-azirines which are trapped by 1/2-naphthols or 2-hydroxy-1,4-naphthoquinone, leading to the construction of two new C-N and one new C-C bonds.

Access to 1a,6b-Dihydro-1H-benzofuro[2,3-b]azirines and Benzofuran-2-amines via Visible Light Triggered Decomposition of α-Azidochalcones.

A novel, efficient, organic process that involves a photocatalyst-free visible light triggered decomposition of α-azidochalcones, followed by intramolecular cyclization, 1,2-acyl migration, and isomerization to construct benzofuran based molecular architectures, is described. The scope and limitation of the synthetic strategy were studied by synthesizing over 30 structurally diverse benzofurans in high yields.

Reductive Deamination by Benzyne for Deoxy Sugar Synthesis Through a Domino Reaction.

Benzyne was developed as a reducing agent in the key step of converting amino sugars and ketoses into deoxy sugars, which occur widely in natural products. Many deoxy sugars exhibit antibiotic and anticancer activities, and furthermore, they play essential biological roles. By treatment with CS2 and then Ac2O, amino sugars and ketoses were converted into the corresponding 1,3-thiazolidine-2-thiones. In the key step, these intermediates were treated with 2-trimethylsilylphenyl triflate (2.0 equiv.) and CsF (3.0 equiv.) in MeCN at 25 °C to produce acyclic enol acetates in 60-63 % yields. Saponification of the enol acetates with NaOMe/MeOH followed by intramolecular cyclization afforded the target 2-deoxy sugars. The key step of the reductive deamination involved a domino 1,2-elimination/[3+2]-cycloaddition/retro [3+2]-ring-opening sequence. The generality of this new method was proven by the use of various substrates, including pentoses, hexoses, monosaccharides, disaccharides, aldoses, and ketoses.

Syntheses of Chroman-2-ones and α-Amino Acids through a Diastereoselective Domino Reaction.

Many 3-aminochroman-2-ones and ß,ß-diarylalanines exhibit significant biological activities. A new method was thus developed for the syntheses of these compounds with high efficiency and diastereoselectivity. First, treatment of various phenols with Erlenmeyer-Plochl (Z)-azlactones and AlCl3 in toluene produced the desired cis-3-aminochroman-2-ones in 65-90% yields under kinetic control. This coupling reaction involved a domino process of Friedel-Crafts alkylation, 1,4-AlCl3 shift, transesterification, and protodealumination in a "single-flask." The corresponding products, however, were not generated by replacement of AlCl3 with a protonic acid. Second, hydrolysis of the resultant 3-amino-4-arylchroman-2-ones by NaHCO3 in a mixture of THF and water gave α-(N-benzoyl)amino acids. Further deprotection of these isolated compounds by use of hydrochloric acid (12 N) in methanol afforded the desired free amino acids in 80-88% yields. Under these optimized conditions, epimerization did not occur at the α carbons of α-(N-benzoyl)- and free α-amino acids. These new findings provide a convenient way to generate 3,4-disubtituted chroman-2-ones and ß,ß-diarylalanine derivatives with very high stereoselectivity.

Visible-Light Driven Photocascade Catalysis: Union of N,N-Dimethylanilines and α-Azidochalcones in Flow Microreactors.

N,N-Dimethylanilines were coupled with α-azidochalcones using visible-light driven Ru(bpy)3(PF6)2 catalyzed photocascade continuous flow microfluidic approach that involves the creation of one C-C and two C-N new bonds. The reaction involves dual photocatalysis ensuing two sp3 C-H bond functionalization of N,N-dimethylanilines. To explore the scope of the reaction, 20 different 1,3-diazabicyclo[3.1.0]hexanes were synthesized in good yields (55-71%).

Visible Light Driven Photocascade Catalysis: Ru(bpy)3(PF6)2/TBHP-Mediated Synthesis of Fused ß-Carbolines in Batch and Flow Microreactors.

1,2,3,4-Tetrahydro-ß-carbolines were coupled with α-keto vinyl azides through an unprecedented visible light-Ru(bpy)3(PF6)2/TBHP mediated photocascade strategy that involves photosensitization, photoredox catalysis and [3 + 2] cycloaddition reaction. The scope and scale-up feasibility of the photocascade strategy was demonstrated by synthesizing 18 different fused ß-carbolines in moderate to good yields using batch and continuous flow microreactor. This operationally simple synthetic protocol allows the formation of one C-C and two C-N new bonds in the overall transformation.

Cu(OAc)2-Et3N mediated oxidative coupling of α-azido ketones with pyridinium ylides: utilizing in situ generated imines for regioselective synthesis of imidazo[1,2-a]pyridines.

Phenacyl azides were reacted with pyridinium ylides in the presence of Cu(OAc)2 (2 mol%) and Et3N utilizing molecular oxygen as a green oxidant to yield imidazo[1,2-a]pyridines in exclusive regioselectivity. Following the optimized protocol, 28 different fused heterocycles were synthesized in high yields (71-92%). In order to get mechanistic insight into the reaction, a few control experiments were carried out and the role of the copper salt was discussed.

One-pot, three-component approach to the synthesis of 3,4,5-trisubstituted pyrazoles.

An operationally simple and high yielding protocol for the synthesis of polyfunctional pyrazoles has been developed through one-pot, three-component coupling of aldehydes, 1,3-dicarbonyls, and diazo compounds as well as tosyl hydrazones. The reaction proceeds through a tandem Knoevenagel condensation, 1,3-dipolar cycloaddition, and transition metal-free oxidative aromatization reaction sequence utilizing molecular oxygen as a green oxidant. The scope of the reaction was studied by varying the aldehyde, 1,3-dicarbonyl, and diazo component individually.

Synthesis of α-amino amidines through molecular iodine-catalyzed three-component coupling of isocyanides, aldehydes and amines.

A facile and efficient synthetic protocol for the synthesis of α-amino amidines has been developed using a molecular iodine-catalyzed three-component coupling reaction of isocyanides, amines, and aldehydes. The presented strategy offers the advantages of mild reaction conditions, low environmental impact, clean and simple methodology, high atom economy, wide substrate scope and high yields.

Rapid access to novel 1,2,3-triazolo-heterocyclic scaffolds via tandem Knoevenagel condensation/azide-alkyne 1,3-dipolar cycloaddition reaction in one pot.

An operationally simple, one-pot, two-step cascade method has been developed to afford biologically important fused 1,2,3-triazolo-heterocyclic scaffolds from 2-alkynyl aryl(heteroaryl) aldehydes and phenacyl azides. This unique atom economical transformation engages four reactive centers (aldehyde, alkyne, active methylene, and azide) under metal-free catalysis.

Dietary fish oil as hepatoprotective agent in Mus musculus.

The administration of galactosamine in omega-3 polyunsatu-rated fatty acid (PUFA) supplemented mice resulted in lesser amount of damage in the liver tissue compared to the mice without prior supplementation of fish oil. Only 50% elevation in the plasma total bilirubin was detected in omega-3 supplemented mice injected with galactosamine over those supplemented with omega-3 without galactosomine injection. The results suggest that very long chain omega-3 PUFA like eicosapentaenoic and docosahexaenoic acid may act as preventive agent for hepatic cirrhosis in Mus musculus.

Controlled in vivo release of nicorandil from a carvone-based transdermal therapeutic system in human volunteers.

The aim of our present study was to prepare and evaluate a carvone-based transdermal therapeutic system (TTS) of nicorandil to find its ability in providing the desired in vivo controlled release profile on dermal application to human volunteers. The effect of EVA 2825, and adhesive-coated EVA 2825, and adhesive-coated EVA 2825-rat skin composite on the in vitro permeation of nicorandil from a carvone-based HPMC gel drug reservoir was studied against a control (rat abdominal skin alone). The carvone-based drug reservoir system was sandwiched between adhesive-coated EVA 2825-release liner composite and a backing membrane. The resultant drug reservoir sandwich was heat-sealed to produce a circle-shaped TTS (20 cm(2)) that was subjected to in vivo evaluation on dermal application to human volunteers against oral administration of immediate-release tablets of nicorandil. The carvone-based TTS provided a steady-state plasma concentration of 20.5 ng/ml for approximately 24 hr in human volunteers. We concluded that the carvone-based TTS of nicorandil provided the desired in vivo controlled-release profile of the drug for the predetermined period of time.

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers.

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.

Bioavailability of nerodilol-based transdermal therapeutic system of nicorandil in human volunteers.

The objective of the present investigation was to design and evaluate a nerodilol-based transdermal therapeutic system (TTS) for finding its ability in providing the desired steady-state plasma concentration of nicorandil in human volunteers. The influence of EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825-rat skin composite on the in vitro permeation of nicorandil from a nerodilol-based HPMC gel drug reservoir was studied against a control (excised rat skin alone). The flux of nicorandil from the nerodilol-based HMPC drug reservoir across excised rat skin (control) was 384.0+/-4.6 microg/cm2 h and this decreased to 222.7+/-7.1 microg/cm2 h when studied across EVA2825 membrane indicating that EVA2825 membrane was effective as rate controlling membrane. The flux of the drug decreased to 183.8+/-5.7 microg/cm2 h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat to EVA2825 membrane. However, the flux of nicorandil across adhesive-coated EVA2825-membrane-rat-skin composite was 164.8+/-1.8 microg/cm2 h, which was 1.74-times of the required flux that prompted for preparation of TTS. The nerodilol-based drug reservoir system was sandwiched between a composite of adhesive-coated EVA2825 membrane-release liner and a backing membrane. The resultant sandwich was heat-sealed to produce circle-shaped TTS (20 cm2) that were subjected to bioavailability study in human volunteers against immediate release nicorandil tablet. The nerodilol-based TTS provided a steady-state plasma concentration of 25.5 ng/ml for 24 h in human volunteers. It was concluded that the nerodilol-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations.

Impacted knife injury of the orbit, maxilla and oropharynx.

Injuries in the maxillofacial region with knife in situ are not common. We report a rare case with knife impacted in the orbit, maxilla and soft palate. Removal was possible only by surgical intervention. Despite the deep penetration, the knife had not injured major structures and hence there was no untoward complication in the outcome.

Formulation of an HPMC gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing in vitro transdermal delivery of nicorandil.

The objective of the present study was to formulate a hydroxypropyl methylcellulose (HPMC) gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing the transdermal delivery of nicorandil so as to develop and fabricate a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation of nicorandil was determined across rat abdominal skin from a solvent system consisting of ethanol or various proportions of ethanol and water. The ethanol-water (70:30 v/v) solvent system that provided an optimal transdermal permeation was used in formulating an HPMC gel drug reservoir system with selected concentrations (0% w/w, 4% w/w, 6% w/w, 8% w/w or 10% w/w) of limonene as a penetration enhancer for further enhancement of transdermal permeation of nicorandil. The amount of nicorandil permeated in 24 h was found increased with an increase in the concentration of limonene in the drug reservoir system up to a concentration of 6% w/w, but beyond this concentration there was no further increase in the amount of drug permeated. The flux of nicorandil was 370.9 +/- 4.2 microg/cm2 x h from the drug reservoir system with 6% w/w of limonene, which is about 2.6 times the required flux to be obtained across rat abdominal skin for producing the desired plasma concentration for the predetermined period in humans. The results of a Fourier Transform Infrared study indicated that limonene enhanced the percutaneous permeation of nicorandil by partially extracting the stratum corneum lipids. It is concluded that the HPMC gel drug reservoir system prepared with a 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene is useful in designing and fabricating a membrane-moderated TTS of nicorandil.

In vivo formation and repair of cyclobutane pyrimidine dimers and 6-4 photoproducts measured at the gene and nucleotide level in Escherichia coli.

In vivo formation and repair of the major UV-induced DNA photoproducts, cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone photoproducts (6-4 PPs), have been examined at the gene and nucleotide level in Escherichia coli. Each type of DNA photoproduct has individually been studied using photoreactivation and two newly developed assays; the multiplex QPCR assay for damage detection at the gene level and the reiterative primer extension (PE) assay for damage detection at the nucleotide level. In the E. coli lacI and lacZ genes, CPDs and 6-4 PPs form in a 2:1 ratio, respectively, during UV irradiation. Repair of 6-4 PPs is more efficient than repair of CPDs since, on the average, 42% of 6-4 PPs are repaired in both genes in the first 40 min following 200 J/m(2) UV irradiation, while 1% of CPDs are repaired. The location, relative frequency of formation, and efficiency of repair of each type of photoproduct was examined in the first 52 codons of the E. coli lacI gene at the nucleotide level. Hotspots of formation were found for each type of lesion. Most photoproducts are at sites where both CPDs and 6-4 PPs are formed. Allowing 40 min of recovery following 200 J/m(2) shows that in vivo repair of 6-4 PPs is about fourfold more efficient than the repair of CPDs. Comparison of the lesion-specific photoproduct distribution of the lacI gene with a UV-induced mutation spectrum from wild-type cells shows that most mutational hotspots are correlated with sites of a majority of CPD formation. However, 6-4 PPs are also formed at some of these sites with relatively high frequency. This information, taken together with the observation that 6-4 PPs are repaired faster than CPDs, suggest that the cause of mutagenic hotspots in wild-type E. coli is inefficient repair of CPDs.

High resolution mapping of UV-induced photoproducts in the Escherichia coli lacI gene. Inefficient repair of the non-transcribed strand correlates with high mutation frequency.

UV-induced DNA photoproduct formation and repair has been examined at the gene and nucleotide level in Escherichia coli using two newly developed quantitative assays. A multiplex quantitative PCR assay was used to measure photoproduct formation and repair at the gene level in both the constitutive lacI gene and the inducible lacZ gene, simultaneously. Both genes displayed similar photoproduct formation frequencies (0.4 lesions/kb per 100 J/m2). Following a 15 minute recovery period, 36% and 39% of the damage resulting from 100 J/m2 was removed from the lacI and lacZ genes, respectively. Under the growth conditions applied, the lacZ gene was expressed at a very low rate resulting in 0.3% of beta-galactosidase activity as compared to induced cells. A newly developed reiterative primer extension assay has been employed to examine photoproduct formation and repair at the nucleotide level. Analysis of UV-induced DNA photoproducts in the first 184 base-pairs of the lacI gene of genomic E. coli DNA has revealed that photoproducts are induced linearly with dose and the slope is sequence context-dependent. A post-irradiation recovery period revealed differences in the repair efficiency at individual nucleotides. Repair of photoproducts on the transcribed strand was generally twice as efficient as repair of photoproducts on the non-transcribed strand, indicating that strand-specific DNA repair occurs in the constitutively transcribed lacI gene of E. coli. Comparison of the UV-induced DNA photoproduct distribution with an established UV-induced mutation spectrum from wild-type cells revealed that photoproducts form at all mutagenic hotspots. Some sites of low frequency mutations were not observed to be sites of photoproduct formation. However, not all photoproducts appeared to be mutagenic. This was especially true for those on the efficiently repaired transcribed strand. It is hypothesized that the preferential repair of photoproducts on this strand may prevent many of these photoproduct sites from becoming mutagenic hotspots. These data strongly support the hypothesis that mutations arise at inefficiently repaired photoproducts on the nontranscribed strand.