Synthesis, computational docking and molecular dynamics studies of a new class of spiroquinoxalinopyrrolidine embedded chromanone hybrids as potent anti-cholinesterase agents.

Novel structurally intriguing heterocycles embedded with spiropyrrolidine, quinoxaline and chromanone units were synthesized in good yields using a [Bmim]Br accelerated multicomponent reaction strategy. The key step of the reaction is 1,3-dipolar cycloaddition involving highly functionalized dipolarophile, viz. 3-benzylidenechroman-4-one, to afford spiroquinoxalinopyrrolidine embedded chromanone hybrid heterocycles. The formation of spiro products occurs via two C-C, two N-C and one C-N bonds possessing four adjoining stereogenic centers, two of which are spiro carbons. The newly synthesized spiro compounds showed potent acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, compounds with fluorine displayed the highest AChE (3.20 ± 0.16 µM) and BChE (18.14 ± 0.06 µM) inhibitory activities. Further, docking studies, followed by all-atom molecular dynamics, showed results that are consistent with in vitro experimental findings. Although docking scores for the synthesized derivatives were higher than those of the standard drug, MD MMPBSA results showed better binding of synthesized derivatives (-93.5 ± 11.9 kcal mol-1) compared to the standard drug galantamine (-66.2 ± 12.3 kcal mol-1) for AChE but exhibited similar values (-98.1 ± 11.2 and -97.9 ± 11.5 kcal mol-1) for BChE. These differences observed in drug binding with AChE/BChE are consistent with RMSD, RMSF, LIG plots, and FEL structural analysis. Taken together, these derivatives could be potential candidates as inhibitors of AChE and BChE.

Nanotechnology-mediated delivery of resveratrol as promising strategy to improve therapeutic efficacy in triple negative breast cancer (TNBC): progress and promises.

INTRODUCTION: Triple-negative breast cancer (TNBC) presents unique challenges in diagnosis and treatment. Resveratrol exhibits potential as a therapeutic intervention against TNBC by regulating various pathways such as the PI3K/AKT, RAS/RAF/ERK, PKCδ, and AMPK, leading to apoptosis through ROS-mediated CHOP activationand the expression of DR4 and DR5. However, the clinical efficacy of resveratrol is limited due to its poor biopharmaceutical characteristics and low bioavailability at the tumor site. Nanotechnology offers a promising approach to improving the biopharmaceutical characteristics of resveratrol to achieve clinical efficacy in different cancers. The small dimension (<200 nm) of nanotechnology-mediated drug delivery system is helpful to improve the bioavailability, internalization into the TNBC cell, ligand-specific targeted delivery of loaded resveratrol to tumor site including reversal of MDR (multi-drug resistance) condition. AREAS COVERED: This manuscript provides a comprehensive discussion on the structure-activity relationship (SAR), underlying anticancer mechanism, evidence of anticancer activity in in-vitro/in-vivo investigations, and the significance of nanotechnology-mediated delivery of resveratrol in TNBC. EXPERT OPINION: Advanced nano-formulations of resveratrol such as oxidized mesoporous carbon nanoparticles, macrophage-derived vesicular system, functionalized gold nanoparticles, etc. have increased the accumulation of loaded therapeutics at the tumor-site, and avoid off-target drug release. In conclusion, nano-resveratrol as a strategy may provide improved tumor-specific image-guided treatment options for TNBC utilizing theranostic approach.

Ion-activated In Situ Gel of Gellan Gum Containing Chrysin for Nasal Administration in Parkinson's Disease.

INTRODUCTION: This study focused on creating an innovative treatment approach for Parkinson's disease (PD), a progressive neurodegenerative condition characterized by the loss of specific neurons in the brain. AIM: The research aimed to develop a nasal gel using gellan gum containing a complex of chrysin with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) to enhance the drug's solubility and stability. METHOD: The formulation process involved utilizing central composite design (CCD) to optimize the concentrations of gellan gum and HPMC E5, with viscosity and mucoadhesive strength as key factors. The resulting optimized in situ gel comprised 0.7% w/v gellan gum and 0.6% w/v HPMC E5, exhibiting desirable viscosity levels for both sol and gel states, along with robust mucoadhesive properties. The formulated gel underwent comprehensive evaluation, including assessments for gelation, drug content, in vitro drug release, ex vivo permeation, and histopathology. RESULT: The findings demonstrated superior drug release from the in situ gel compared to standalone chrysin. Ex vivo studies revealed effective drug permeation through nasal mucosa without causing harm. Moreover, experiments on neuronal cells exposed to oxidative stress (H2O2- induced) showcased significant neuroprotection conferred by chrysin and its formulations. These treatments exhibited notable enhancements in cell viability and reduced instances of apoptosis and necrosis, compared to the control group. The formulations exhibited neuroprotective properties by mitigating oxidative damage through mechanisms, like free radical scavenging and restoration of antioxidant enzyme activity. CONCLUSION: In conclusion, this developed in situ gel formulation presents a promising novel nasal delivery system for PD therapy. By addressing challenges related to drug properties and administration route, it holds the potential to enhance treatment outcomes and improve the quality of life for individuals with Parkinson's disease.

Tacrolimus loaded nanostructured lipid carriers using Moringa oleifera seed oil: design, optimization and in-vitro evaluations.

The proposed research aims to develop Tacrolimus-loaded nanostructured lipid carriers (TAC-loaded NLCs) to overcome poor aqueous solubility and dissolution rate to enhance its oral absorption. A central composite design was used to optimise the amount of Poloxamer 188 and D-α-Tocopherol-polyethylene-glycol-succinate (TPGS). The optimised TAC-loaded NLCs contain stearic acid (250 mg), Moringa oleifera (MO) seed oil (50 mg), TAC (Tacrolimus: 10 mg), TPGS (60 mg), and Poloxamer 188 (1% w/v) with a mean diameter of 393.3 ± 29.68 nm, a zeta potential of -18.3 ± 6.19 mV, high entrapment efficiency (92.12 ± 1.14% w/w), and desirability (0.989). TAC-loaded NLCs showed ∼12 times higher drug dissolution efficiency, while in-vitro anti-inflammatory studies showed ∼1.8 times lower IC50 (half-maximal inhibitory concentration) than TAC suspension. The lyophilised TAC-loaded NLCs were found to be stable after 3 months. Thus, the present study concludes the successful encapsulation of TAC in NLCs made of stearic acid and MO seed oil.

3D Printing Technology as a Promising Tool to Design Nanomedicine-Based Solid Dosage Forms: Contemporary Research and Future Scope.

3D printing technology in medicine is gaining great attention from researchers since the FDA approved the first 3D-printed tablet (Spritam®) on the market. This technique permits the fabrication of various types of dosage forms with different geometries and designs. Its feasibility in the design of different types of pharmaceutical dosage forms is very promising for making quick prototypes because it is flexible and does not require expensive equipment or molds. However, the development of multi-functional drug delivery systems, specifically as solid dosage forms loaded with nanopharmaceuticals, has received attention in recent years, although it is challenging for formulators to convert them into a successful solid dosage form. The combination of nanotechnology with the 3D printing technique in the field of medicine has provided a platform to overcome the challenges associated with the fabrication of nanomedicine-based solid dosage forms. Therefore, the major focus of the present manuscript is to review the recent research developments that involved the formulation design of nanomedicine-based solid dosage forms utilizing 3D printing technology. Utilization of 3D printing techniques in the field of nanopharmaceuticals achieved the successful transformation of liquid polymeric nanocapsules and liquid self-nanoemulsifying drug delivery systems (SNEDDS) to solid dosage forms such as tablets and suppositories easily with customized doses as per the needs of the individual patient (personalized medicine). Furthermore, the present review also highlights the utility of extrusion-based 3D printing techniques (Pressure-Assisted Microsyringe-PAM; Fused Deposition Modeling-FDM) to produce tablets and suppositories containing polymeric nanocapsule systems and SNEDDS for oral and rectal administration. The manuscript critically analyzes contemporary research related to the impact of various process parameters on the performance of 3D-printed solid dosage forms.

Recent Progress in Chitosan-Based Nanomedicine for Its Ocular Application in Glaucoma.

Glaucoma is a degenerative, chronic ocular disease that causes irreversible vision loss. The major symptom of glaucoma is high intraocular pressure, which happens when the flow of aqueous humor between the front and back of the eye is blocked. Glaucoma therapy is challenging because of the low bioavailability of drugs from conventional ocular drug delivery systems such as eye drops, ointments, and gels. The low bioavailability of antiglaucoma agents could be due to the precorneal and corneal barriers as well as the low biopharmaceutical attributes of the drugs. These limitations can be overcome by employing nanoparticulate drug delivery systems. Over the last decade, there has been a lot of interest in chitosan-based nanoparticulate systems to overcome the limitations (such as poor residence time, low corneal permeability, etc.) associated with conventional ocular pharmaceutical products. Therefore, the main aim of the present manuscript is to review the recent research work involving the chitosan-based nanoparticulate system to treat glaucoma. It discusses the significance of the chitosan-based nanoparticulate system, which provides mucoadhesion to improve the residence time of drugs and their ocular bioavailability. Furthermore, different types of chitosan-based nanoparticulate systems are also discussed, namely nanoparticles of chitosan core only, nanoparticles coated with chitosan, and hybrid nanoparticles of chitosan. The manuscript also provides a critical analysis of contemporary research related to the impact of this chitosan-based nanomedicine on the corneal permeability, ocular bioavailability, and therapeutic performance of loaded antiglaucoma agents.

AngioVac system guided removal of vegetations from pacemaker lead-related infective endocarditis.

The AngioVac aspiration system is a catheter-based technique that has been used for removal of unwanted intravascular material in growing numbers of institutions around the world since 2013. It provides an alternative and a less invasive approach for the treatment of venous thromboembolism and intrinsic or cardiac implantable electronic devices (CIED)-related infective endocarditis. This system uses venous cannulas and extracorporeal filtering mechanisms to effectively remove thrombi or vegetations resulting in less invasion and minimal blood loss. We present a case of a woman in her mid-50s who underwent successful AngioVac-guided removal of lead vegetations followed by percutaneous CIED removal.

A Comprehensive Review on Recent Advances and Considerations for the Selection of Cell-based In-vitro Techniques for the Assessment of Permeability of Drug Molecules.

OBJECTIVE: The main focus of this article is to analyze numerous in-vitro methods and their modifications currently used to assess the absorption or permeability of drug molecules from different formulations. METHODS: In the literature, no single method can be applied as a gold standard for measuring the exact permeability of each drug molecule. Various in-vitro methods, including tissue and cell-based models, are reported to assess the absorption of drugs. Caco2 cell is a widely used model for absorption studies but sometimes provides inaccurate results. Alternative methods like Madin-Darby canine kidney, IEC- 18, TC-7, 2/4/A1, and IPEC-J2 cell lines are also used. In this study, the merits and demerits of each method have been described, along with the factors affecting the results of absorption studies. The selection of an appropriate method is critical in accurately assessing the permeability and absorption of drugs by mechanisms like vesicular and active transport. This review article aims to provide in-depth knowledge regarding the different in-vitro methods, strategies, and selection of appropriate in-vitro models to predict intestinal absorption. CONCLUSION: A flow chart diagram for decision-making in selecting an appropriate in-vitro permeability model for formulation has been proposed for estimating permeability.

The Research Trends and Scientometric Assessment of Rheumatoid Arthritis in India During 2016-2021.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the synovial joints, causing swelling and joint damage. RA has become a major public health concern, harming more than 1500 people per lakh of the world's population. This inflammatory disorder is more common in females in comparison to males (3:1). In the present work, a scientometric analysis of published articles on RA during the last five years [1st January 2016 to 2021] on 19/08/2021 in the Scopus database is performed and investigates the contribution of India. In this study, the top most productive countries and the contribution of India in this field were analyzed. The different journals, funding agencies, and productive authors from India who contributed to this field are also recognized. The average citation impact is 10 citations per paper. A total of 61% share was found for the International collaboration in India's publication on rheumatoid arthritis. In India's output on rheumatoid arthritis, medicine produced the largest percentage of paper (60 percent). The top 15 journals publishing the maximum number of Indian papers contribute 1% share of global rheumatoid arthritis research (The highest number of papers (95 papers) published by the Indian Journal of Rheumatology). During the period 2016-2021, the top 10 highly cited papers got a total of 7045 citations, averaging 705 citations per publication. India was found to have a 5% (1974 publications) share of global output (42312 publications). In conclusion, there is a small number of researches on rheumatoid arthritis in a country, which holds the 2nd position in population across the world. There is a need for more research on rheumatoid arthritis in India.

Blockchain Powered Vaccine Efficacy for Pharma Sector.

Infectious and contagious diseases exist in humanity for many centuries which causes a curb in the growth of the population. Immunization plays a vital role to prevent mortality and morbidity against infectious diseases. COVID-19 pandemic continues to rage the urgency of developing a vaccine that should ensure the safety, efficacy, swift and fair deployment, implementation, and monitoring of vaccines across the globe. In the present context, the vaccine production to immunization campaign is a critical challenge. Therefore, an effective vaccine supply chain mechanism is required to address issues such as counterfeit vaccines, reduce vaccine wastages, and vaccine record fraud. In this paper, a blockchain-enabled vaccine supply chain is proposed to ensure the correctness, transparency, trust, and immutable log and improve the efficiency of vaccine distribution in the cold chain. The uniqueness of the proposed system is to provide distributed system to verify the reliability and efficacy of the vaccine from production to end beneficiaries' feedback about the vaccine. Our proposed system gives a clear view to the users as well as to the healthcare provider about the vaccination and ensures the anticounterfeit vaccine. The proposed system minimizes counterfeit vaccines and records, provides transparent communication between stakeholders in the supply chain, and improves the security of the vaccine supply chain and immutable feedback system about the vaccine.

Recent Updates on Applications of Lipid-Based Nanoparticles for Site- Specific Drug Delivery.

BACKGROUND: Site-specific drug delivery is a widespread and demanding area nowadays. Lipid-based nanoparticulate drug delivery systems have shown promising effects for targeting drugs among lymphatic systems, brain tissues, lungs, and skin. Recently, lipid nanoparticles have been used for targeting the brain via the mucosal route for local therapeutic effects. Lipid nanoparticles (LNPs) can help in enhancing the efficacy and lowering the toxicities of anticancer drugs to treat the tumors, particularly in lymph after metastases of tumors. LNPs contain a nonpolar core that can improve the absorption of lipophilic drugs into the lymph node and treat tumors. Cellular uptake of drugs can also be enhanced using LNPs and therefore, LNPs are the ideal carrier for treating intracellular infections, such as leishmaniasis, tuberculosis and parasitic infection in the brain, etc. Furthermore, specific surface modifications with molecules like mannose, or PEG could improve the macrophage uptake and hence effectively eradicate parasites hiding in macrophages. METHODS: An electronic literature search was conducted to update the advancements in the field of site-specific drug delivery utilizing lipid-based nanoparticles. A search of the Scopus database (https://www.scopus.com/home.uri) was conducted using the following keywords: lipid-based nanoparticles; site-specific delivery. CONCLUSION: Solid lipid nanoparticles have shown site-specific targeted delivery to various organs including the liver, oral mucosa, brain, epidermis, pulmonary and lymphatic systems. These lipidbased systems showed improved bioavailability as well as reduced side effects. Therefore, the focus of this article is to review the recent research studies on LNPs for site-specific or targeting drug delivery.

Awareness about role of health literacy and self efficacy in tobacco cessation among primary health care workers: A quantitative questionnaire study.

Background: The purpose of this study was to measure primary health care providers' understanding of the significance of health literacy and self-efficacy in cigarette quitting. Material and Methods: The current study used a quantitative descriptive questionnaire to collect data. The research was carried out among primary health care providers in a rural location near the Azamgarh Dental College in Uttar Pradesh. Medical officials, nursing personnel, and dental practitioners, if existent, are examples of primary health professionals. Azamgarh district is divided into 22 blocks. 22 primary health facilities were selected from these 22 blocks. 54 medical officers and 98 other primary health workers (ANMs, GNMs, and Asha workers) were questioned at these primary health facilities. Results: The majority of study participants {132 (86.84%)} were aware of the bad effects of tobacco consumption. Most of the study participants don't know about health literacy {115 (75.65%)} and self-efficacy {78 (51.32%)}. The majority of them did not know the questionnaire to test health literacy {114 (75.02%)} and self-efficacy {150 (98.68%)}. poor mean awareness score (20.77 ± 3.33) was significant (p = 0.001) in the age group 25-35 years. Anganwadi workers were having significantly (p = 0.002) highest poor awareness score (22.67 ± 2.34). Conclusion: From the above results, it was concluded that awareness of the role of health literacy and self-efficacy in tobacco cessation among primary health workers was poor. Almost all study participants had not attended any training programs on tobacco cessation.

A Comprehensive Review on Chrysin: Emphasis on Molecular Targets, Pharmacological Actions and Bio-pharmaceutical Aspects.

Chrysin (a flavonoid) has shown various promising pharmacological activities viz. anticancer, anti-diabetic, immune-modulation, antidepressant, and anti-asthmatic. Additionally, it exhibited potential protective effects against various toxins on different organs like the liver, brain, kidney, and heart. A multitude of studies have been conducted to explore the possible targets for its possible mechanism of action. However, its therapeutic applications have been limited due to its poor oral bioavailability. The major reason for its poor bioavailability is its extensive first-pass metabolism. A critical review of the pharmacological properties of chrysin and its associated molecular targets has not been discussed as yet comprehensively. Therefore, the emphasis of the present work is to provide an in-depth understanding of molecular targets accountable for the pharmacological actions of chrysin. Moreover, a schematic diagram was made for the first time to represent the comprehensive pharmacokinetic properties of chrysin, which helps to understand the biopharmaceutical aspect for its successful delivery. An in-depth understanding of the biopharmaceutical properties of chrysin will help in adopting a suitable formulation approach to overcome poor oral bioavailability. Additionally, it facilitates to study the possible pharmacokinetic interactions of chrysin with other drugs. Hence, we found that chrysin is a miraculous natural agent with myriad therapeutic properties, and its benefit can be exploited with an in-depth understanding of molecular targets, pharmacological actions, and biopharmaceutical attributes.

Blockchain-based online education content ranking.

Nowadays, internet technology plays a vital role in all the fields of our daily lives ranging from the world economy, professional careers, higher education, and almost all the spheres that are deeply impacted. In the current situation, due to COVID19, the dependence on the Internet for almost everything, including learning, getting daily needs, etc., is heavily dependent on the Internet. Online learning is made possible by the Internet, and today most students, educators, researchers are leveraging online learning platforms to enhance their knowledge at their own pace. Generally, the quality of the E-learning courses is evaluated with the help of the courses' review and rating mechanisms. In the present context, review systems are centralized, storing highly valuable information at one location and are liable to manipulation, hacking, and tampering. In this paper, the Blockchain-based Online Education Content Ranking system is proposed for an online review and ranking system that offers a decentralized trustworthy system, ensuring the integrity of the rating and the independence and integrity of content reviews by Subject Matter Experts (SME).

Performance and outcomes of transvenous rotational lead extraction: Results from a prospective, monitored, international clinical study.

BACKGROUND: Transvenous lead extraction (TLE) plays a critical role in managing patients with cardiovascular implantable electronic devices. Mechanical TLE tools, including rotational sheaths, are used to overcome fibrosis and calcification surrounding leads. Prospective clinical data are limited regarding the safety and effectiveness of use of mechanical TLE devices, especially rotational tools. OBJECTIVE: To prospectively investigate the safety and effectiveness of mechanical TLE in real-world usage. METHODS: Patients were enrolled at 10 sites in the United States and Europe to evaluate the use of mechanical TLE devices. Clinical success, complete procedural success, and complications were evaluated through follow-up (median, 29 days). Patient data were source verified and complications were adjudicated by an independent clinical events committee (CEC). RESULTS: Between October 2018 and January 2020, mechanical TLE tools, including rotational sheaths, were used to extract 460 leads with a median indwell time of 7.4 years from 230 patients (mean age 64.3 ± 14.4 years). Noninfectious indications for TLE were more common than infectious indications (61.5% vs 38.5%, respectively). The extracted leads included 305 pacemaker leads (66.3%) and 155 implantable cardioverter-defibrillator leads (33.7%), including 85 leads with passive fixation (18.5%). A bidirectional rotational sheath was needed for 368 leads (88.0%). Clinical success was obtained in 98.7% of procedures; complete procedural success was achieved for 96.3% of leads. CEC-adjudicated device-related major complications occurred in 6 of 230 (2.6%) procedures. No isolated superior vena cava injury or procedural death occurred. CONCLUSION: This prospective clinical study demonstrates that use of mechanical TLE tools, especially bidirectional rotational sheaths, are effective and safe.

Advancement in design of nanostructured lipid carriers for cancer targeting and theranostic application.

BACKGROUND: Cancer development is associated with abnormal, uncontrolled cell growth and causes significant economic and social burdens to society. The global statistics of different cancers have been increasing because of the aging population, and the increasing prevalence of risk factors such as stress condition, overweight, changing reproductive patterns, and smoking. The prognosis of cancer treatment is high, if diagnosed in the early stage. Late-stage diagnosis, however, is still a big challenge for the clinician. The usual treatment scheme involves chemotherapy and surgery followed by radiotherapy. SCOPE OF REVIEW: Chemotherapy is the most widely used therapeutic approach against cancer. However, it suffers from the major limitation of poor delivery of anticancer therapeutics to specific cancer-targeted tissues/cells. MAJOR CONCLUSIONS: Nanomedicines, particularly nanostructured lipid carriers (NLCs) can improve the efficacy of encapsulated payload either through an active or passive targeting approach against different cancers. The targeted nanomedicine can be helpful in transporting drug carriers to the specifically tumor-targeted tissue/cells while sparing abstaining from the healthy tissue/cells. The active targeting utilizes the binding of a specific cancer ligand to the surface of the NLCs, which improves the therapeutic efficacy and safety of the cancer therapeutics. GENERAL SIGNIFICANCE: This review shed light on the utilization of NLCs system for targeted therapy in different cancers. Furthermore, modification of NLCs as cancer theranostics is a recent advancement that is also discussed in the manuscript with a review of contemporary research carried out in this field.

Coronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol.

Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.

Nanoparticles as Adjuvants in Vaccine Delivery.

Nanotechnology provides an excellent platform for the development of a new generation of vaccines. These are based on purified subunit proteins or polysaccharides, recombinant proteins, synthetic peptides, or nucleic acids. These types of vaccines may be insufficiently immunogenic, thus requiring adjuvants that augment their immunogenicity. Nanoparticles (NPs) can act as adjuvants for vaccines, hence they are referred to as a nano-adjuvant (NA). NPs can either encapsulate or adsorb the vaccine antigen or DNA in an appropriate formulation, thus increasing stability, cellular uptake, and immunogenicity. In addition, the biodistribution and systemic release of a vaccine can also be controlled by different NA formulations. This review provides an overview of the classification of NAs and also addresses factors influencing the stability, release, and immunogenicity of the formulated vaccine. A basic understanding of these factors enables a more rational design of NA formulations. Applications of NAs and key challenges in their formulation development are also discussed.

Pycnodysostosis with Osteomyelitis of Maxilla: Case Report of Radiological Analysis.

Pycnodysostosis is an autosomal recessive, rare genetic osteosclerotic disorder that caused by mutation in gene coding for Cathepsin K. The bones in pycnodysostosis are abnormally dense and brittle because of insufficient reabsorption process. This syndrome has a number of characteristic clinical and radiographic signs that differentiate it from other osteosclerotic conditions. This is a rare case report of a male patient with a history of multiple fractures of bones and osteomyelitis of maxilla which is a rare entity.