Preparation and assessment of agar/TEMPO-oxidized bacterial cellulose cryogels for hemostatic applications.

In this work, we have demonstrated agar and oxidized bacterial cellulose cryogels as a potential hemostatic dressing material. TEMPO-oxidized bacterial cellulose (OBC) was incorporated into the agar matrix, improving its mechanical and hemostatic properties. The oxidation of bacterial cellulose (BC) was evidenced by chemical characterization studies, confirming the presence of carboxyl groups. The in vitro blood clotting test conducted on agar/OBC composite cryogels demonstrated complete blood clotting within 90 seconds, indicating their excellent hemostatic efficacy. The cryogels exhibited superabsorbent properties with a swelling degree of 4200%, enabling them to absorb large amounts of blood. Moreover, the compressive strength of the composite cryogels was appreciably improved compared to pure agar, resulting in a more stable physical structure. The platelet adhesion test proved the significant ability of the composite cryogels to adhere to and aggregate platelets. Hemocompatibility and cytocompatibility tests have verified the safety of these cryogels for hemostatic applications. Finally, the material exhibited remarkable in vivo hemostatic performance, achieving clotting times of 64 seconds and 35 seconds when tested in the rat tail amputation model and the liver puncture model, respectively. The experiment results were compared with those of commercial hemostat, Axiostat, and Surgispon, affirming the potential of agar/OBC composite cryogel as a hemostatic dressing material.

Mapping the Landscape of Health Research Priorities for Effective Pandemic Preparedness in Human Mpox Virus Disease.

The global re-emergence of monkeypox (Mpox) in non-endemic regions in 2022 has highlighted the critical importance of timely virus detection and robust public health surveillance in assessing outbreaks and their impact. Despite significant Mpox research being conducted worldwide, there is an urgent need to identify knowledge gaps and prioritize key research areas in order to create a roadmap that maximizes the utilization of available resources. The present research article provides a comprehensive mapping of health research priorities aimed at advancing our understanding of Mpox and developing effective interventions for managing its outbreaks, and, as evidenced by the fact that achieving this objective requires close interdisciplinary collaboration. The key research priorities observed were identifying variants responsible for outbreaks; discovering novel biomarkers for diagnostics; establishing suitable animal models; investigating reservoirs and transmission routes; promoting the One Health approach; identifying targets for vaccination; gaining insight into the attitudes, experiences, and practices of key communities, including stigma; and ensuring equity during public health emergencies. The findings of this study hold significant implications for decision making by multilateral partners, including research funders, public health practitioners, policy makers, clinicians, and civil society, which will facilitate the development of a comprehensive plan not only for Mpox but also for other similar life-threatening viral infections.

Analysing role of airborne particulate matter in abetting SARS-CoV-2 outbreak for scheming regional pandemic regulatory modalities.

The mutating SARS-CoV-2 necessitates gauging the role of airborne particulate matter in the COVID-19 outbreak for designing area-specific regulation modalities based on the environmental state-of-affair. To scheme the protocols, the hotspots of air pollutants such as PM2.5, PM10, NH3, NO, NO2, SO2, and and environmental factors including relative humidity (RH), and temperature, along with COVID-19 cases and mortality from January 2020 till December 2020 from 29 different ground monitoring stations spanning Delhi, are mapped. Spearman correlation coefficients show a positive relationship between SARS-COV-2 with particulate matter (PM2.5 with r > 0.36 and PM10 with r > 0.31 and p-value <0·001). Besides, SARS-COV-2 transmission showed a substantial correlation with NH3 (r = 0.41), NO2 (r = 0.36), and NO (r = 0.35) with a p-value <0.001, which is highly indicative of their role in SARS-CoV-2 transmission. These outcomes are associated with the source of PM and its constituent trace elements to understand their overtone with COVID-19. This strongly validates temporal and spatial variation in COVID-19 dependence on air pollutants as well as on environmental factors. Besides, the bottlenecks of missing latent data, monotonous dependence of variables, and the role air pollutants with secondary environmental variables are discussed. The analysis set the foundation for strategizing regional-based modalities considering environmental variables (i.e., pollutant concentration, relative humidity, temperature) as well as urban and transportation planning for efficient control and handling of future public health emergencies.

A Preliminary Pharmacodynamic Study for the Management of Alzheimer's Disease Using Memantine-Loaded PLGA Nanoparticles.

Alzheimer's disease is becoming a common disorder of the elderly population due to shrinkage of the brain size with age and many other neurological complications. To provide an effective treatment option, memantine-encapsulated polymeric nanoparticles were prepared in the study. The nanoparticles were prepared by using nanoprecipitation followed by homogenization and ultrasonication methods, characterized on the basis of particle size, polydispersity index, and zeta potential. Further, in vitro release profile, cytotoxicity analysis, and Giemsa staining were conducted. To observe the efficacy of nanoparticles in scopolamine-induced Alzheimer models in vivo studies were also carried out. The results showed that nanoparticles were in the nano range with a particle size of 58.04 nm and - 23 mV zeta potential. The in vitro release was also sustained till 24 h with ~ 100% release in selected media phosphate buffer saline, simulated nasal fluid, and artificial cerebrospinal fluid. The cytotoxicity results with ~ 98 to 100% cell viability and no morphological changes through Giemsa staining indicated that nanoparticles were not leading to cell toxicity. The gamma scintigraphy studies showed higher uptake of the drug in the target site through the intranasal route and pharmacodynamic studies indicated that nanoparticles were able to inhibit the spatial memory impairment significantly as compared to the control group. The findings clearly indicated that the developed memantine nanoparticles could act as an alternative approach for the management of Alzheimer's disease.

Amelioration of oxidative stress utilizing nanoemulsion loaded with bromocriptine and glutathione for the management of Parkinson's disease.

Parkinson's disease (PD) is triggered by the formation of free radicals in dopaminergic neurons, which results in oxidative stress-induced neurodegeneration. The objective of the work was to relieve oxidative stress by employing intranasal delivery of Bromocriptine Mesylate (BRM) and Glutathione (GSH) loaded nanoemulsion for the better management of PD. The depth of permeation of the nanoemulsion was assessed through confocal laser scanning microscopy (CLSM) which revealed higher nanoemulsion permeation in contrast to suspension. Biocompatibility of nanoemulsion was confirmed by nasal cilio toxicity study. The DPPH study showed that the nanoemulsion had significant antioxidant activity. Biochemical estimation studies in Wistar rats were carried out in order to determine the effect of nanoemulsion on oxidative stress. The levels of GSH, superoxide dismutase (SOD), and catalase (CAT) were significantly enhanced; and the level of thiobarbituric acid reactive substances (TBARS) was significantly reduced after the intranasal administration of nanoemulsion in the haloperidol-induced model of PD. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also determined which reduced significantly after the administration of nanoemulsion. The oxidative stress levels were lowered with nanoemulsion, showing the combined antioxidant capability of BRM and GSH. The neuroprotective effect of the prepared nanoemulsion was confirmed by histopathological studies. Pharmacokinetic study revealed a higher concentration of BRM and GSH in the brain of Wistar rats after intranasal administration of nanoemulsion with a higher Brain/Plasma ratio. A higher value of AUC(0-8) of nanoemulsion in the brain after intranasal administration revealed that BRM and GSH remained in the brain for a longer period due to sustained release from nanoemulsion. According to the findings, BRM and GSH loaded nanoemulsion has the potential to provide a combined and synergistic anti-oxidant effect for efficient management of PD.

In vitro & in vivo evaluations of PLGA nanoparticle based combinatorial drug therapy for baclofen and lamotrigine for neuropathic pain management.

AIM: Baclofen and Lamotrigine via PLGA nanoparticles were developed for nose-to-brain delivery for the treatment of Neuropathic pain. METHODS: Nanoparticles were prepared using the modified nano-precipitation method. The prepared NPs were characterised and further in vitro and in vivo studies were performed. RESULTS: The Bcf-Ltg-PLGA-NPs were ∼177.7 nm with >75%(w/w) drugs encapsulated. In vitro dissolution studies suggested zero-order release profiles following the Korsmeyer-Peppas model. In vitro cytotoxicity and staining studies on mammalian cells showed dose dependant cytotoxicity where nanoparticles were significantly less toxic (>95% cell-viability). ELISA studies on RAW-macrophages showed Bcf-Ltg-PLGA-NPs as a potential pro-inflammatory-cytokines inhibitor. In vivo gamma-scintigraphy studies on rats showed intra-nasal administration of 99mTc-Bcf-Ltg-PLGA-NPs showed Cmax 3.6%/g at Tmax = 1.5h with DTE% as 191.23% and DTP% = 38.61% in brain. Pharmacodynamics evaluations on C57BL/6J mice showed a significant reduction in licks/bites during inflammation-induced phase II pain. CONCLUSION: The findings concluded that the combination of these drugs into a single nanoparticle-based formulation has potential for pain management.

Baclofen and Lamotrigine loaded PLGA nanoparticles were prepared with a size of 177.7nm, PDI 0.057 and Zeta Potential −15.8 mVIn vitro cell lines based studies showed dose dependant cytotoxicity and Bcf-Ltg-PLGA-NPs were found to be pro-inflammatory cytokines inhibitorsIn vivo Pharmacokinetic studies showed C_max 3.6%/g at T_max = 1.5 h with Drug Targeting Efficiency 191.23% and Drug Target Organ Transport 38.61% in the brain for prepared nanoparticlesIn vivo pharmacodynamics studies showed a significant reduction in licks/bites during inflammation-induced phase II pain.

Treatment of Alzheimer's diseases using donepezil nanoemulsion: an intranasal approach.

Alzheimer disease (AD) is very common among the older people. There are few medications available as oral and suspension dosage forms for the management of AD. Due to the rising cases of AD and the associated risks of the existing line of treatment, oil in water (o/w) nanoemulsion (NE) loaded with donepezil was prepared to explore intranasal route of administration. The NE was prepared using labrasol (10%), cetyl pyridinium chloride (1% in 80% water), and glycerol (10%), with a drug concentration of 1 mg/ml. The developed NE was characterized for particle size, polydispersity index (PDI), and zeta potential. In vitro release studies were conducted to observe the release of drug. Further in vivo studies of developed NE were done on Sprague Dawley rats using technetium pertechnetate (99mTc) labeled formulations to investigate the nose to brain drug delivery pathway. The nanoemulsion showed particle size of 65.36 nm with a PDI of 0.084 and zeta potential of -10.7 mV. In vitro release studies showed maximum release of 99.22% in 4 h in phosphate-buffered saline, 98% in 2 h in artificial cerebrospinal fluid, and 96% in 2 h in simulated nasal fluid. The cytotoxicity and antioxidant activity of the NE showed dose-dependent cytotoxicity and % radical scavenging activity (%RSA). The images of giemsa staining also confirmed that the developed formulation has no impact on the morphology of cells. Scintigrams showed maximum uptake of NE in the brain. The findings suggested that the developed NE loaded with donepezil hydrochloride could serve as a new approach for the treatment of Alzheimer via nose to brain drug delivery. Graphical abstract.

Memantine nanoemulsion: a new approach to treat Alzheimer's disease.

Aim: A nanoemulsion loaded with memantine for intranasal delivery to bypass the blood-brain barrier for the treatment of Alzheimer disease.Method: The nanoemulsion was prepared using homogenisation and ultrasonication methods. The developed nanoemulsion was characterised, in vitro release and antioxidant potential was analysed. The in vivo studies were carried out by radiolabelling the memantine with technetium pertechnetate.Results: The finalised NE showed particle-size of ∼11 nm and percentage transmittance of ∼99%. The in vitro release studies showed 80% drug release in simulated nasal fluid. The nanoemulsion showed 98% cell viability and antioxidative assays confirmed that the encapsulation of memantine in a nanoemulsion sustained its antioxidative potential. Gamma images and biodistribution results also confirmed higher uptake of formulation with %radioactivity of 3.6 ± 0.18%/g at 1.5 h in brains of rats administered intranasally.Conclusion: The developed nanoemulsion could be used as a potential carrier of memantine for a direct nose to brain delivery.

Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles.

Direct nose-to-brain delivery of drugs and faster onset of action have made intra-nasal route a much sought-after alternative to conventional routes of drug delivery to the brain. Lamotrigine is used for the treatment and management of neuropathic pain, and in the present work, lamotrigine (LTG)-PLGA nanoparticles were developed for intra-nasal delivery. The LTG-PLGA nanoparticles were prepared using modified nanoprecipitation method via high-speed homogenization and ultra-sonication techniques. Entrapment efficiency (EE%) of developed LTG-PLGA-NPs was found to be 84.87 ± 1.2% with drug loading of 10.21 ± 0.89%. The particle size of developed nanoparticles was found to be 184.6 nm with PDI value of 0.082 and zeta potential of - 18.8 mV. Dissolution profiles were studied in PBS (pH 7.4), simulated nasal fluid, and simulated cerebrospinal fluid where almost complete release was observed within 5 h in CSF. In vitro, cytotoxicity was analyzed using MTT assay where dose-dependent cytotoxicity was observed for developed LTG-PLGA-NPs. In vitro cytokine analysis showed positive effects of LTG-PLGA-NPs as pro-inflammatory cytokine suppressors. Further, in vivo studies were performed for radiolabeled formulation and drug (99mTc-LTG-PLGA-NPs and 99mTc-LTG-aqueous) using Sprague Dawley rats where with the help of gamma scintigraphy studies, various routes of administration viz. oral, intra-nasal, and intra-venous were compared. Various pharmacokinetic parameters were evaluated using biodistribution studies to estimate the drug levels in blood and brain. For 99mTc-LTG-PLGA-NPs via intra-nasal route, drug targeting efficiency (DTE%) was found to be 129.81% and drug target organ transport (DTP%) to be 22.81% in brain with Cmax of 3.82%/g within Tmax 1.5 h. Thus, the developed PLGA nanoparticles for intra-nasal delivery provide a possible alternative for existing available drug formulation for neuropathic pain management.

Baclofen-Loaded Poly (D,L-Lactide-Co-Glycolic Acid) Nanoparticles for Neuropathic Pain Management: In Vitro and In Vivo Evaluation.

In this work, poly (D,L-lactide-co-glycolic acid) (PLGA) nanoparticles of baclofen (Bcf-PLGA-NPs) were developed and optimized using nanoprecipitation method. The average particle size of the Bcf-PLGA-NP was found to be 124.8 nm, polydispersity index of 0.225, and zeta potential was found to be in the range of -20.4 mV. In vitro dissolution studies showed that Bcf was released from PLGA NPs in a sustained manner from 50% release in 2.5 hours to 80%-85% in 24 hours. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on Neuro-2a neuroblastoma cell line showed comparably low cytotoxicity of Bcf-PLGA-NPs as compared with aqueous solution of Bcf at reported Cmax values of the drug. To explore the nose-to-brain pathway, in vivo studies were carried out in Sprague-Dawley rats by radiolabeling of Bcf with technetium-99m (99mTc). Gamma scintigraphy images of the rats that were administered through intranasal (i.n.) route showed the maximum uptake of radiolabeled NPs from nose to brain at 3 hours as compared with the rats administered with NPs intravenously and orally. To assess the Bcf concentration in brain and blood, biodistribution studies were performed and following i.n. route the NPs were dispersed in brain (3.5%/g) and blood (3%/g) at 3 hours, and these observations were in agreement with the gamma scintigrams. Hence, from the results it was suggested that the developed PLGA NPs could serve as a potential carrier for the Bcf in the treatment of neuropathic pain.