Novel Drug Delivery Approaches for the Localized Treatment of Cervical Cancer.

Cervical cancer (CC) is the fourth leading cancer type in females globally. Being an ailment of the birth canal, primitive treatment strategies, including surgery, radiation, or laser therapy, bring along the risk of infertility, neonate mortality, premature parturition, etc. Systemic chemotherapy led to systemic toxicity. Therefore, delivering a smaller cargo of therapeutics to the local site is more beneficial in terms of efficacy as well as safety. Due to the regeneration of cervicovaginal mucus, conventional dosage forms come with the limitations of leaking, the requirement of repeated administration, and compromised vaginal retention. Therefore, these days novel strategies are being investigated with the ability to combat the limitations of conventional formulations. Novel carriers can be engineered to manipulate bioadhesive properties and sustained release patterns can be obtained thus leading to the maintenance of actives at therapeutic level locally for a longer period. Other than the purpose of CC treatment, these delivery systems also have been designed as postoperative care where a certain dose of antitumor agent will be maintained in the cervix postsurgical removal of the tumor. Herein, the most explored localized delivery systems for the treatment of CC, namely, nanofibers, nanoparticles, in situ gel, liposome, and hydrogel, have been discussed in detail. These carriers have exceptional properties that have been further modified with the aid of a wide range of polymers in order to serve the required purpose of therapeutic effect, safety, and stability. Further, the safety of these delivery systems toward vital organs has also been discussed.

Chemometric profiling and anti-arthritic activity of aerial parts of Glinus oppositifolius (L.) Aug. DC.

ETHNOPHARMACOLOGICAL RELEVANCE: Glinus oppositifolius (L.) Aug. DC. belongs to the family Molluginaceae, an annual prostrate herb traditionally used to treat inflammations, arthritis, malarial, wounds, fevers, diarrhoea, cancer, stomach discomfort, jaundice, and intestinal parasites. However, the anti-arthritic activity of the aerial part has still not been reported. AIM OF THE STUDY: To investigate the antioxidant and anti-arthritic activity of G. oppositifolius in Complete Freund's Adjuvant (CFA) induced rats. MATERIALS AND METHODS: The dried aerial parts of this plant material were defatted with n-hexane and extracted by methanol using a soxhlet apparatus. The in vitro anti-arthritic activity of methanolic extract of G. oppositifolius (MEGO) was evaluated in protein denaturation, membrane stabilization, and inhibition of proteinase assay at 25, 50, 100, 200, and 400 µg/ml concentrations. Female Wistar rats were immunized sub-dermally into the right hind paw with 0.1 ml of CFA. Rats were administered with MEGO at doses of 200 and 400 mg/kg once daily for fourteen days after arthritis induction. Assessment of arthritis was performed by measuring paw diameter, arthritic index, arthritic score, body weight, organ weight, and hematological and biochemical parameters, followed by the analysis of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin-1-beta (IL-1ß), cyclooxygenase-2 (COX-2), interleukin 13 (IL-13) and interleukin 10 (IL-10) and histopathological study. In vivo antioxidant effect was investigated in enzymatic assays. The presence of phytoconstituents was analyzed by Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS), respectively. In silico molecular docking study of the compounds was carried out against COX-2, IL-1ß, IL-6, and TNF-α using AutoDock 4.2 and BIOVIA-Discovery Studio Visualizer software. RESULTS: MEGO's in vitro anti-arthritic activity showed dose-dependent inhibition of protein denaturation, membrane stabilization, and proteinase inhibition, followed by significant in vivo anti-arthritic activity. The rats treated with MEGO showed tremendous potential in managing arthritis-like symptoms by restoring hematological, biochemical, and histological changes in CFA-induced rats. MEGO (200 and 400 mg/kg) showed a significant alleviation in the levels of hyper expressed inflammatory mediators (TNF-α, IL-1ß, and IL-6) and oxidative stress (SOD, CAT, GSH, and LPO) in CFA-induced rats. Spergulagenin-A as identified by LC-MS analysis, exhibited the highest binding affinity against COX-2 (-8.6), IL-1ß (7.2 kcal/mol), IL-6 (-7.4 kcal/mol), and TNF-α (-6.5 kcal/mol). CONCLUSIONS: Provided with the comprehensive investigation, methanolic extract of G. oppositifolius against arthritic-like condition is a proof of concept that revalidates its ethnic claim. The presence of Spergulagenin-A might be responsible for the anti-arthritic activity.

Development of Betulin-Loaded Nanostructured Lipid Carriers for the Management of Imiquimod-Induced Psoriasis.

Psoriasis is a complex and persistent autoimmune skin disease. The present research focused on the therapeutic evaluation of betulin-loaded nanostructured lipid carriers (BE-NLCs) towards managing psoriasis. The BE-NLCs were synthesized using the emulsification cum solidification method, exhibiting a spherical shape with a particle size of 183.5±1.82nm and a narrow size distribution window (PDI: 0.142±0.05). A high zeta potential -38.64±0.05mV signifies the relative stability of the nano-dispersion system. BE-NLCs show a drug loading and entrapment efficiency of 47.35±3.25% and 87.8±7.86%, respectively. In vitro release study, BE NLCs show a cumulative percentage release of 90.667±5.507% over BE-sol (57.334±5.03%) and BD-oint (42±4.58%) for 720min. In an ex vivo 24-h permeation study, % cumulative amount permeated per cm2 was found to be 55.667±3.33% from BE-NLCs and 32.012±3.26% from BE-sol, demonstrating a better permeability of 21.66% when compared to the standard formulation BD-oint. The in vivo anti-psoriatic activity in the IMQ-induced model shows topical application of BE-sol, BE-NLCs, and BD-oint resulted in recovery rates of 56%, 82%, and 65%, respectively, based on PASI (Psoriasis Area and Severity Index) score. Notably, BE-NLCs demonstrated a more significant reduction in spleen mass, indicating attenuation of the local innate immune system in psoriatic mice. Reductions in TNF-α, IL-6, and IL-17 levels were observed in both BE-sol and BE-NLCs groups compared to the disease control (DC) group, with BE-NLCs exhibiting superior outcomes (74.05%, 44.76%, and 49.26% reduction, respectively). Soy lecithin and squalene-based NLCs could be better carrier system for the improvement of the therapeutic potential of BE towards management of psoriasis.

Spray-Dried Mucoadhesive Re-dispersible Gargle of Chlorhexidine for Improved Response Against Throat Infection: Formulation Development, In Vitro and In Vivo Evaluation.

Drug delivery to the buccal mucosa is one of the most convenient ways to treat common mouth problems. Here, we propose a spray-dried re-dispersible mucoadhesive controlled release gargle formulation to improve the efficacy of chlorhexidine. The present investigation portrays an approach to get stable and free-flowing spray-dried porous aggregates of chlorhexidine-loaded sodium alginate nanoparticles. The ionic gelation technique aided with the chlorhexidine's positive surface charge-based crosslinking, followed by spray drying of the nanoparticle's dispersion in the presence of lactose- and leucine-yielded nano-aggregates with good flow properties and with a size range of about 120-350 nm. Provided with the high entrapment efficiency (87%), the particles showed sustained drug release behaviors over a duration of 10 h, where 87% of the released drug got permeated within 12 h. The antimicrobial activity of the prepared formulation was tested on S. aureus, provided with a higher zone of growth inhibition than the marketed formulation. Aided with an appropriate mucoadhesive strength, this product exhibited extended retention of nanoparticles in the throat region, as shown by in vivo imaging results. In conclusion, the technology, provided with high drug retention and extended effect, could be a potential candidate for treating several types of throat infections.

Development and Evaluation of Dutasteride Nanoemulgel for the Topical Delivery against Androgenic Alopecia.

BACKGROUND: Dutasteride is approximately three times more potent than finasteride in treating alopecia. For reducing systemic exposure to dihydrotestosterone (DHT), researchers have shown special interest in developing topical formulations for treating androgenic alopecia. Dutasteride emulsification may lead to good skin penetration and improved availability in different lipophilic skin environments. OBJECTIVES: This study aimed to encapsulate the drug into the lipidic carrier system for better local availability in the scalp skin, develop and evaluate nanoemulgel of dutasteride to ensure efficient topical administration, and perform the in-vivo activity of the developed gel for improved efficacy against alopecia. METHODS: Dutasteride-loaded nanoemulsion was prepared by a high-speed homogenizer, followed by thickening of the dispersion using Carbopol 934. Skin permeation and accumulation were investigated in the excised skin of male Swiss albino mice. The nanoemulgel was characterized based on pH, stress stability, viscosity, and hardness. RESULTS: The optimized dutasteride-loaded nanoemulsion had a size of 252.33 ± 8.59 nm, PDI of 0.205 ± 0.60, and drug content of 98.65 ± 1.78%. Stress stability was performed was well observed in nanoemulsion formulation. Nanoemulgel evaluation results were as follows: pH 5-6 was desirable for topical application, hardness was 43 gm, and spreadability was 79 gm with in vitro release of nanoemulgel at 91.98% and permeation study at 13.67%. CONCLUSION: The in vivo studies demonstrated the growth of newer hair follicles and increased hair diameter and length in dutasteride-loaded nanoemulgel-treated alopecia animals compared to the marketed sample and testosterone-treated group. Provided with the same and long-term storage stability, the developed formulation is supposed to offer a good option for the topical administration of dutasteride in treating androgenic alopecia.

Identification of starvation-mimetic bioactive phytocomponent from Withania somnifera using in-silico molecular modelling and flow cytometry-based analysis for the management of malaria.

Multidrug resistance episodes in malaria increased from 3.9% to 20% from 2015 to 2019. Synchronizing the clinical manifestation in chronological sequence led to a unique impression on glucose demand (increased up to 100-fold) by the parasite-infected RBCs. Hence, restriction in the glucose uptake to parasite-infected RBCs could be an alternative approach to conquer the global burden of malaria to a greater extent. A C28 steroidal lactone Withaferin A (WS-3) isolated from Withania somnifera leave extract shows better thermodynamically stable interactions with the glucose transporters (GLUT-1 and PfHT) to standard drugs metformin and lopinavir. MD simulations for a trajectory period of 100 ns reflect stable interactions with the interactive amino acid residues such as Pro141, Gln161, Gln282, Gln283, Trp388, Phe389, and Phe40, Asn48, Phe85, His168, Gln169, Asn311 which potentiating inhibitory activity of WS-3 against GLUT-1 and PfHT respectively. WS-3 was non-hemotoxic (%hemolysis <5%) for a high concentration of up to 1 mg/ml in the physiological milieu. However, the %hemolysis significantly increased up to 30.55 ± 0.929% in a parasitophorous simulated environment (pH 5.0). Increased hemolysis of WS-3 could be due to the production of ROS in an acidic environment. Further, the inhibitory activity of WS-3 against both glucose transporters was supported with flow cytometry-based analysis of parasite-infected RBCs. Results show that WS-3 has low mean fluorescence intensities for both target proteins compared to conventional drugs, suggesting a potential sugar transporter inhibitor against GLUT-1 and PfHT for managing malaria. Communicated by Ramaswamy H. Sarma.

Metronidazole loaded chitosan-phytic acid polyelectrolyte complex nanoparticles as mucoadhesive vaginal delivery system for bacterial vaginosis.

Bacterial vaginosis (BV) is a recurring infection that is difficult to treat due to the limited bioavailability of antimicrobials. In this study, Metronidazole (MTZ)-loaded chitosan nanoparticles (MCSNP) were synthesized employing phytic acid (PA) as a crosslinking agent for treating bacterial vaginosis. The prepared MCSNPs were characterized for size, shape, surface charge, compatibility, cytotoxicity, biofilm inhibition, and in-vitro/in-vivo antimicrobial activities. Morphological examination revealed that nanoparticles generated from 0.535 % w/v chitosan and 0.112 % w/v PA were non-spherical, discontinuous, and irregular, with zeta potential ranging from 25.00 ± 0.45 to 39 ± 0.7. The results of DSC and XRD demonstrated no change in the physical state of the drug in the finished formulation. The optimized formulation demonstrates a cumulative drug release of about 98 ± 1.5 % within 8 h. Antimicrobial studies demonstrated that the optimized formulation had enhanced efficacy against acid-adapted BV pathogens, with a MIC value of 0.9 ± 0.1 µg/mL. Compared to the MTZ alone, the in-vivo antibacterial results of in the case of developed nanoparticles showed a four-fold reduction in bacterial count in female Swiss albino mice. Based on the experimental findings, it was concluded that MCSNPs, due to their excellent physiochemical and antibacterial properties, could serve as a potential topical alternative for treating BV.

Design and evaluation of antibacterials crosslinked chitosan nanoparticle as a novel carrier for the delivery of metronidazole to treat bacterial vaginosis.

Bacterial vaginosis (BV) is a recurring, chronic infection that is difficult to treat due to the limited bioavailability of antimicrobials within vaginal epithelial cells. Vaginal administration, because of lower dosing and systemic exposure offers a viable option for treating vaginal infections. In this study, Metronidazole-loaded chitosan nanoparticles were synthesised employing borax (BX) or tannic acid (TA) as an antimicrobial crosslinking agent for treating BV. The prepared NPs were characterized for various physical, physicochemical, pharmaceutical, thermal and antibacterial properties. Morphological investigation revealed that nanoparticles prepared from 0.5 % w/v chitosan, 1.2 % w/v BX, and 0.4 % w/v metronidazole (MTZ) were non-spherical, with particle sizes of 377.4 ± 37.3 nm and a zeta potential of 34 ± 2.1 mV. The optimised formulation has MIC values of 24 ± 0.5 and 59 ± 0.5 µg/mL, against Escherichia coli (E.coli) and Candida albicans (C.albicans) respectively. The results of DSC and XRD demonstrated no change in the physical state of the drug in the finished formulation. Under simulated vaginal fluid, the optimised formulation demonstrates a cumulative drug release of about 90 % within 6h. The prepared borax crosslinked NPs exhibit anti-fungal activities by inhibiting ergosterol synthesis. The in-vivo antibacterial data indicated a comparable reduction in bacterial count compared to the marketed formulation in female Swiss albino mice treated with optimised nanoparticles. According to histopathological findings, the prepared nanoparticle was safe for vaginal use. Based on the experimental findings, it was concluded that MBCSNPs, due to their good physiochemical and antimicrobial properties, could serve as a potential topical alternative for treating BV and reducing fungal infection.

Critical Care Ultrasound Competency of Fellows and Faculty in Pulmonary and Critical Care Medicine: A Nationwide Survey.

Purpose: Competency assessment standards for Critical Care Ultrasonography (CCUS) for Graduate Medical Education (GME) trainees in pulmonary/critical care medicine (PCCM) fellowship programs are lacking. We sought to answer the following research questions: How are PCCM fellows and teaching faculty assessed for CCUS competency? Which CCUS teaching methods are perceived as most effective by program directors (PDs) and fellows. Methods: Cross-sectional, nationwide, electronic survey of PCCM PDs and fellows in accredited GME training programs. Results: PDs and fellows both reported the highest rates of fellow competence to use CCUS for invasive procedural guidance, but lower rates for assessment of deep vein thrombosis and abdominal organs. 54% and 90% of PDs reported never assessing fellows or teaching faculty for CCUS competency, respectively. PDs and fellows perceived hands-on workshops and directly supervised CCUS exams as more effective learning methods than unsupervised CCUS archival with subsequent review and self-directed learning. Conclusions: There is substantial variation in CCUS competency assessment among PCCM fellows and teaching faculty nationwide. The majority of training programs do not formally assess fellows or teaching faculty for CCUS competence. Guidelines are needed to formulate standardized competency assessment tools for PCCM fellowship programs.

Radiation therapy margin reduction for patients with localized prostate cancer: A prospective study of the dosimetric impact and quality of life.

OBJECTIVES: To investigate the impact of reducing Clinical Target Volume (CTV) to Planning Target Volume (PTV) margins on delivered radiation therapy (RT) dose and patient reported quality-of-life (QOL) for patients with localized prostate cancer. METHODS: Twenty patients were included in a single institution IRB-approved prospective study. Nine were planned with reduced margins (4 mm at prostate/rectum interface, 5 mm elsewhere), and 11 with standard margins (6/10 mm). Cumulative delivered dose was calculated using deformable dose accumulation. Each daily CBCT dataset was deformed to the planning CT (pCT), dose was computed, and accumulated on the resampled pCT using a parameter-optimized, B-spline algorithm (Elastix, ITK/VTK). EPIC-26 patient reported QOL was prospectively collected pre-treatment, post-treatment, and at 2-, 6-, 12-, 18-, 24-, 36-, 48-, and 60-month follow-ups. Post -RT QOL scores were baseline corrected and standardized to a [0-100] scale using EPIC-26 methodology. Correlations between QOL scores and dosimetric parameters were investigated, and the overall QOL differences between the two groups (QOLMargin-reduced -QOLcontrol ) were calculated. RESULTS: The median QOL follow-up length for the 20 patients was 48 months. Difference between delivered dose and planned dose did not reach statistical significance (p > 0.1) for both targets and organs at risk between the two groups. At 4 years post-RT, standardized mean QOLMargin-reduced -QOLcontrol were improved for Urinary Incontinence, Urinary Irritative/Obstructive, Bowel, and Sexual EPIC domains by 3.5, 14.8, 10.2, and 16.1, respectively (higher values better). The control group showed larger PTV/rectum and PTV/bladder intersection volumes (7.2 ± 5.8, 18.2 ± 8.1 cc) than the margin-reduced group (2.6 ± 1.8, 12.5 ± 8.3 cc), though the dose to these intersection volumes did not reach statistical significance (p > 0.1) between the groups. PTV/rectum intersection volume showed a moderate correlation (r = -0.56, p < 0.05) to Bowel EPIC domain. CONCLUSIONS: Results of this prospective study showed that margin-reduced group exhibited clinically meaningful improvement of QOL without compromising the target dose coverage.

Simulation of New York City's Ventilator Allocation Guideline During the Spring 2020 COVID-19 Surge.

Importance: The spring 2020 surge of COVID-19 unprecedentedly strained ventilator supply in New York City, with many hospitals nearly exhausting available ventilators and subsequently seriously considering enacting crisis standards of care and implementing New York State Ventilator Allocation Guidelines (NYVAG). However, there is little evidence as to how NYVAG would perform if implemented. Objectives: To evaluate the performance and potential improvement of NYVAG during a surge of patients with respect to the length of rationing, overall mortality, and worsening health disparities. Design, Setting, and Participants: This cohort study included intubated patients in a single health system in New York City from March through July 2020. A total of 20 000 simulations were conducted of ventilator triage (10 000 following NYVAG and 10 000 following a proposed improved NYVAG) during a crisis period, defined as the point at which the prepandemic ventilator supply was 95% utilized. Exposures: The NYVAG protocol for triage ventilators. Main Outcomes and Measures: Comparison of observed survival rates with simulations of scenarios requiring NYVAG ventilator rationing. Results: The total cohort included 1671 patients; of these, 674 intubated patients (mean [SD] age, 63.7 [13.8] years; 465 male [69.9%]) were included in the crisis period, with 571 (84.7%) testing positive for COVID-19. Simulated ventilator rationing occurred for 163.9 patients over 15.0 days, 44.4% (95% CI, 38.3%-50.0%) of whom would have survived if provided a ventilator while only 34.8% (95% CI, 28.5%-40.0%) of those newly intubated patients receiving a reallocated ventilator survived. While triage categorization at the time of intubation exhibited partial prognostic differentiation, 94.8% of all ventilator rationing occurred after a time trial. Within this subset, 43.1% were intubated for 7 or more days with a favorable SOFA score that had not improved. An estimated 60.6% of these patients would have survived if sustained on a ventilator. Revising triage subcategorization, proposed improved NYVAG, would have improved this alarming ventilator allocation inefficiency (25.3% [95% CI, 22.1%-28.4%] of those selected for ventilator rationing would have survived if provided a ventilator). NYVAG ventilator rationing did not exacerbate existing health disparities. Conclusions and Relevance: In this cohort study of intubated patients experiencing simulated ventilator rationing during the apex of the New York City COVID-19 2020 surge, NYVAG diverted ventilators from patients with a higher chance of survival to those with a lower chance of survival. Future efforts should be focused on triage subcategorization, which improved this triage inefficiency, and ventilator rationing after a time trial, when most ventilator rationing occurred.

AWAreness during REsuscitation - II: A multi-center study of consciousness and awareness in cardiac arrest.

INTRODUCTION: Cognitive activity and awareness during cardiac arrest (CA) are reported but ill understood. This first of a kind study examined consciousness and its underlying electrocortical biomarkers during cardiopulmonary resuscitation (CPR). METHODS: In a prospective 25-site in-hospital study, we incorporated a) independent audiovisual testing of awareness, including explicit and implicit learning using a computer and headphones, with b) continuous real-time electroencephalography(EEG) and cerebral oxygenation(rSO2) monitoring into CPR during in-hospital CA (IHCA). Survivors underwent interviews to examine for recall of awareness and cognitive experiences. A complementary cross-sectional community CA study provided added insights regarding survivors' experiences. RESULTS: Of 567 IHCA, 53(9.3%) survived, 28 of these (52.8%) completed interviews, and 11(39.3%) reported CA memories/perceptions suggestive of consciousness. Four categories of experiences emerged: 1) emergence from coma during CPR (CPR-induced consciousness [CPRIC]) 2/28(7.1%), or 2) in the post-resuscitation period 2/28(7.1%), 3) dream-like experiences 3/28(10.7%), 4) transcendent recalled experience of death (RED) 6/28(21.4%). In the cross-sectional arm, 126 community CA survivors' experiences reinforced these categories and identified another: delusions (misattribution of medical events). Low survival limited the ability to examine for implicit learning. Nobody identified the visual image, 1/28(3.5%) identified the auditory stimulus. Despite marked cerebral ischemia (Mean rSO2 = 43%) normal EEG activity (delta, theta and alpha) consistent with consciousness emerged as long as 35-60 minutes into CPR. CONCLUSIONS: Consciousness. awareness and cognitive processes may occur during CA. The emergence of normal EEG may reflect a resumption of a network-level of cognitive activity, and a biomarker of consciousness, lucidity and RED (authentic "near-death" experiences).

Antiviral application of Carbohydrate Polymers: A review.

BACKGROUND: Viral disease is a well-known cause of a significant impact on economic losses and threatens developed and developing societies. High mutation rates and the lack of ability of conventional formulations to target specific cells pose substantial hurdles to the successful treatment of viral diseases.

Methods: We conducted a preliminary search by a standard procedure. With hand searching, we conducted an advanced search across several electronic databases. After defining the selection criteria, two writers independently reviewed and evaluated the first 500 abstracts before screening the remaining 300. Since there was 97% agreement on the screening decisions, only one reviewer conducted the screening. The pre-planned data extraction process was accomplished, and the thoroughness of the description of participation techniques was assessed. Additional data extraction was carried out for articles with the most detailed illustrations. Four stakeholder representatives co-authored this systematic review.

Results: Incorporating selective carbohydrate polymers into the antiviral pharmaceutical compositions could help to manage biological complications associated with viral infections. We included 172 papers in which authors were involved in a systematic review. The present review explains the role of carbohydrate polymers (chitosan, carrageenan, alginate, cyclodextrin, dextran, and heparin) in the prevention and treatment of viral infections in terms of their source, molecular weight, surface charge, chemical composition, and structure. Additionally, the review describes the primary mechanism of drug delivery performance of carbohydrate polymers to improve the antiviral properties and pharmacokinetic behaviour of lamivudine, zidovudine, acyclovir, etc.

Conclusion: The article discussed the role of carbohydrate polymers in mitigating virus-induced associated complications like bacterial infection, cardiovascular disorder, oxidative stress, and metabolic disorder. As a result, this work will provide valuable information to scientists, researchers, and clinicians for suitable carbohydrate polymer-based pharmaceutical development.

Opportunity in nanomedicine to counter the challenges of current drug delivery approaches used for the treatment of malaria: a review.

Malaria is a life-threatening parasitic disease transmitted by the infected female Anopheles mosquito. The development of drug tolerance and challenges related to the drugs' pharmacodynamic and pharmacokinetic parameters limits the antimalarial therapeutics response. Currently, nanotechnology-based drug delivery system provides an integrative platform for antimalarial therapy by improving the drug physicochemical properties, combating multidrug resistance, and lowering antimalarial drug-related toxicity. In addition, surface engineered nanocarrier systems offer a variety of alternatives for site-specific/targeted delivery of antimalarial therapeutics, anticipating better clinical outcomes at low drug concentrations and low toxicity profiles, as well as reducing the likelihood of the emergence of drug resistance. So, constructing nano carrier-based approaches for drug delivery has been considered the foremost strategy to combat malaria. This review focuses on the numerous nanotherapeutic strategies utilised to treat malaria as well as the benefits of nanotechnology as a potentially effective therapeutic.

Isolation and structure elucidation of a steroidal moiety from Withania somnifera and in silico evaluation of antimalarial efficacy against artemisinin resistance Plasmodium falciparum kelch 13 protein.

According to the 2021 Malaria report, 241 million clinical episodes with 627000 deaths penalty was estimated across the worldwide. However, mutation in the propeller domain of Plasmodium falciparum kelch 13 protein resulted in longer parasite clearance time following an artemisinin-based treatment and had a greater survival rate of ring-stage parasites even after a brief exposure to a high dose of artesunate. Clinical manifestations become more complex and worse with the emerging trend of drug resistance against artemisinin derivatives and the poor effectiveness of malaria vaccination drive. Steroidal lactone (withanolide) moiety (C-28) isolated from methanolic leaf extract Withania somnifera show a greater affinity towards Pfkelch 13 protein in comparison to the artemisinin derivatives (artesunate, artemether). The isolated compound was characterized to be withaferin A with a percentage yield of 29.01% w/w in chloroform fraction, 1.75% w/w in methanolic extract, and 0.29% w/w in raw leaf powder. Structure-based analysis shows that withaferin A (docking score -8.253, -9.802) has a higher affinity for two distinct binding pockets I and II of the Plasmodium falciparum kelch 13 protein than artesunate (docking score -4.470, -3.656). Further, Gibbs binding free energy signifies thermodynamic stability of the docked complex of withaferin A (-43.25, -43.76 Kcal/mol) in comparison to artesunate docked complex (-8.49, -5.75 Kcal/mol). The pharmacokinetic profile of withaferin A shows more drug-likeness characteristics without violating Jorgensen's rule of three, and Lipinski's rule of five. Hence above experimental findings suggest withaferin A could be a suitable therapeutic adjunct for preclinical evaluation of antimalarial potentiality in artemisinin-resistant malaria. HIGHLIGHTsMalaria is a life-threatening parasitic disease caused by Plasmodium species.The emerging trend of artemisinin resistance and severe side effects (CNS and cardiotoxicity) are the potential challenges faced by antimalarial therapeutics.Artemisinin-mimic potentiality (ROS-mediated antiparasitic activity) of withaferin A shows a strong affinity towards artemisinin resistance Plasmodium falciparum kelch 13 protein.The pharmacokinetic profiling of the withaferin A signifies its drug-likeness characteristics without violating Jorgensen's rule of three, and Lipinski's rule of five.Based on molecular docking and pharmacokinetic profiling, withaferin A could be a suitable therapeutic adjunct for preclinical investigation of antimalarial potentiality in artemisinin-resistant malaria.Communicated by Ramaswamy H. Sarma.

Gastroretentive Drug Delivery System in Cancer Chemotherapy.

BACKGROUND: Chemotherapy for stomach cancer often includes several side effects. The primary reasons for the failure of such treatment approaches are low drug concentrations in target tissues and a short stomach residence time. OBJECTIVE: Gastroretentive controlled drug delivery systems improves the therapeutic performance of chemotherapeutic drugs following oral administration because of the longer gastric retention time. The goal of this study was to find suitable gastroretentive formulations that might be used for the localized treatment of stomach cancer. METHODS: The purpose of this study is to summarize current advances in gastro-retentive drug administration for oral chemotherapy, with a focus on floating, mucoadhesive, and swellable systems. This article also discusses the potentials and limitations of existing gastroretentive drug delivery systems used in cancer chemotherapy. RESULTS: Due to increased stomach retention and modified drug release properties, gastroretentive controlled drug delivery systems improve the therapeutic performance of anti-cancer drugs used to treat stomach cancer. CONCLUSION: Gastroretentive drug delivery systems appear to be a promising carrier for localized chemotherapy with smaller doses and better patient compliance. However, selection of drug candidates, drugfood interactions and chemotherapy-induced gastric discomfort remain the key characteristics that must be addressed to improve treatment outcomes.

Phytochemical investigation, structural elucidation, in silico study and anti-psoriatic activity of potent bioactive from Betula utilis.

Psoriasis is a chronic autoimmune pathological condition characterized by hyperactivation of proinflammatory cytokines (IL-6, TNF-α, IL-17, IL-23, etc.). Severe drug-associated toxicities like hepatotoxicity and nephrotoxicity (Methotrexate), teratogenicity (Tazarotene), hypercholesterolemia (Cyclosporine) and hypercalcemia (tacalcitol), are the forefront challenges that demand an alternative approach for the treatment of psoriasis. In the present study, a natural lead molecule 'Betulin' (BE, lup-20(29)-ene-3b,28-diol) was isolated from Betula utilis and subsequently, structure-based molecular docking was employed to identify the molecular target for psoriasis. The computational analysis reflects better affinity of BE towards pro-inflammatory cytokine as compared to standard drugs. Apart from this BE shows a greater affinity towards the overexpressed Glut-1 receptor in comparison to standard drug Metformin (Met). Based on the in silico screening the isolated lead compound was further processed for the evaluation of anti-psoriatic activity via imiquimod (IMQ 5%) induced psoriasis-like skin inflammation model. In vivo screening models were characterized by different parameters (psoriasis area and severity index (PASI) scores, macroscopically and behavioral evaluation, splenomegaly, cytokine levels and histological changes) and compared among the experimental groups. The experimental finding reflects comparable results of PASI score, i.e., 57.14% and 61.9% recovery of test BE-solution (180 mg/kg) and standard Betamethasone di-propionate ointment (BD-oint.0.5 mg/g), respectively. Focusing on other parameters, BE shows relative results such as an enhanced macroscopically with behavioral conditions, reducing the expression of proinflammatory cytokine as well as restoring histological changes with that of BD. These findings suggest that BE-isolated phytoconstituents from Betula utilis could be a potential agent and a step closer to psoriasis treatment. HIGHLIGHTPsoriasis is a multifaceted, immunologically mediated disease consequences production of high levels of proinflammatory mediators and overexpression of Glut-1 transporters that trigger keratinocyte proliferation and inflammatory cascades.A Himalayan silver birch, Betula utilis (Bhojpatra) contains many steroidal terpenes which are responsible for various pharmacological activities that could be exploited in drug development in psoriasis.The computational analysis of BE reflects a better affinity toward the proinflammatory cytokines with their target receptors and indicates a satisfactory range with a slight deviation from Jorgensen and Lipinski's rule and possesses a significant drug choice for psoriasis.Preclinical findings of BE-solution (BE-sol) give a positive response towards IMQ-induced psoriasis-like skin inflammation model.[Figure: see text]Communicated by Ramaswamy H. Sarma.

PVP-microneedle array for drug delivery: mechanical insight, biodegradation, and recent advances.

Microneedle arrays are micron-sized needles usually attached to a supporting base or patch facilitated drug delivery for systemic effects. Polyvinylpyrrolidone (PVP) is a lactam polymer containing an internal amide linkage. Because of its versatility and biocompatibility, it has been widely utilized to treat several skin, bone and eye problems. Due to its specific and unique properties, the researchers realize its utility as a polymer of tremendous potential. PVP-based dissolvable microneedles have widely been utilized as a carrier for delivering DNAs, proteins, vitamins, and several biological macromolecules transdermally. However, it does not get biodegraded into the body. Therefore, the presence of its fragments in the body post-treatment needs proper justification. The adequate justification for the fate of the fragment's end products in the body will allow even better utilization of PVP. This review analyses and illustrates various experimental findings to highlight the most recent advancements and applications of PVP microneedles in drug delivery systems and cosmetology and the potential for PVP microneedles in treating dermal and systemic disorders. This review presents the expected mode of PVP biodegradation in aqueous and soil environments as a waste material, its inertness, biocompatibility, and the importance of PVP as a fabricating material, pharmaceutical uses, and non-toxic profile.