Liposomal composition tuning improves intranasal brain drug delivery: Role of cholesterol and formulation rheology.

Intranasal Antiviral Drug Delivery and Coronavirus Disease 2019 (COVID-19): A State of the Art Review.

Although numerous studies have suggested the pathological mechanisms underlying stroke-induced brain damage, most clinical trials on the drug treatment of ischemic stroke have been unsuccessful. One of the key obstacles for establishing effective therapies for stroke and other neurological diseases is the blockage of entrance of drugs and therapeutic cells into the brain by the blood-brain barriers (BBB). A number of studies have suggested that intranasal drug delivery is a promising approach for effectively delivering drugs into the brain by bypassing the BBB. There may be at least one intracellular transport-mediated route and two extracellular transport-mediated routes for the nose-to-brain delivery. Recent studies have further suggested that intranasal delivery may also deliver therapeutic cells into the brain more effectively and less invasively compared to traditional approaches. However, multiple key questions regarding intranasal drug and cell delivery for treating neurological disorders remain unanswered. Future studies on intranasal delivery in humans as well as the mechanisms underlying the intranasal delivery may suggest novel biological mechanisms and markedly enhance our capacity of treating stroke and other neurological diseases.

The present study was conducted to present information about the cholesterol and total lipid content in fresh and roasted chicken meat with skin (breast and drumstick meat), most commonly consumed in Serbia. In addition, to assess the possible effects of carcass weight and nutrition on total lipid and cholesterol content in examined meat cuts. A total number of 48 samples of breast and drumstick muscle of broilers from two farms (Farm I and II), fed ad libitum by commercial diets for growing broilers, were taken in summer, 2012 and autumn, 2013. Total lipid and cholesterol content were determined in raw and heat-processed breast and drumstick muscle with skin. Total lipid content was determined by extraction of fat by petrol ether (Soxhlet) after acid hydrolysis of samples (SRPS ISO 1443/1992).Cholesterol determination was performed after direct saponification (without prior lipid extraction) by using HPLC/PDA system. Generally, all parameters measured were influenced by interaction of care and management and broiler performance at the 5% level or less. The total lipid content in samples of raw breast muscle of chicken from Farm I were the highest in summer (5.53%), (4.2%, in autumn), compared to samples of chickens from Farm II (3.05% in summer and 2.61% in autumn). The total lipid content in samples of raw drumstick were significantly differ (p < 0.001) between Farm I (9.63%) and Farm II (5.19%), only in summer. Cholesterol content (mg/100 g) in the raw breast muscle from Farm I was 53.9 (autumn) and 62.1 (summer), while in samples from Farm II was 46.97 (autumn) and 49.53 (summer). There was significant difference (p < 0.001) in cholesterol content in raw breast muscle of chickens in summer from two farms. In raw drumstick from Farm I the average cholesterol content (mg/100 g) was 70.24 (autumn) and 83.95 (summer), while in samples of chickens from Farm II was 65.05 (autumn) and 60.92 (summer). These differences were significant for cholesterol levels in drumstic between farms in summer (p < 0.001). In heat-processed meat belonging to chickens from Farm I, breast and drumstick contained higher quantities of total lipids compared to samples from Farm II. These differences was significant (p < 0.01) in drumstick between Farm I and II (autumn) and were 13.37%, and 11.10%, respectively. The average cholesterol content (mg/100 g) in samples of heat-processed meat of chicken from Farm I varied between 70.32 (autumn) and 87.37 (summer) and from 75.23 (autumn) to 78.92 (summer) in drumstick, versus 64.33 (summer) and 66.24 (autumn) in breast muscle and from 81.31(summer) to 91.6 (autumn) in drumstick samples of chickens from Farm II. We conclude that factors, such as feed composition, genotype (breed) and gender, influence the total lipid and cholesterol content in the meat. There were no obviously effects of slaughter traits on cholesterol and total lipid content. The results presented here, also shows that further investigations have to be conducted on greater number of samples.

<sec><title>Objective</title> To explore the effects of acupuncture at Baihui through Qubin acupoint on the expression of heme oxygenase 1 （HO-1） and inflammatory factors in rats with acute intracerebral hemorrhage from the levels of behavior, histology and molecular biology, so as to provide an experimental basis for clinical acupuncture in the treatment of intracerebral hemorrhage. </sec><sec><title>Methods</title> A total of 108 Wistar male rats were randomly divided into sham operation group, model group, acupuncture + model group （referred to as acupuncture group）. Each group was divided into 3 subgroups according to 1 d, 3 d and 7 d, with 12 rats in each group. The rat model of intracerebral hemorrhage was established by autologous blood injection. The sham operation group received various surgical operations similar to the model group, but no blood injection was performed; the model group received intracerebral hemorrhage model production without any intervention; the acupuncture group was used to create a intracerebral hemorrhage model, and treatment began 12 hours after the model was created. The Berderson scoring method was used to determine the animal success model, and rats with a score of 1-3 were included in the experiment. The rats with intracerebral hemorrhage in the acupuncture group were treated by acupuncture Baihui through Qubin acupoint. The depth of the needle was 20 mm, and the needle was twirled at 100 r/min with small amplitude. Twist the needle once every 5 minutes, and keep the needle for 30 minutes each time, once a day. Modified Neurological Severity Score （mNSS） was used to evaluate the neurological function of rats after intracerebral hemorrhage on 1 d, 3 d and 7 d. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of brain tissue. The expression of HO-1, nuclear transcription factor-κB （NF-κB）, Interleukin-1β (IL-1β), transforming growth factor-β （TGF-β） protein in hematoma tissue was detected by Western blot method at three time points of 1 d, 3 d and 7 d. </sec><sec><title>Results</title> 1） There were no obvious neurological deficits in the sham operation group at all time points; the rats in the model group showed neurological deficit symptoms on the 1st day, and there were still obvious neurological deficits on the 3rd and 7th days; compared with the model group, the acupuncture group had significantly lower neurological scores at each time point （<italic>P</italic><0.01）. 2） Normal nerve cells and glial cells were seen in the basal ganglia of rats in the sham operation group. Rats in the model group showed hemorrhage foci after the 1st day of modeling; the hemorrhage foci increased on the 3rd day, and the pathological structure of the brain tissue was obviously damaged; the hematoma area decreased on the 7th day. Compared with the model group, the acupuncture group had a lower degree of damage to the pathological structure of the brain tissue at each time point. 3） The sham operation group showed a small amount of HO-1 protein expression. The expression of HO-1 protein in the model group increased at each time point. Compared with the model group, the expression of HO-1 protein in the acupuncture group increased significantly on the 3rd and 7th day （<italic>P</italic><0.05）. 4） In the sham operation group, a small amount of NF-κB, IL-1β, and TGF-β protein expression were seen; the expression of NF-κB, IL-1β, and TGF-β protein in the model group was significantly increased at each time point, and the relative expression was the highest on the third day; compared with the model group, the protein expression of NF-κB, IL-1β, and TGF-β in the acupuncture group was significantly reduced on 1st, 3rd and 7th day （<italic>P</italic><0.05）. </sec><sec><title>Conclusion</title> Acupuncture can reduce the neurological deficit scores in rats with intracerebral hemorrhage, possibly by promoting the expression of HO-1 protein, inhibiting the expression of NF-κB, IL-1β, and TGF-β proteins, reducing inflammatory reactions, and exerting a protective effect on the brain. </sec>

This review aims to provide an overview and update of current literature on the use of intranasal (IN) drug delivery in pediatric emergency medicine (PEM), in terms of the anatomy, physiology, pharmacokinetics, limitations, drug delivery methods, necessary training, safety, contraindications, effectiveness, current indications and trends, and implications for clinical practice and future developments in IN drug administration. We evaluate how IN medication use in PEM has recently evolved, what recent research has revealed about the utility of IN drug delivery in PEM, and what the future of IN drug delivery might look like.

Intranasal drug delivery system is a non-invasive drug delivery route with the advantages of no first-pass effect, rapid effect and brain targeting. It is a feasible alternative to drug delivery via injection, and a potential drug delivery route for the central nervous system. However, the nasal physiological environment is complex, and the nasal delivery system requires "integration of medicine and device". Its delivery efficiency is affected by many factors such as the features and formulations of drug, delivery devices and nasal cavity physiology. Some strategies have been designed to improve the solubility, stability, membrane permeability and nasal retention time of drugs. These include the use of prodrugs, adding enzyme inhibitors and absorption enhancers to preparations, and new drug carriers, which can eventually improve the efficiency of intranasal drug delivery. This article reviews recent publications and describes the above mentioned aspects and design strategies for nasal intranasal drug delivery systems to provide insights for the development of intranasal drug delivery systems.

Thymosin β4 (Tβ4), a G-actin binding protein, has diverse biological functions. This study tested the effects of Tβ4 on oligodendrogenesis in a rat model of intracerebral hemorrhage (ICH). ICH was induced by stereotactic injection of 100 μm of autologous blood into the striatum in 32 male Wistar rats. The rats were randomly divided into four groups: 1) saline control group (n = 8); 2) 3 mg/kg Tβ4-treated group (n = 8); 3) 6 mg/kg Tβ4-treated group (n = 8); and 4) 12 mg/kg Tβ4treated group (n = 8). Tβ4 or saline was administered intraperitoneally starting at 24 h post ICH and then every 3 days for 4 additional doses. The neurological functional outcome was evaluated by behavioral tests (i.e., modified Neurological Severity Score and corner turn test) at multiple time points after ICH. Animals were sacrificed at 28 days post ICH, and histological studies were completed. Tβ4 treatment improved neurological functional recovery significantly and increased actively proliferating oligodendrocytic progenitor cells and myelinating oligodendrocytes in the ICH-affected brain tissue, compared with the saline-treated group. The high-dose treatment of Tβ4 showed better restorative effects compared with the low-dose treatment. Tβ4 treatment enhanced ICH-induced oligodendrogenesis that may contribute to the enhanced functional recovery after ICH. Further investigation is warranted to determine the associated underlying mechanisms of Tβ4 treatment for ICH.

Intranasal (IN) drug delivery is a non-invasive and effective route for the administration of drugs to the brain at pharmacologically relevant concentrations, bypassing the blood–brain barrier (BBB) and minimizing adverse side effects. IN drug delivery can be particularly promising for the treatment of neurodegenerative diseases. The drug delivery mechanism involves the initial drug penetration through the nasal epithelial barrier, followed by drug diffusion in the perivascular or perineural spaces along the olfactory or trigeminal nerves, and final extracellular diffusion throughout the brain. A part of the drug may be lost by drainage through the lymphatic system, while a part may even enter the systemic circulation and reach the brain by crossing the BBB. Alternatively, drugs can be directly transported to the brain by axons of the olfactory nerve. To improve the effectiveness of drug delivery to the brain by the IN route, various types of nanocarriers and hydrogels and their combinations have been proposed. This review paper analyzes the main biomaterials-based strategies to enhance IN drug delivery to the brain, outlining unsolved challenges and proposing ways to address them.

Dysfunction of the hypothalamus is associated with endocrine imbalances, growth abnormalities, and reproductive disorders. However, there is a lack of targeted treatment strategies focused on the hypothalamus. In this study, we constructed a multifunctional nanocarrier system (S@ANP) to directly target the hypothalamic neurokinin receptor 3 (NK3R) via an intranasal delivery strategy. This system could overcome the primary obstacles in drug delivery for hypothalamus‐related diseases. Under the guidance of a modified (Trp7, β‐Ala8)‐neurokinin A (4‐10) peptide with cysteine, nanoparticles encapsulated with SB222200, an NK3R inhibitor, were found to readily penetrate hypothalamic cells with substantial loading capacity, encapsulation efficiency, and sustained release in vitro. Moreover, intranasal delivery represents an optimal delivery strategy that allows for a significant reduction in oral dosage and enables nanoparticles to bypass the blood‒brain barrier and target relevant parts of the brain. The mucolytic agent N‐acetyl‐L‐cysteine (NAC) was loaded into the nanoparticles (S@ANP + NAC) to increase mucosal solubility and intranasal delivery efficiency. In vivo evaluations showed that S@ANP + NAC could effectively target the hypothalamus and modulate NK3R‐regulated hypothalamic functions in mice. Due to its high hypothalamic targeting efficiency and low toxicity, this intranasal nanoparticle drug delivery system may serve as a potential strategy for precision therapy of hypothalamic disorders.

Background:Sirtuin-3 (Sirt3) has been documented to protect against mitochondrial dysfunction and apoptosis. Honokiol (HKL) is a Sirt3 pharmacological activator with reported neuroprotective effects in multiple neurological disorders. The present study aimed to explore the neuroprotective effects of HKL and the role of Sirt3 following intracerebral hemorrhage (ICH).Methods:An in vivo ICH model in rats was established by injecting autologous blood into the right basal ganglia. PC12 cells were stimulated with hemin. For the in vivo investigation, the modified Neurological Severity Scores and the Morris water maze test were performed to assess neurological deficits. Hematoxylin–Eosin and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining were employed to evaluate the histopathology and apoptosis. Immunohistochemical staining was used to investigate the expression of Sirt3. Adenosine triphosphate (ATP) levels were quantified to assess mitochondrial dysfunction. Cell counting kit-8, lactate dehydrogenase assay, and flow cytometry were used to analyze cell vitality and apoptosis in vitro. Immunofluorescence staining was performed to observe mitochondrial morphology and dynamin-related protein 1 (Drp1) localization to mitochondria. Western blot was applied to quantify the expression of Sirt3, Bax, Bcl-2, cleaved-caspase-3, Drp1, phosphorylation of Drp1 at serine-616, and phosphorylation of Drp1 at serine-637 in vivo and in vitro.Results:HKL treatment alleviated neurological deficits, attenuated the histopathological damage and cell apoptosis, and restored the decreased ATP levels in ICH rats. HKL improved cell survival rate, reduced cell apoptosis, and inhibited mitochondrial fission in PC12 cells. Moreover, both in vivo and in vitro models showed increased phosphorylation of Drp1 at Ser616, and reduced phosphorylation of Drp1 at Ser637. Meanwhile, immunofluorescence co-localization analysis revealed that hemin increased the overlap of Drp1 and mitochondria in PC12 cells. The phosphorylation and mitochondrial translocation of Drp1 were effectively reversed by HKL treatment. Importantly, the selective Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine suppressed these effects.Conclusion:Our findings demonstrated that HKL ameliorated ICH-induced apoptosis and mitochondrial fission by Sirt3, suggesting that HKL has immense prospects for the treatment of ICH.

Intranasal (IN) drug delivery is a promising noninvasive route for targeting the central nervous system (CNS) bypassing the blood-brain-barrier (BBB). This review critically examines the underlying mechanisms, challenges in predicting nasal drug delivery outcomes, and future directions for applying physiologically based pharmacokinetic (PBPK) modeling to support such predictions. The nasal cavity comprises distinct anatomical and physiological features in the olfactory region (upper posterior part of the nasal cavity) and the respiratory region (middle part and lateral walls of the nasal cavity), both of which play essential roles in drug deposition, systemic absorption, and general passage. However, since the biological composition of the olfactory and trigeminal nerves in the nasal area is not well-known, the prediction of drug absorption to systemic circulation from nasal mucosa or direct transport from nose to brain are fraught with many challenges. Thus, addressing the impacts of drug permeability, mucociliary clearance, enzymatic degradation, and nasomucosal toxicity are still essential challenges when developing nasal formulations for drugs. PBPK models have the capability of integrating complex anatomical, physiological, and biological aspects of the systems when such data are available. Nevertheless, translation from in vitro experiments or animal studies into humans requires addressing knowledge gaps in systems parameters. Future investigations should focus on generating the necessary missing information as well as refining the models. Application of advanced modeling methods for simulation of drug deposition, in conjunction with refined nasal PBPK models, is envisaged to improve the prediction of clinical outcomes for CNS targeted IN drug delivery.

Background: The epithelial layer of the nasal mucosa is the first barrier for drug permeation during intranasal drug delivery. With increasing interest for intranasal pathways, adequate in vitro models are required. Here, porcine olfactory (OEPC) and respiratory (REPC) primary cells were characterised against the nasal tumour cell line RPMI 2650. Methods: Culture conditions for primary cells from porcine nasal mucosa were optimized and the cells characterised via light microscope, RT-PCR and immunofluorescence. Epithelial barrier function was analysed via transepithelial electrical resistance (TEER), and FITC-dextran was used as model substance for transepithelial permeation. Beating cilia necessary for mucociliary clearance were studied by immunoreactivity against acetylated tubulin. Results: OEPC and REPC barrier models differ in TEER, transepithelial permeation and MUC5AC levels. In contrast, RPMI 2650 displayed lower levels of MUC5AC, cilia markers and TEER, and higher FITC-dextran flux rates. Conclusion: To screen pharmaceutical formulations for intranasal delivery in vitro, translational mucosal models are needed. Here, a novel and comprehensive characterisation of OEPC and REPC against RPMI 2650 is presented. The established primary models display an appropriate model for nasal mucosa with secreted MUC5AC, beating cilia and a functional epithelial barrier, which is suitable for long-term evaluation of sustained release dosage forms.

Otitis media (OM) is a common disease affecting humans, especially paediatric populations. OM refers to inflammation of the middle ear and can be broadly classified into two types, acute and chronic. Bacterial infection is one of the most common causes of OM. Despite the introduction of vaccines, the incidence of OM remains significantly high worldwide. In this mini-review article, we discuss the recent treatment modalities for OM, such as suspension gel, transcutaneous immunization, and intranasal and transtympanic drug delivery, including therapies that are currently undergoing clinical trials. We provide an overview of how these recent advancements in therapeutic strategies can facilitate the circumvention of current treatment challenges involving preadolescence soft palate dysfunction, biofilm formation, tympanic membrane (ear drum) barrier and the attainment of efficacious drug concentrations in the middle ear. While traditional first-line immunization strategies are generally not very efficacious against biofilms, new technologies that use transdermal or intranasal drug delivery via chitosan-PsaA nanoparticles have shown promising results in experimental animal models of OM. Sustained drug delivery systems such as penta-block copolymer poloxamer 407-polybutylphosphoester (P407-PBP) or poloxamer 407 (e.g. OTO-201, with the brand name 'OTIPRIO') have demonstrated that treatments can be reduced to a single topical application. The emergence of effective new treatment modalities opens up promising new avenues for the treatment of OM that could lead to improved quality of life for many children and their families.

Normobaric oxygen (NBO) therapy may be neuroprotective in acute ischemic stroke. However, how NBO may affect intracerebral hemorrhage is unclear. We tested NBO in a rat model of striatal intracerebral hemorrhage. Intracerebral hemorrhage was induced by stereotactic injection of collagenase Type VII (0.5 U) into the right striatum of male Sprague-Dawley rats. One hour later, rats were randomized into controls (n=13) versus NBO treatment (n=13). NBO was applied for 2 hours. Hemorrhagic blood volume, brain water content, and neurological outcomes (forelimb placement test, forelimb asymmetry, neuroscore) were quantified at 72 hours. Experiments were repeated in a second independent laboratory to assess reproducibility in neurological outcomes (n=10 per group). NBO did not worsen hemorrhage severity or brain edema. There were no significant differences in hemorrhagic blood volumes (control, 6.4±0.9 μL versus NBO, 7.0±2.1 μL; P=0.18) or brain water content (control, 81.9%±1.1% versus NBO, 81.6%±0.5%; P=0.58). NBO did not affect any of the neurological outcome tests in the primary or secondary studies. NBO therapy may not worsen outcomes in intracerebral hemorrhage.

Alzheimer's is the primary cause of death in the various countries that affect wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for the systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN's). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities. 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer's disease, ex vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs. Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data. From in vivo biodistribution studies, pharmacokinetics parameters, and gamma scintigraphy images of various drugs, it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes. Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but the intranasal route shows better results that pave the way for success in the future if properly explored.