Exploration of oxadiazole clubbed benzhydrylpiperazine pharmacophoric features as structural feature for antidepressant activity: In vitro, in vivo and in silico analysis.

Arylpiperazine clubbed various heterocyclic molecules present potential pharmacophoric structural features for the development of psychoactive drugs. There are various CNS active molecules possessing arylpiperazine moiety in their pharmacophore approved by USFDA. In the current study, we have explored the benzhydrylpiperazine moiety clubbed with various substituted oxadiazole moieties (AP1-12) for their monoamine oxidase (MAO) inhibition and antidepressant potential. Compounds AP3 and AP12 exhibited highly potent and selective MAO-A inhibition with IC50 values of 1.34 ± 0.93 µM and 1.13 ± 0.54 µM, respectively, and a selectivity index of 10- and 13-folds, respectively. Both the compounds displayed reversible binding character at the active site of MAO-A. In further in vivo evaluation, both the compounds AP3 and AP12 displayed potential antidepressant-like character in FST and TST studies via significantly reduced immobility time in comparison to non-treated animals. These compounds displayed no cytotoxicity in SH-SY5Y cell lines, which indicates that these compounds are safe for further evaluation. In silico studies reveal that synthesized compounds possess drug-likeness with minimal to no toxicity. In silico studies were conducted to understand the binding interactions and stability of compounds at the binding pocket of enzyme and observed that both the best compounds fit well at the active site of MAO-A lined by amino acid residues Tyr69, Asn181, Phe208, Ile335, Leu337, Phe352, and Tyr444 similar to standard MAO-A inhibitor clorgiline. The molecular dynamic studies demonstrated that AP3 and AP12 formed quite a stable complex at the active site of MAO-A and did not break under small abruption forces. The favourable binding interactions and appropriate ADMET properties present the benzhydrylpiperazine clubbed oxadiazole pharmacophoric features as a potential structural skeleton for further clinical evaluation and development of a new antidepressant drug molecule.

Insights into Translational and Biomedical Applications of Hydrogels as Versatile Drug Delivery Systems.

Hydrogels are a network of crosslinked polymers which can hold a huge amount of water in their matrix. These might be soft, flexible, and porous resembling living tissues. The incorporation of different biocompatible materials and nanostructures into the hydrogels has led to emergence of multifunctional hydrogels with advanced properties. There are broad applications of hydrogels such as tissue culture, drug delivery, tissue engineering, implantation, water purification, and dressings. Besides these, it can be utilized in the field of medical surgery, in biosensors, targeted drug delivery, and drug release. Similarly, hyaluronic acid hydrogels have vast applications in biomedicines such as cell delivery, drug delivery, molecule delivery, micropatterning in cellular biology for tissue engineering, diagnosis and screening of diseases, tissue repair and stem cell microencapsulation in case of inflammation, angiogenesis, and other biological developmental processes. The properties like swellability, de-swellability, biodegradability, biocompatibility, and inert nature of the hydrogels in contact with body fluids, blood, and tissues make its tremendous application in the field of modern biomedicines nowadays. Various modifications in hydrogel formulations have widened their therapeutic applicability. These include 3D printing, conjugation, thiolation, multiple anchoring, and reduction. Various hydrogel formulations are also capable of dual drug delivery, dental surgery, medicinal implants, bone diseases, and gene and stem cells delivery. The presented review summarizes the unique properties of hydrogels along with their methods of preparation and significant biomedical applications as well as different types of commercial products available in the market and the regulatory guidance.

Correlation Between Optical Coherence Tomography Angiography Findings at 3 to 6 Weeks and Functional Outcome at 3 Months Following Acute Ischaemic Stroke Due to Extracranial Carotid Artery Atherosclerotic Disease.

We wanted to evaluate if optical coherence tomography angiography OCTA findings could predict the functional outcome in extracranial carotid artery atherosclerotic disease (ECAD) associated stroke. This exploratory study was performed on adults with acute ischaemic stroke due to ECAD at 3-6 weeks following stroke onset with risk factor matched controls without carotid artery stenosis. Twenty-three stroke patients (cases) and 23 controls were enrolled. There was significant difference between cases and controls in deep vessel density at the macula (p = .0007) and in radial peripapillary capillary perfusion density (RPCPD) at the optic nerve head (ONH) (p = .0007). Statistically significant difference was noted in the total superficial vessel density (SVD) at the macula (SVD within 1 standard deviation [SD] versus SVD beyond 1 SD of control data) in the ipsilateral eye and functional outcome at 3 months (poor versus very good outcome, modified Rankin scale [mRS] 0-1 versus mRS 2-6, respectively; p = .0361). There was statistically insignificant correlation between the RPCPD at the ONH and the National Institutes of Health Stroke Scale score at admission, mRS at discharge, and mRS at 3 months following stroke onset (r = .33, r = .35, r = .39; p = .11, p = .09, p = .06, respectively). The findings of this exploratory study suggested that OCTA findings may predict 3 month outcomes in cases of ECAD-related stroke and could be useful in decision making in future intervention studies as to whether intervene or not in patients having critical or non-critical ECAD for preventing stroke.

Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders.

The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent transporters belonging to family of dicarboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized.

Compendium of naringenin: potential sources, analytical aspects, chemistry, nutraceutical potentials and pharmacological profile.

Naringenin is flavorless, water insoluble active principle belonging to flavanone subclass. It exhibits a diverse pharmacological profile as well as divine nutraceutical values. Although several researchers have explored this phytoconstituent to evaluate its promising properties, still it has not gained recognition at therapeutic levels and more clinical investigations are still required. Also the neutraceutical potential has limited marketed formulations. This compilation includes the description of reported therapeutic potentials of naringenin in variety of pathological conditions alongwith the underlying mechanisms. Details of various analytical investigations carried on this molecule have been provided along with brief description of chemistry and structural activity relationship. In the end, various patents filed and clinical trial data has been provided. Naringenin has revealed promising pharmacological activities including cardiovascular diseases, neuroprotection, anti-diabetic, anticancer, antimicrobial, antiviral, antioxidant, anti-inflammatory and anti-platelet activity. It has been marketed in the form of nanoformulations, co-crystals, solid dispersions, tablets, capsules and inclusion complexes. It is also available in various herbal formulations as nutraceutical supplement. There are some pharmacokinetic issue with naringenin like poor absorption and low dissolution rate. Although these issues have been sorted out upto certain extent still further research to investigate the bioavailability of naringenin from herbal supplements and its clinical efficacy is essential.

A comprehensive compiled review is presented on source, health benefits, chemistry and analysis, and marketed products of naringenin.Naringenin is a promising phytoconstituent as nutraceutical.Valorization of fruit peels of citrus fruits is a critical step for food and nutraceutical industry.Structure-activity relationship of naringenin derivatives.Nano-formulations incorporating naringenin in themselves can be used for targeted delivery for critical disorders.Naringenin obtained from the peels can be efficiently used in breads, cookies, cakes and other food products.

Design, synthesis and biological evaluation of oxadiazole clubbed piperazine derivatives as potential antidepressant agents.

Piperazine derivatives have been of great interest to medicinal chemists in the development of antidepressant drugs due to their distinct molecular and structural features along with their pharmacological profile. In this study, we have designed and synthesized a series of 10 compounds of piperazine clubbed oxadiazole derivatives (5a-j) and screened for their MAO inhibitory activity. Compound 5f and 5 g were found to be the most potent MAO-A inhibitors of the series with IC50 values of 0.96 ± 0.04 µM µM and 0.81 ± 0.03 µM, respectively with a selectivity index of 18-folds and 9-folds over MAO-B isoform. The compounds were found to be reversible inhibitors of MAO-A with no cytotoxicity against SH-SY5Y neuronal cells. The compounds also displayed good antioxidant activity. Further, in vivo TST studies revealed that both the compounds 5f and 5 g possessed good anti-depressant-like activity and reduced the immobility time significantly although were found inactive in FST studies. The molecular docking studies revealed that both compounds fit well at the active site of MAO-A enzyme as similar to clorgyline and form a stable complex. The results were confirmed via molecular dynamic studies which demonstrate the stable complex formation between MAO-A and 5f & 5 g. The appropriate drug-like characteristics with favourable ADMET profile, these molecules presented this piperazine clubbed oxadiazole structural framework as a key pharmacophore for the development of new antidepressant molecules along with strong candidature for further clinical investigations.

Clinical and radiological spectrum of anti-myelin oligodendrocyte glycoprotein (MOG) antibody encephalitis: single-center observational study.

OBJECTIVE: The objective was to describe the clinical presentations, radiologic features, and outcomes of patients with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibody (MOG). BACKGROUND: During the past decade, the spectrum of the myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD) has expanded. Recently, patients with MOG antibody encephalitis (MOG-E) who do not fulfill the criteria for ADEM have been reported. In this study, we aimed to describe the spectrum of MOG-E. METHODS: Sixty-four patients with MOGAD were screened for encephalitis-like presentation. We collected the clinical, radiological, laboratory, and outcome data of the patients who presented with encephalitis and compared it with the non-encephalitis group. RESULTS: We identified sixteen patients (nine males and seven females) with MOG-E. The median age of the encephalitis population was significantly lower than the non-encephalitis group (14.5 years (11.75-18) vs. 28 years (19.75-42), p = 0.0004). Twelve out of sixteen patients (75%) had fever at the time of encephalitis. Headache and seizure were present in 9/16 (56.2%) and 7/16 (43.75%) patients, respectively. FLAIR cortical hyperintensity was present in 10/16 (62.5%) patients. Supratentorial deep gray nuclei were involved in 10/16 (62.5%) patients. Three patients had tumefactive demyelination, and one patient had a leukodystrophy-like lesion. Twelve of 16 (75%) patients had a good clinical outcome. Patient with leukodystrophy pattern and other with generalized CNS atrophy showed a chronic progressive course. CONCLUSION: MOG-E can have heterogeneous radiological presentations. FLAIR cortical hyperintensity, tumefactive demyelination, and leukodystrophy-like presentations are novel radiological presentations associated with MOGAD. Though majority of MOG-E have a good clinical outcome, few patients can have chronic progressive disease even on immunosuppressive therapy.

A Compiled Update on Nutrition, Phytochemicals, Processing Effects, Analytical Testing and Health Effects of Chenopodium album: A Non-Conventional Edible Plant (NCEP).

Bathua (Chenopodium album) is a rich source of extensive-ranging nutrients, including bio-active carbohydrates, flavonoids and phenolics, minerals, and vitamins that translate to countless health benefits such as anticancer, antidiabetic, anti-inflammatory, antimicrobial, and antioxidant activity. Ascaridole, an important phytoconstituent present in aerial parts of the plant, contributes to its anthelmintic property. Even with vast historical use and significant health benefits, its renown has not spread, and utilization has significantly decreased in recent decades. Gradually, the plant has become known under the name of Non-conventional edible plant (NCEP). This compilation is prepared to bring out the plant under the spotlight for further research by foregrounding previous studies on the plant. Scientific research databases, including PubMed, Google Scholar, Scopus, SpringerLink, ScienceDirect, and Wiley Online, were used to fetch data on C. album. This review offers over up-to-date knowledge on nutritious values, phytochemical composition, volatile compounds, as well as health benefits of C. album. The ethnobotanical and ethnomedicinal uses of the plant in India and other parts of the world are deliberately discussed. Scrutinizing the reported literature on C. album reveals its powerful nutrient composition advantageous in the development of food products. The impact of various cooking and processing methods on the nutritional profile and bioavailability are discussed. The future perspectives with regards to the potential for food and nutraceutical products are critically addressed. This review proves the necessity of breakthrough research to investigate the pharmacology and safety of phytochemicals and nutraceutical development studies on the C. album.

Spectrum of Movement Disorders of Late-Onset Niemann-Pick Disease Type C.

Niemann-Pick disease type C (NPC), is a rare lysosomal storage disorder, which has a variable presentation based on the age of onset. We describe five adult/adolescent-onset NPC cases presenting with a range of movement disorders along with vertical supranuclear gaze palsy as part of the clinical presentation. A diagnostic delay of 4-17 years from the symptom onset was found in this case series. A high index of clinical suspicion in adult/adolescent patients presenting with vertical supranuclear gaze palsy along with various movement disorder phenomenology can help in the early diagnosis of NPC.

Liquid extraction surface analysis-mass spectrometry: An advanced and environment-friendly analytical tool in modern analysis.

The liquid extraction surface analysis technique is a new high-throughput instrument for ambient mass spectrometry. The benefits of the liquid extraction surface analysis-mass spectrometry approach are the high throughput screening of samples and the absence of sample preparation. liquid extraction surface analysis-mass spectrometry also consumes less solvent for extraction, making it more environmentally friendly and there is no substrate restriction. It utilizes advanced instrumentation like the use of robotic pipettes, nanoelectrospray systems, electronspray ionization chips which makes it highly efficient. In recent years, liquid extraction surface analysis-mass spectrometry has seen widespread use in a variety of analytical fields including drug metabolite analysis, mapping drug distribution in tissues, protein and lipid characterization, etc. In this review, we have summarized the basic working principles of the liquid extraction surface analysis-mass spectrometry approach in detail along with a detailed description of the recently reported applications in the analysis of proteins, lipids, drugs and foods. The investigated analytes along with detection methodologies and significant outcomes of various research reports have been presented with the help of tables. This tool has also been utilized in clinical investigations of biological fluids, fingerprint analysis and authentication of agarwood.

INSTRuCT: Protocol, Infrastructure, and Governance.

Background and Purpose: Very few large scale multicentric stroke clinical trials have been done in India. The Indian Council of Medical Research funded INSTRuCT (Indian Stroke Clinical Trial Network) as a task force project with the objectives to establish a state-of-the-art stroke clinical trial network and to conduct pharmacological and nonpharmacological stroke clinical trials relevant to the nation and globally. The purpose of the article is to enumerate the structure of multicentric stroke network, with emphasis on its scope, challenges and expectations in India. Methods: Multiple expert group meetings were conducted by Indian Council of Medical Research to understand the scope of network to perform stroke clinical trials in the country. Established stroke centers with annual volume of 200 patients with stroke with prior experience of conducting clinical trials were included. Central coordinating center, standard operating procedures, data and safety monitoring board were formed. Discussion: In first phase, 2 trials were initiated namely, SPRINT (Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in India) and Ayurveda treatment in the rehabilitation of patients with ischemic stroke in India (RESTORE [Rehabilitation of Ischemic stroke Patients in India: A Randomized controlled trial]). In second phase, 4 trials have been approved. SPRINT trial was the first to be initiated. SPRINT trial randomized first patient on April 28, 2018; recruited 3048 patients with an average of 128.5 per month so far. The first follow-up was completed on May 27, 2019. RESTORE trial randomized first patient on May 22, 2019; recruited 49 patients with an average of 3.7 per month so far. The first follow-up was completed on August 30, 2019. Conclusions: In next 5 years, INSTRuCT will be able to complete high-quality large scale stroke trials which are relevant globally. REGISTRATION: URL: http://www.ctri.nic.in/; Unique Identifier: CTRI/2017/05/008507.

Neuronavigation based 10 sessions of repetitive transcranial magnetic stimulation therapy in chronic migraine: an exploratory study.

INTRODUCTION: Chronic migraine is a disease of altered cortical excitability. Repetitive transcranial magnetic stimulation provides a novel non-invasive method to target the nociceptive circuits in the cortex. Motor cortex is one such potential target. In this study, we targeted the left motor cortex using fMRI-guided neuronavigation. MATERIALS AND METHODS: Twenty right-handed patients were randomized into real and sham rTMS group. Baseline subjective pain assessments were done using visual analog scale (VAS) and questionnaires: State-Trait Anxiety Inventory, Becks Depression Inventory, and Migraine Disability Assessment (MIDAS) questionnaire. Objectively, pain was assessed by means of thermal pain thresholds using quantitative sensory testing. For corticomotor excitability parameters, resting motor thresholds and motor-evoked potentials were mapped. For rTMS total, 600 pulses in 10 trains at 10 Hz with an intertrain interval of 60 s were delivered in each session. Ten such sessions were given 5 days per week over 2 consecutive weeks. The duration of each session was 10 min. Real rTMS was administered at 70% of Resting MT. All the tests were repeated post-intervention and after 1 month of follow-up. There are no studies reporting the use of fMRI-based TMS for targeting the motor cortex in CM patients. RESULTS: We observed a significant reduction in the mean VAS rating, headache frequency, and MIDAS questionnaire in real rTMS group which was maintained after 1 month of follow-up. CONCLUSION: Ten sessions of fMRI-based rTMS over the left motor cortex may provide long-term pain relief in CM, but further studies are warranted to confirm our preliminary findings.

Educating Caregivers to Reduce Complications and Improve Outcomes of Stroke Patients (ECCOS) - A Cluster-Randomized Trial.

OBJECTIVES: Stroke constitutes a significant public health problem in developing countries. Caregivers provide an important support system for patient care but usually lack knowledge and skill to attend their stroke patients. We assessed whether a caregiver-directed educational intervention would reduce hospital-acquired complications and improve stroke patients' outcomes. MATERIALS AND METHODS: We randomly assigned two Neurology inpatient wards to receive either standard care or an educational intervention. The coprimary outcomes included incidence of hospital-acquired complications and in-hospital mortality. Secondary outcomes included the modified Rankin Scale and mortality at three months. RESULTS: Among 164 patients recruited, 82 received intervention, and standard care each. The mean (Standard deviation) Glasgow coma scale of patients was 11.01 (3.4), and National Institute of Health Stroke Scale was 19.17 (8.54). The incidence of complications (72 in the intervention versus 81 in the control group; p=0.56) was not different. Ten patients (12.2%) in the intervention group and 16 (19.5%) in the control group (p=0.20) died in-hospital. Twenty patients (27.8%) in the intervention and twelve (18.2%) in the control group attained modified Rankin Scale 0-2 at three months (p=0.12). The mortality at three months (20 [24.4%] in the intervention versus 25 [30.5%] in the control group) was not different (p=0.38). The intervention group had fewer complications (42 versus 68 in the control group; p=0.01) during the initial ten days of hospital stay, but adjusted analysis revealed no difference. CONCLUSION: A structured educational intervention did not reduce the incidence of hospital-acquired complications, mortality, or morbidity. However, there was a trend towards fewer complications in the initial days of hospital stay. Extended hospital stay, caregiver fatigue, and dilution of the intervention over time might be reasons for the apparent lack of effect. CLINICAL TRIAL REGISTRATION-URL: http://www.ctri.nic.in. Unique identifier: CTRI/2018/11/016312.

Calculation of Prognostic Scores, Using Delayed Imaging, Outperforms Baseline Assessments in Acute Intracerebral Hemorrhage.

Background and Purpose- Patients with intracerebral hemorrhage (ICH) are often subject to rapid deterioration due to hematoma expansion. Current prognostic scores are largely based on the assessment of baseline radiographic characteristics and do not account for subsequent changes. We propose that calculation of prognostic scores using delayed imaging will have better predictive values for long-term mortality compared with baseline assessments. Methods- We analyzed prospectively collected data from the multicenter PREDICT study (Prediction of Hematoma Growth and Outcome in Patients With Intracerebral Hemorrhage Using the CT-Angiography Spot Sign). We calculated the ICH Score, Functional Outcome in Patients With Primary Intracerebral Hemorrhage (FUNC) Score, and modified ICH Score using imaging data at initial presentation and at 24 hours. The primary outcome was mortality at 90 days. We generated receiver operating characteristic curves for all 3 scores, both at baseline and at 24 hours, and assessed predictive accuracy for 90-day mortality with their respective area under the curve. Competing curves were assessed with nonparametric methods. Results- The analysis included 280 patients, with a 90-day mortality rate of 25.4%. All 3 prognostic scores calculated using 24-hour imaging were more predictive of mortality as compared with baseline: the area under the curve was 0.82 at 24 hours (95% CI, 0.76-0.87) compared with 0.78 at baseline (95% CI, 0.72-0.84) for ICH Score, 0.84 at 24 hours (95% CI, 0.79-0.89) compared with 0.76 at baseline (95% CI, 0.70-0.83) for FUNC, and 0.82 at 24 hours (95% CI, 0.76-0.88) compared with 0.74 at baseline (95% CI, 0.67-0.81) for modified ICH Score. Conclusions- Calculation of the ICH Score, FUNC Score, and modified ICH Score using 24-hour imaging demonstrated better prognostic value in predicting 90-day mortality compared with those calculated at presentation.

Redefining Hematoma Expansion With the Inclusion of Intraventricular Hemorrhage Growth.

Background and Purpose- Definitions of significant hematoma expansion traditionally focus on changes in intraparenchymal volume. The presence of intraventricular hemorrhage (IVH) is a predictor of poor outcome, but current definitions of hematoma expansion do not include IVH expansion. We evaluated whether including IVH expansion to current definitions of hematoma expansion improves the ability to predict 90-day outcome. Methods- Using data from the PREDICT-ICH study (Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT), we compared a standard definition of hematoma expansion (≥6 mL or ≥33%) to revised definitions that includes new IVH development or expansion (≥6 mL or ≥33% or any IVH; ≥6 mL or ≥33% or IVH expansion ≥1 mL). The primary outcome was poor clinical outcome (modified Rankin Scale score, 4-6) at 90 days. Diagnostic accuracy measures were calculated for each definition, and C statistics for each definition were compared using nonparametric methods. Results- Of the 256 patients eligible for primary analysis, 127 (49.6%) had a modified Rankin Scale score of 4 to 6. Sensitivity and specificity for the standard definition (n=80) were 45.7% (95% CI, 36.8-54.7) and 82.9% (95% CI, 75.3-88.9), respectively. The revised definition, ≥6 mL or ≥33% or any IVH (n=113), possessed a sensitivity of 63.8% (95% CI, 54.8-72.1) and specificity of 75.2% (95% CI, 66.8-82.4). Overall accuracy was significantly improved with the revised definition (P=0.013) and after adjusting for relevant covariates, was associated with a 2.55-fold increased odds (95% CI, 1.31-4.94) of poor outcome at 90 days. A second revised definition, ≥6 mL or ≥33% or IVH expansion ≥1 mL, performed similarly (sensitivity, 56.7% [95% CI, 47.6-65.5]; specificity, 78.3% [95% CI, 40.2-85.1]; aOR, 2.40 [95% CI, 1.23-4.69]). Conclusions- In patients with mild-to-moderate ICH, including IVH expansion to the definition of hematoma expansion improves sensitivity with only minimal decreases to specificity and improves overall prediction of 90-day outcome.

Synthetic and therapeutic perspectives of nitrogen containing heterocycles as anti-convulsants.

Epilepsy is one of the commonly prevailing neurological disorders. According to the reports, it is evident that about 80% of the epileptic cases have been observed in developing countries. Although there are many drugs with significant potency available in the market; still there is an issue of selectivity and toxicity. Therefore, continuous attempts have been made by the researchers to develop newer therapeutic agents against epilepsy. Many synthetic strategies have been available in the literature to synthesize various classes of anticonvulsants with promising activity. In the presented review, authors have summarized some newer synthetic routes being used for the synthesis of nitrogen-containing anticonvulsants taking a cue from the reported established anticonvulsant drugs viz. vigabatrin, sodium valproate, oxcarbazepine, felbamate, retigabine, and gabapentin. Various derivatives with the substitution for better anticonvulsant profile have been described in the figures for easy comparative study. The structure-activity relationship (SAR) of compounds with maximum potency has also been discussed. This article may serve as a boost for the researchers to modify the pre-existing synthetic routes as well as to improve potency and yield of the compounds.

Design, synthesis and neuropharmacological evaluation of new 2,4-disubstituted-1,5-benzodiazepines as CNS active agents.

Benzodiazepines (BZDs) represent a class of privilege scaffold in the modern era of medicinal chemistry as CNS active agents and BZD based drugs are used to treat different psychotic disorders. Inspired from the therapeutic potential of BZDs as promising CNS active agents, in the present work three different series of 1,5-benzodiazepines bearing various substitutions at position 2 and 4 of the benzodiazepine core were synthesized by condensing different substituted chalcones with o-phenylenediamine in the presence of piperidine as a base catalyst. Structural characterization of title compounds was done by using various analytical techniques such as IR, NMR, elemental analysis and mass spectral data. All the synthesized compounds (9a-d, 10a-e and 11a-c) were subjected to in vivo neuropharmacological studies to evaluate their CNS depressant and antiepileptic activity. Results of in vivo evaluation data showed that analogue 11b exhibited potent CNS depressant activity which was comparable to the standard drug diazepam. Compounds 10b and 10c displayed significant antiepileptic activity however they were less potent than the standard drug phenobarbitone. Molecular docking studies were performed using MOE software to find the interaction pattern and binding mode at the GABAA receptor (PDB Id: 6HUP). The results of the docking studies were in good agreement with the observed in vivo activity and revealed the satisfactory binding mode of the compounds within the binding site of the protein. The docking scores for the most promising candidates 10c, 11b and Diazepam were found to be -9.18, -9.46 and -9.88, respectively. Further, the compounds showed compliance with the Lipinski's 'rule of five' and exhibited favourable drug-likeness scores. The identified leads can be explored further for the design and development of new BZD based psychotropic agents.

Impact of Continuous Education and Training in Reduction of Central Line-associated Bloodstream Infection in Neurointensive Care Unit.

BACKGROUND: Patients in the neurointensive care unit have high utilization of devices, thereby increased chance of getting device-associated infection (DAI). Central line-associated bloodstream infection (CLABSI) remains one of the most important DAI. Education remains an important part of the hospital infection control and improves the infection-control practices. MATERIALS AND METHODS: To evaluate the effectiveness of a quality initiative in reducing incidence of CLABSI, a prospective study (January 2017-December 2018) was done estimating CLABSI incidence before and after the intervention. Continuous teaching and training for hand hygiene practice and central-line catheter hub care were used as the tool for this study. RESULTS: The quality improvement (QI) initiative achieved a 48% reduction in the CLABSI rate from the baseline rate of 8.7 to 4.5 per 1000 catheter days. The overall mortality showed a reduction from 1.5 to 0.05% during the post-intervention period. There was a significant improvement in compliance with the hand hygiene practice and catheter hub care in the post-intervention period. DISCUSSION AND CONCLUSION: This study demonstrates adherence to hand hygiene and catheter hub care with continuous teaching, training, and supervision was highly effective in reducing the CLABSI rate. CLINICAL SIGNIFICANCE: Central line-associated bloodstream infection is one of the most important DAI causing significant morbidity and mortality in critically ill patient. Our findings support that continuous educational intervention of hand hygiene with and training on the catheter hub care are two most important preventive measures in the reduction of CLABSI incidence. HOW TO CITE THIS ARTICLE: Mohapatra S, Kapil A, Suri A, Pandia MP, Bhatia R, Borkar S, et al. Impact of Continuous Education and Training in Reduction of Central Line-associated Bloodstream Infection in Neurointensive Care Unit. Indian J Crit Care Med 2020;24(6):414-417.

Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients.

Rare missense variants play a crucial role in amyotrophic lateral sclerosis (ALS) pathophysiology. We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of ALS pathophysiology in our cohort, we investigated the frequency of tolerated and benign novel/rare variants, which could be potentially ALS susceptible. These variants were identified in 5.36% (8/149) of sporadic ALS (sALS) cases; with one novel variant each in ERBB4, SETX, DCTN1, and MATR3; four rare variants, one each in PON2 and ANG and two different rare variants in SETX. Identified variants were either absent or present at extremely rare frequencies (MAF < 0.01) in large population databases and were absent in 50 healthy controls sequenced through Sanger method. Furthermore, an oligogenic basis of ALS was observed in three sALS, with co-occurrence of intermediate-length repeat expansions in ATXN2 and a rare/novel variant in DCTN1 and SETX genes. Additionally, molecular dynamics and biochemical functional analysis of an angiogenin variant (R21G) identified from our cohort demonstrated loss of ribonucleolytic and nuclear translocation activities. Our findings suggest that rare variants could be potentially pathogenic and functional studies are warranted to decisively establish the pathogenic mechanisms associated with them.

Synthesis, biological evaluation and molecular docking studies of novel 3,5-disubstituted 2,4-thiazolidinediones derivatives.

A series of thirteen novel 2,4-thiazolidinedione derivatives were synthesized through three step reaction procedure. The title compounds were synthesized by Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione ring. Various physicochemical and spectral studies were conducted to characterize the synthesized derivatives including- IR, Mass, 1H NMR, 13C NMR and elemental analysis. The derivatives were screened for in vivo anti diabetic, in vivo anti-inflammatory and in vitro free radical scavenging activities by carrageenan induced rat paw edema method, alloxan induced diabetes in wistar rats method and FRAP (ferric reducing antioxidant power) method respectively. Some of the derivatives emerged out as potent antidiabetic, anti inflammatory and free radical scavenging agents. Molecular docking was carried out to investigate some possible structural insights into the potential binding patterns of the most potent anti-diabetic molecules NB7,NB12 and NB13 with the active sites of target PPARγ (PDB ID: 2PRG) using MOE software. Dichloro derivative compound NB-7 has shown great potential in the present study as it not only has maximum antidiabetic activity but also possess excellent anti-inflammatory and antioxidant potential.