Quality by design aided self-nano emulsifying drug delivery systems development for the oral delivery of Benidipine: Improvement of biopharmaceutical performance.

The primary objective of the research effort is to establish efficient solid self-nanoemulsifying drug delivery systems (S-SNEDDS) for benidipine (BD) through the systematic application of a quality-by-design (QbD)-based paradigm. Utilizing Labrafil M 2125 CS, Kolliphor EL, and Transcutol P, the BD-S-SNEDDS were created. The central composite design was adopted to optimize numerous components. Zeta potential, drug concentration, resistance to dilution, pH, refractive index, viscosity, thermodynamic stability, and cloud point were further investigated in the most efficient formulation, BD14, which had a globule size of 156.20 ± 2.40 nm, PDI of 0.25, zeta potential of -17.36 ± 0.18 mV, self-emulsification time of 65.21 ± 1.95 s, % transmittance of 99.80 ± 0.70%, and drug release of 92.65 ± 1.70% at 15 min. S-SNEDDS were formulated using the adsorption process and investigated via Fourier transform infrared spectroscopy, Differential scanning calorimeter, Scanning electron microscopy, and powder X-ray diffraction. Optimized S-SNEDDS batch BD14 dramatically decreased blood pressure in rats in contrast to the pure drug and the commercial product, according to a pharmacodynamics investigation. Accelerated stability tests validated the product's stability. Therefore, the development of oral S-SNEDDS of BD may be advantageous for raising BD's water solubility and expanding their releasing capabilities, thereby boosting oral absorption.

Withanolides from Withania somnifera as an immunity booster and their therapeutic options against COVID-19.

Traditionally, Withania somnifera is widely used as an immune booster, anti-viral, and for multiple medicinal purposes. The present study investigated the withanolides as an immune booster and anti-viral agents against the coronavirus-19. Withanolides from Withania somnifera were retrieved from the open-source database, their targets were predicted using DIGEP-Pred, and the protein-protein interaction was evaluated. The drug-likeness score and intestinal absorptivity of each compound were also predicted. The network of compounds, proteins, and modulated pathways was constructed using Cytoscape, and docking was performed using autodock4.0, and selected protein-ligand complexes were subjected to 100 ns Molecular Dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Withanolide_Q was predicted to modulate the highest number of proteins, showed human intestinal absorption, and was predicted for the highest drug-likeness score. Similarly, combined network interaction identified Withanolide_Q to target the highest number of proteins; RAC1 was majorly targeted, and fluid shear stress and atherosclerosis associated pathway were chiefly regulated. Similarly, Withanolide_D and Withanolide_G were predicted to have a better binding affinity with PLpro, Withanolide_M with 3CLpro, and Withanolide_M with spike protein based on binding energy and number of hydrogen bond interactions. MD studies suggested Withanoside_I with the highest binding free energy (ΔGbind-31.56 kcal/mol) as the most promising inhibitor. Among multiple withanolides from W. somnifera, Withanolide_D, Withanolide_G, Withanolide_M, and Withanolide_Q were predicted as the lead hits based on drug-likeness score, modulated proteins, and docking score to boost the immune system and inhibit the COVID-19 infection, which could primarily act against COVID-19. HighlightsWithanolides are immunity boosters.Withanolides are a group of bio-actives with potential anti-viral properties.Withanolide_G, Withanolide_I, and Withanolide_M from Withania somnifera showed the highest binding affinity with PLpro, 3CLpro, and spike protein, respectively.Withanolides from Withania somnifera holds promising anti-viral efficacy against COVID-19.Communicated by Vsevolod Makeev.

Network pharmacology of AYUSH recommended immune-boosting medicinal plants against COVID-19.

The Ministry of AYUSH recommended the use of a decoction of the mixture of Ocimum tenuiflorum, Cinnamomum verum, Piper nigrum, Zingiber officinale, and Vitis vinifera as a preventive measure by boosting the immunity against the severity of infection caused by a novel coronavirus (COVID-19). The present study aimed to identify the probable modulated pathways by the combined action of AYUSH recommended herbal tea and golden milk formulation as an immune booster against COVID-19. Reported phytoconstituents of all the medicinal plants were retrieved from the ChEBI database, and their targets were predicted using DIGEP-Pred. STRING database and Cytoscape were used to predict the protein-protein interaction and construct the network, respectively. Likewise, MolSoft and admet SAR2.0 were used to predict the druglikeness score and ADMET profile of phytoconstituents. The study identified the modulation of HIF-1, p53, PI3K-Akt, MAPK, cAMP, Ras, Wnt, NF-kappa B, IL-17, TNF, and cGMP-PKG signaling pathways to boost the immune system. Further, multiple pathways were also identified which are involved in the regulation of pathogenesis of the multiple infections and non-infectious diseases due to the lower immune system. Results indicated that the recommended herbal formulation not only modulated the pathways involved in boosting the immunity but also modulated the multiple pathways that are contributing to the progression of multiple disease pathogenesis which would add the beneficial effect in the co-morbid patients of hypertension and diabetes. The study provides the scientific documentation of the role of the Ayurvedic formulation to combat COVID-19.

Gene ontology enrichment analysis of PPAR-γ modulators from Cassia glauca in diabetes mellitus.

BACKGROUND: PPAR-γ has an integrative role in the management of insulin resistance; ligands of this receptor have emerged as potent insulin sensitizers and may modulate proteins involved in the pathogenesis of diabetes mellitus. Hence the present study is aimed to identify PPAR-γ modulators from the plant Cassia glauca and predict the ontology enrichment analysis utilizing various in-silico tools. METHODS: ChEBI database was used to mine the phytoconstituents present in the plant C. glauca, SwissTargetPrediction database was used to identify the targets, and scrutinizing of phytoconstituents modulating PPAR-γ was performed. Autodock4.0 was used to dock phytoconstituent ligands with the target PPAR-γ. Multiple open-source databases and in-silico tools were utilized to predict the drug-likeness characters and predict side effects of the phytoconstituents modulating PPAR-γ and STRING database was used to construct a network between the modulated genes. RESULTS: Twenty-four phytoconstituents were identified from the plant Cassia glauca from which four were found to modulate PPAR-γ, sennoside was predicted to have the greatest drug-likeness score and a significantly less side effect whereas diphenyl sulfone was predicted to show hepatotoxicity with the greatest pharmacological activity of 0.815. [epicatechin-(4beta- > 8)]5-epicatechin showed the lowest binding affinity with target PPAR-γ i.e. -8.6 kcal/mol and possessing a positive drug-likeness score with no side effect data. CONCLUSION: Bioctives were found free from probable side effects leaving out diphenyl sulfone having a prediction of hepatotoxicity, the anti-diabetic property of the plant may be due to the presence of [epicatechin-(4beta- > 8)]5-epicatechin which needs further validation by in-vitro and in-vivo protocols.

Screening of JAK-STAT modulators from the antiviral plants of Indian traditional system of medicine with the potential to inhibit 2019 novel coronavirus using network pharmacology.

The majority of the bioactives under investigation were predicted to target TNF receptor-associated factor 5 in the Janus kinase/signal transducers and activators of the transcription pathway. Similarly, druglikeness prediction identified vitexilactone to possess the highest druglikeness score, i.e., 0.88. Furthermore, proteins targeted in the Janus kinase/signal transducers and activators of transcription pathway were also predicted to regulate multiple pathways, i.e., ErbB, AGE-RAGE, NF-kappa B, Measles, insulin, mTOR, chemokine, Ras, and pathways associated with infectious and non-infectious pathogenesis, where the immune system is compromised. Similarly, the docking study identified sesaminol 2-O-ß-D-gentiobioside to possess the highest binding affinity with 3CLpro, PLpro, and spike proteins. Furthermore, phylogeny comparison identified the common protein domains with other stains of microbes like murine hepatitis virus strain A59, avian infectious bronchitis virus, and porcine epidemic diarrhea virus CV777.

In silico analysis of phytoconstituents from Tinospora cordifolia with targets related to diabetes and obesity.

Traditionally, Tinospora cordifolia is commonly used in the treatment of diabetes and obesity; has been evaluated for their anti-diabetic and anti-obese potency in experimental animal models. However, the binding affinity of multiple bioactives with various proteins involved in the pathogenesis of diabetes and obesity has not been reported yet. Hence, the present study aimed to assess the binding affinity of multiple bioactives from T. cordifolia with various targets involved in the pathogenesis of diabetes and obesity. The ligands and targets were retrieved from the PubChem and Protein Data Bank respectively and docked using autodock4.0. Druglikeness and absorption, distribution, metabolism, excretion, and toxicity profile were predicted using Molsoft and admetSAR1 respectively. The multiple bioactives from T. cordifolia were identified to interact with multiple proteins involved in the pathogenesis of diabetes/obesity, i.e., isocolumbin (- 9 kcal/mol) with adiponectin (PDB: 4DOU), ß-sitosterol (- 10.9 kcal/mol) with cholesteryl ester transfer protein (PDB: 2OBD), tinocordiside (- 6.9 kcal/mol) with lamin A/C (PDB: 3GEF), berberine (- 9.5 kcal/mol) with JNK1 (PDB:3ELJ), ß-sitosterol & isocolumbin (- 10.1 kcal/mol) with peroxisome proliferator-activated receptor-γ (PDB:4CI5), berberine (- 7.5 kcal/mol) with suppressor of cytokine signaling 3 (PDB: 2BBU), isocolumbin (- 9.6 kcal/mol) with pancreatic α-amylase (PDB: 1B2Y), isocolumbin (- 9 kcal/mol) with α-glucosidase (PDB: 3TOP), and ß-sitosterol (- 10.8 kcal/mol) with aldose reductase (PDB: 3RX2). Similarly, among the selected bioactives, tembetarine scored highest druglikeness score, i.e., 1.21. In contrast, isocolumbin scored lowest drug-likeness character i.e. - 0.52. The predicted result of phytochemicals from T. cordifolia for acute oral toxicity, rat acute toxicity, fish toxicity, drug-likeness score, and aqueous solubility showed the probability of lower side/adverse effects in human consumption. The study suggests processing for bioactives from T. cordifolia against diabetes and obesity via in-vitro and in-vivo approaches.

Gene set enrichment analysis of α-amylase and α-glucosidase inhibitors of Cassia glauca.

BACKGROUND: The present study aimed to evaluate in vitro α-amylase and α-glucosidase inhibitory activity of various extracts of Cassia glauca, predict the binding affinity of multiple phytoconstituents with both enzymes via in silico molecular docking and identify the probably modulated pathways by the lead hit. METHODS: Different extracts of Cassia glauca i.e. acetone, ethanol, and aqueous extracts were evaluated for α-amylase and α-glucosidase inhibitory activity using in vitro method in which starch and 4-Nitrophenyl ß-D-glucopyranoside were used as substrate respectively. Similarly, the docking study was performed using autodock4 to predict the binding affinity of phytoconstituents with α-amylase and α-glucosidase. After docking, ten different poses were obtained for the ligand molecule. Among them, the pose of ligand molecule with the lowest binding energy was visualized in Discovery Studio 2019. RESULTS AND CONCLUSION: Among the multiple extracts, the aqueous extract showed the highest α-amylase (IC50:652.10 ± 20.09) and α-glucosidase (IC50:482.46 ± 8.70) inhibitory activity. Similarly, cassiaoccidentalin B was predicted to have the highest binding affinity with both enzymes. The potency of aqueous extract to inhibit α-amylase and α-glucosidase could be due to multiple water-soluble compounds like saponins, flavonoids, and glycosides.

Prevalence of self-medication with antibiotics and associated factors in the community of Asmara, Eritrea: a descriptive cross sectional survey.

BACKGROUND: Development of drug resistance caused by self-medication with antibiotics, can be seen as one of the growing global threats. Self-medication is defined as the selection and use of medicines by individuals to treat self-recognized illnesses or symptoms. The purpose of this study is to assess the practice of self-medication with antibiotics and associated factors among the community of Asmara, Eritrea. METHODS: This was a community based descriptive cross-sectional study conducted in 16 selected sub-districts of Asmara from September to November 2017. A Two-stage cluster sampling was employed to select study sites and participants. Data was collected in a face to face interview with a structured questionnaire and entered to CSPro version 6.2. Descriptive statistics, cross-tabulation and logistic regression were executed using SPSS version 22. RESULTS: A total of 580 study participants were recruited with a response rate of 99.5% (N = 577). The prevalence of Self-medication with antibiotics (SMA) in this study was found to be 45.1% [95% CI (40.5, 49.6)] and majority of them practiced once or twice in a period of 12 months. The main reasons for SMA were previous successful experience (34.4%) and the illness being 'not serious enough to seek medical care' (25.7%). Of those who self-medicated, 84.1% of used amoxicillin at least once. Wound infection (17.9%) and sore throat (13.9%) were the most self-recognized complaints that required self-medication. Antibiotics were supplied and recommended mostly by the community drug outlets. Only Sex (p = 0.046), knowledge (p = 0.019) and attitude (p < 0.001) of the participants were found significantly associated with the practice of SMA in the multivariate logistic regression. CONCLUSIONS: Though majority of the respondents considered self-medication with antibiotics as inappropriate practice, about half of them were practicing it anyway. Therefore immediate attention from relevant bodies is required.

Safety of lacosamide in children with refractory partial epilepsy.

OBJECTIVES: The study was carried out to investigate the safety of lacosamide on children with refractory partial epilepsy. MATERIALS & METHODS: The study was carried out at a tertiary care hospital after obtaining approval from the institutional ethics committee. Patients aged between 5 and 15 years taking oral lacosamide (LCM) tablets that were given orally as an adjunctive anti-epileptic drug were enrolled for assessing safety, tolerability and its effect on the behavioural life at every visit of titration, during the treatment period (3 months) and at 2 follow up visits that were done at monthly intervals. Adverse events reported by caregiver or by investigator were recorded. Patients/caregivers also completed a 25 items on Connor's behavioural rating clinical scale at every visit. RESULTS: Out of 531 screened patients, 79 patients with refractory partial epilepsy were enrolled after they fulfilled the inclusion and exclusion criteria. Mean age of the children was 8.84 ± 3.09 years (5-15 years), of which 53 were males and 26 females. The mean age at onset of seizures in males was 6.46 ± 3.57 and in females, 6.38 ± 3.39 years. Seventy-six children of 79, completed 3 months of treatment period showed significant (p < 0.001) decrease in the frequency of seizures, significant improvement in behaviour and showed good tolerability. Three (3.79%) patients dropped out of the study due to hyperactive behaviour, vomiting and lack of seizure control respectively. CONCLUSIONS: Lacosamide is a well-tolerated newer antiepileptic drug that is effective in refractory partial epilepsy paediatric patients and concurrently improved patient's behaviour.

Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy.

BACKGROUND: A unicentre, prospective study was performed to investigate the efficacy of lacosamide as adjunctive therapy in children with refractory partial epilepsy. METHODS: The study was performed at a tertiary care hospital over a period of 30 months between November 2011 and May 2014. Seventy-nine children with refractory partial epilepsy (age 5-15 years) who had failed two or more antiepileptic drugs and in whom lacosamide was used as an add-on drug were enrolled. Lacosamide tablets were administered orally, at a dose of 25 mg for 1 week followed by 50 mg twice daily for the remaining period. Efficacy and tolerability evaluation was performed at every visit of titration, maintenance period (3 months), and two follow-up visits at monthly interval. Electrocardiogram and liver function tests were performed before enrollment and at the end of 3 months of lacosamide therapy. Patient's caregiver or investigator observed adverse events were recorded in a predesigned pro forma. RESULTS: A total of 79 patients with uncontrolled partial epilepsy screened from 531 epileptic children were enrolled, after they satisfied the inclusion and exclusion criteria. The mean age of children enrolled was 8.8 ± 3.1 years (range 5-15 years); 53 children (67.0%) were boys. Mean weight of the patients was 24.2 ± 9.8 kg. The mean age at the onset of seizures was 6.4 ± 3.5 years. The mean dose of lacosamide administered was 4.1 mg/kg. Three patients (3.8%) dropped out of the study, because of vomiting, aggressive behavior, and poor response, respectively. Of 76 patients (96.2%) entering the maintenance period, 35 patients (44.3%) were seizure free, 32 patients (40.6%) indicated ≥50% reduction in seizure frequency, 3 patients (3.8%) indicated 25-49% seizure reduction, and 9 patients (11.4%) either had no change in seizure frequency or experience increase in seizure frequency. CONCLUSION: Lacosamide is an effective add-on antiepileptic drug for children with refractory partial epilepsy and is well tolerated.