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Sample records for intranasal nanoparticle transit

  1. Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Harmon, Brendan Trevor

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic A9 nigrostriatal tract. For dopamine neurons specifically, glial cell-derived neurotrophic factor (GDNF) has been shown to promote their survival and proliferation both in culture and in vivo. GDNF has also proven to be neuroprotective and restorative in various animal models of PD and some human clinical trials. However, its delivery to the brain has required invasive surgical routes which are not clinically practical for many patients. The main objective of this project was to test intranasal delivery to the brain of a nanoparticle vector incorporating an expression plasmid for GDNF (pGDNF). The intranasal route circumvents the blood-brain barrier, allowing larger sized vectors into the central nervous system while avoiding peripheral distribution. This approach would provide a renewable source of GDNF within the target areas of the brain, the striatum and the substantia nigra (SN) without the need for surgical injections or frequent re-dosing. A PEGylated polylysine compacted plasmid nanoparticle vector (PEG-CK30), developed by Copernicus Therapeutics, Inc., has been shown to transfect neurons and glial cells in vivo while lacking the safety issues present with other vectors. The first goal of this work was to determine if these PEG-CK30 compacted plasmid nanoparticles can successfully transfect cells and express the reporter protein, enhanced green fluorescent protein (eGFP) in the rat brain after intranasal administration. Initial in vivo experiments utilized the expression plasmid pCG, expressing eGFP under the fast-acting cytomegalovirus (CMV) promoter. Intranasal administration of pCG nanoparticles resulted in evidence of transfection of brain cells, as shown both qualitatively, by GFP-immunohistochemistry, and quantitatively, by GFP-ELISA. Expression was detected throughout the rat brain two days post-administration. Following the proof

  2. Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Harmon, Brendan Trevor

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic A9 nigrostriatal tract. For dopamine neurons specifically, glial cell-derived neurotrophic factor (GDNF) has been shown to promote their survival and proliferation both in culture and in vivo. GDNF has also proven to be neuroprotective and restorative in various animal models of PD and some human clinical trials. However, its delivery to the brain has required invasive surgical routes which are not clinically practical for many patients. The main objective of this project was to test intranasal delivery to the brain of a nanoparticle vector incorporating an expression plasmid for GDNF (pGDNF). The intranasal route circumvents the blood-brain barrier, allowing larger sized vectors into the central nervous system while avoiding peripheral distribution. This approach would provide a renewable source of GDNF within the target areas of the brain, the striatum and the substantia nigra (SN) without the need for surgical injections or frequent re-dosing. A PEGylated polylysine compacted plasmid nanoparticle vector (PEG-CK30), developed by Copernicus Therapeutics, Inc., has been shown to transfect neurons and glial cells in vivo while lacking the safety issues present with other vectors. The first goal of this work was to determine if these PEG-CK30 compacted plasmid nanoparticles can successfully transfect cells and express the reporter protein, enhanced green fluorescent protein (eGFP) in the rat brain after intranasal administration. Initial in vivo experiments utilized the expression plasmid pCG, expressing eGFP under the fast-acting cytomegalovirus (CMV) promoter. Intranasal administration of pCG nanoparticles resulted in evidence of transfection of brain cells, as shown both qualitatively, by GFP-immunohistochemistry, and quantitatively, by GFP-ELISA. Expression was detected throughout the rat brain two days post-administration. Following the proof

  3. Systemic and behavioral effects of intranasal administration of silver nanoparticles.

    PubMed

    Davenport, Laurie L; Hsieh, Heidi; Eppert, Bryan L; Carreira, Vinicius S; Krishan, Mansi; Ingle, Taylor; Howard, Paul C; Williams, Michael T; Vorhees, Charles V; Genter, Mary Beth

    2015-01-01

    Use of silver nanoparticles (AgNPs) for their antimicrobial properties is widespread. Much of the previous work on the toxicity of AgNPs has been conducted in vitro or following oral or intravenous administration in vivo. Intranasal (IN) instillation of AgNPs mimics inhalation exposure and allows further exploration of the toxicity of these particles via respiratory tract exposure. The present study involved 1) single-dose exposures to assess tissue distribution and toxicity and 2) repeated exposures to assess behavioral effects of IN AgNP exposure (nominally uncoated 25 nm AgNP). AgNP deposition was localized in the liver, gut-associated lymphoid tissue, and brain. Decrease cellularity in spleen follicles was observed in treated mice, along with changes in cell number and populations in the spleen. The splenic GSH:GSSG ratio was also reduced following AgNP exposure. Expression of the oxidative stress-responsive gene Hmox1 was elevated in the hippocampus, but not cortex of treated mice, as was the level of HMOX1 protein. Mice receiving 7 days of IN exposure to 50 mg/kg AgNPs exhibited similar learning- and memory-related behaviors to control mice, except that treated mice spent significantly less time in the target quadrant of the Morris Water Maze during the acquisition phase probe trial. These findings indicate systemic distribution and toxicity following IN administration of AgNPs. PMID:26340819

  4. Systemic and Behavioral Effects of Intranasal Administration of Silver Nanoparticles

    PubMed Central

    Davenport, Laurie L.; Hsieh, Heidi; Eppert, Bryan L.; Carreira, Vinicius S.; Krishan, Mansi; Ingle, Taylor; Howard, Paul C.; Williams, Michael T.; Vorhees, Charles V.; Genter, Mary Beth

    2015-01-01

    Use of silver nanoparticles (AgNPs) for their antimicrobial properties is widespread. Much of the previous work on the toxicity of AgNPs has been conducted in vitro or following oral or intravenous administration in vivo. Intranasal (IN) instillation of AgNPs mimics inhalation exposure and allows further exploration of the toxicity of these particles via respiratory tract exposure. The present study involved 1) single-dose exposures to assess tissue distribution and toxicity and 2) repeated exposures to assess behavioral effects of IN AgNP exposure (nominally uncoated 25 nm AgNP). AgNP deposition was localized in the liver, gut-associated lymphoid tissue, and brain. Decrease cellularity in spleen follicles was observed in treated mice, along with changes in cell number and populations in the spleen. The splenic GSH:GSSG ratio was also reduced following AgNP exposure. Expression of the oxidative stress-responsive gene Hmox1 was elevated in the hippocampus, but not cortex of treated mice, as was the level of HMOX1 protein. Mice receiving 7 days of IN exposure to 50 mg/kg AgNPs exhibited similar learning- and memory-related behaviors to control mice, except that treated mice spent significantly less time in the target quadrant of the Morris Water Maze during the acquisition phase probe trial. These findings indicate systemic distribution and toxicity following IN administration of AgNPs. PMID:26340819

  5. UEA I-bearing nanoparticles for brain delivery following intranasal administration.

    PubMed

    Gao, Xiaoling; Chen, Jun; Tao, Weixing; Zhu, Jianhua; Zhang, Qizhi; Chen, Hongzhuan; Jiang, Xinguo

    2007-08-01

    Surface engineering of nanoparticles with lectins opened a novel pathway to improve the brain uptake of agents loaded by biodegradable PEG-PLA nanoparticles following intranasal administration. Ulex europeus agglutinin I (UEA I), specifically binding to l-fucose, which is largely located in the olfactory epithelium, was selected as a promising targeting ligand and conjugated onto the PEG-PLA nanoparticles surface with an optimized protocol relying on maleimide-mediated covalent binding technique. The in vivo results in rats suggested that UEA I modification at the nanoparticles surface facilitated the absorption of a fluorescent marker--6-coumarin associated with the nanoparticles into the brain following intranasal administration with significant increase in the area under the concentration-time curve (about 1.7 times) in different brain tissues compared with that of coumarin incorporated in the unmodified ones. UEA I-conjugation also elevated the brain-targeting efficiency of nanoparticles. Inhibition experiment of specific sugar suggested that the interactions between the nasal mucosa and the lectinised nanoparticles were due to the immobilization of carbohydrate-binding pockets on the surface of the nanoparticles. Distribution profiles of UEA I-modified nanoparticles indicated their higher affinity to the olfactory mucosa than to the respiratory one. Therefore, the UEA I-modified nanoparticles might serve as potential carriers for brain drug delivery, especially for mental therapeutics with multiple biological effects. PMID:17499948

  6. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease.

    PubMed

    Zhang, Chi; Chen, Jie; Feng, Chengcheng; Shao, Xiayan; Liu, Qingfeng; Zhang, Qizhi; Pang, Zhiqing; Jiang, Xinguo

    2014-01-30

    Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of β-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as

  7. Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer's disease.

    PubMed

    Muntimadugu, Eameema; Dhommati, Raju; Jain, Anjali; Challa, Venu Gopala Swami; Shaheen, M; Khan, Wahid

    2016-09-20

    Poor brain penetration of tarenflurbil (TFB) was one of the major reasons for its failure in phase III clinical trials conducted on Alzheimer's patients. Thus there is a tremendous need of developing efficient delivery systems for TFB. This study was designed with the aim of improving drug delivery to brain through intranasally delivered nanocarriers. TFB was loaded into two different nanocarriers i.e., poly (lactide-co-glycolide) nanoparticles (TFB-NPs) and solid lipid nanoparticles (TFB-SLNs). Particle size of both the nanocarriers (<200nm) as determined by dynamic light scattering technique and transmission electron microscopy, assured transcellular transport across olfactory axons whose diameter was ≈200nm and then paving a direct path to brain. TFB-NPs and TFB-SLNs resulted in 64.11±2.21% and 57.81±5.32% entrapment efficiencies respectively which again asserted protection of drug from chemical and biological degradation in nasal cavity. In vitro release studies proved the sustained release of TFB from TFB-NPs and TFB-SLNs in comparison with pure drug, indicating prolonged residence times of drug at targeting site. Pharmacokinetics suggested improved circulation behavior of nanoparticles and the absolute bioavailabilities followed this order: TFB-NPs (i.n.)>TFB-SLNs (i.n.)>TFB solution (i.n.)>TFB suspension (oral). Brain targeting efficiency was determined in terms of %drug targeting efficiency (%DTE) and drug transport percentage (DTP). The higher %DTE (287.24) and DTP (65.18) were observed for TFB-NPs followed by TFB-SLNs (%DTE: 183.15 and DTP: 45.41) among all other tested groups. These encouraging results proved that therapeutic concentrations of TFB could be transported directly to brain via olfactory pathway after intranasal administration of polymeric and lipidic nanoparticles. PMID:27185298

  8. Cationic liposome-hyaluronic acid hybrid nanoparticles for intranasal vaccination with subunit antigens

    PubMed Central

    Ochyl, Lukasz J.; Akerberg, Jonathan; Moon, James J.

    2015-01-01

    Here we report the development of a new cationic liposome-hyaluronic acid (HA) hybrid nanoparticle (NP) system and present our characterization of these NPs as an intranasal vaccine platform using a model antigen and F1-V, a candidate recombinant antigen for Yersinia pestis, the causative agent of plague. Incubation of cationic liposomes composed of DOTAP and DOPE with anionic HA biopolymer led to efficient ionic complexation and formation of homogenous liposome-polymer hybrid NPs, as evidenced by fluorescence resonance energy transfer, dynamic light scattering, and nanoparticle tracking analyses. Incorporation of cationic liposomes with thiolated HA allowed for facile surface decoration of NPs with thiol-PEG, resulting in the formation of DOTAP/HA core-PEG shell nanostructures. These NPs, termed DOTAP-HA NPs, exhibited improved colloidal stability and prolonged antigen release. In addition, cytotoxicity associated with DOTAP liposomes (LC50 ~0.2 mg/ml) was significantly reduced by at least 20-fold with DOTAP-HA NPs (LC50 > 4 mg/ml), as measured with bone marrow dendritic cells (BMDCs). Furthermore, NPs co-loaded with ovalbumin (OVA) and a molecular adjuvant, monophosphoryl lipid A (MPLA) promoted BMDC maturation and upregulation of co-stimulatory markers, including CD40, CD86, and MHC-II, and C57BL/6 mice vaccinated with NPs via intranasal route generated robust OVA-specific CD8+ T cell and antibody responses. Importantly, intranasal vaccination with NPs co-loaded with F1-V and MPLA induced potent humoral immune responses with 11-, 23-, and 15-fold increases in F1-V-specific total IgG, IgG1, and IgG2c titers in immune sera by day 77, respectively, and induced balanced Th1/Th2 humoral immune responses, compared with the lack of sero-conversion in mice immunized with the equivalent doses of soluble F1-V vaccine. Overall, these results suggest that liposome-polymer hybrid NPs may serve as a promising vaccine delivery platform for intranasal vaccination against Y

  9. Cationic liposome-hyaluronic acid hybrid nanoparticles for intranasal vaccination with subunit antigens.

    PubMed

    Fan, Yuchen; Sahdev, Preety; Ochyl, Lukasz J; J Akerberg, Jonathan; Moon, James J

    2015-06-28

    Here we report the development of a new cationic liposome-hyaluronic acid (HA) hybrid nanoparticle (NP) system and present our characterization of these NPs as an intranasal vaccine platform using a model antigen and F1-V, a candidate recombinant antigen for Yersinia pestis, the causative agent of plague. Incubation of cationic liposomes composed of DOTAP and DOPE with anionic HA biopolymer led to efficient ionic complexation and formation of homogenous liposome-polymer hybrid NPs, as evidenced by fluorescence resonance energy transfer, dynamic light scattering, and nanoparticle tracking analyses. Incorporation of cationic liposomes with thiolated HA allowed for facile surface decoration of NPs with thiol-PEG, resulting in the formation of DOTAP/HA core-PEG shell nanostructures. These NPs, termed DOTAP-HA NPs, exhibited improved colloidal stability and prolonged antigen release. In addition, cytotoxicity associated with DOTAP liposomes (LC50~0.2mg/ml) was significantly reduced by at least 20-fold with DOTAP-HA NPs (LC50>4mg/ml), as measured with bone marrow derived dendritic cells (BMDCs). Furthermore, NPs co-loaded with ovalbumin (OVA) and a molecular adjuvant, monophosphoryl lipid A (MPLA) promoted BMDC maturation and upregulation of co-stimulatory markers, including CD40, CD86, and MHC-II, and C57BL/6 mice vaccinated with NPs via intranasal route generated robust OVA-specific CD8(+) T cell and antibody responses. Importantly, intranasal vaccination with NPs co-loaded with F1-V and MPLA induced potent humoral immune responses with 11-, 23-, and 15-fold increases in F1-V-specific total IgG, IgG1, and IgG2c titers in immune sera by day 77, respectively, and induced balanced Th1/Th2 humoral immune responses, whereas mice immunized with the equivalent doses of soluble F1-V vaccine failed to achieve sero-conversion. Overall, these results suggest that liposome-polymer hybrid NPs may serve as a promising vaccine delivery platform for intranasal vaccination against Y

  10. Intranasal delivery of nanoparticles encapsulating BPI3V proteins induces an early humoral immune response in mice.

    PubMed

    Mansoor, Fawad; Earley, Bernadette; Cassidy, Joseph P; Markey, Bryan; Foster, Colin; Doherty, Simon; Welsh, Michael D

    2014-06-01

    Vaccine adjuvants are typically designed to stimulate both systemic and mucosal immune responses. Polymeric nanoparticles have been used as adjuvants in the development of vaccines against a number of viral pathogens and tested in laboratory animals. The objective of the study was to assess if synthetic bovine parainfluenza virus type-3 (BPI3V) peptide motifs and solubilised BPI3V proteins encapsulated in poly (dl-lactic-co-glycolide) (PLGA) nanoparticles (NPs) induce specific humoral immune responses in a mouse model following intranasal administration. BPI3V-specific and peptide specific IgG ELISAs were used to measure serum IgG levels to BPI3V. Intranasal delivery of PLGA nanoparticles encapsulating BPI3V proteins elicited an early, gradually increasing BPI3V-specific IgG response that persisted over the subsequent 6 weeks, suggesting slow, persistent release of antigen. PLGA-BPI3V particles administered intranasally induced a stronger IgG antibody response at an earlier time point compared with solubilised BPI3V antigen alone. Such an approach could be deployed in the development of new generation vaccines. PMID:24726021

  11. Solid lipid nanoparticles of ondansetron HCl for intranasal delivery: development, optimization and evaluation.

    PubMed

    Joshi, Ashwini S; Patel, Hitesh S; Belgamwar, Veena S; Agrawal, Anshuman; Tekade, Avinash R

    2012-09-01

    The present investigation deals with the development and statistical optimization of solid lipid nanoparticles (SLNs) of ondansetron HCl (OND) for intranasal (i.n.) delivery. SLNs were prepared using the solvent diffusion technique and a 2(3) factorial design. The concentrations of lipid, surfactant and cosurfactant were independent variables in this design, whereas, particle size and entrapment efficiency (EE) were dependent variables. The particle size of the SLNs was found to be 320-498 nm, and the EE was between 32.89 and 56.56 %. The influence of the lipid, surfactant and cosurfactant on the particle size and EE was studied. A histological study revealed no adverse response of SLNs on sheep nasal mucosa. Transmission electron microscopic analysis showed spherical shape particles. Differential scanning calorimetry and X-ray diffraction studies indicated that the drug was completely encapsulated in a lipid matrix. In vitro drug release studies carried out in phosphate buffer (pH 6.6) indicated that the drug transport was of Fickian type. Gamma scintigraphic imaging in rabbits after i.n. administration showed rapid localization of the drug in the brain. Hence, OND SLNs is a promising nasal delivery system for rapid and direct nose-to-brain delivery. PMID:22802103

  12. Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles.

    PubMed

    Di Gioia, Sante; Trapani, Adriana; Mandracchia, Delia; De Giglio, Elvira; Cometa, Stefania; Mangini, Vincenzo; Arnesano, Fabio; Belgiovine, Giuliana; Castellani, Stefano; Pace, Lorenzo; Lavecchia, Michele Angelo; Trapani, Giuseppe; Conese, Massimo; Puglisi, Giovanni; Cassano, Tommaso

    2015-08-01

    The aim of this study was to evaluate chitosan (CS)-, glycol chitosan (GCS)- and corresponding thiomer-based nanoparticles (NPs) for delivering dopamine (DA) to the brain by nasal route. Thus, the polyanions tripolyphosphate and sulfobutylether-β-cyclodextrin (SBE-β-CD), respectively, were used as polycation crosslinking agents and SBE-β-CD also in order to enhance the DA stability. The most interesting formulation, containing GCS and SBE-β-CD, was denoted as DA GCS/DA-CD NPs. NMR spectroscopy demonstrated an inclusion complex formation between SBE-β-CD and DA. X-ray photoelectron spectroscopy analysis revealed the presence of DA on the external surface of NPs. DA GCS/DA-CD NPs showed cytotoxic effect toward Olfactory Ensheathing Cells only at higher dosage. Acute administration of DA GCS/DA-CD NPs into the right nostril of rats did not modify the levels of the neurotransmitter in both right and left striatum. Conversely, repeated intranasal administration of DA GCS/DA-CD NPs into the right nostril significantly increased DA in the ipsilateral striatum. Fluorescent microscopy of olfactory bulb after acute administration of DA fluorescent-labeled GCS/DA-CD NPs into the right nostril showed the presence of NPs only in the right olfactory bulb and no morphological tissue damage occurred. Thus, these GCS based NPs could be potentially used as carriers for nose-to-brain DA delivery for the Parkinson's disease treatment. PMID:26032293

  13. Using Gelatin Nanoparticle Mediated Intranasal Delivery of Neuropeptide Substance P to Enhance Neuro-Recovery in Hemiparkinsonian Rats

    PubMed Central

    Xiang, Qi; Yu, Wen-Ze; Lin, Qian; Tian, Fu-Rong; Mao, Kai-Li; Lv, Chuan-Zhu; Wáng, Yi-Xiáng J.; Lu, Cui-Tao

    2016-01-01

    Purpose Intranasal administration of phospholipid-based gelatin nanoparticles (GNP) was prepared to investigate the neuro-recovery effects of neuropeptide Substance P (SP) on hemiparkinsonian rats. Methods The SP-loaded gelatin nanoparticles (SP-GNP) were prepared by a water-in-water emulsion method and possessed high stability, encapsulating efficiency and loading capacity. PC-12 cells were used to examine the growth enhancement of SP-GNP in vitro by MTT assays and flow cytometry (FCM). The therapeutic effects of SP-GNP on 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats were assessed by quantifying rotational behavior and the levels of tyrosine hydroxylase (TH), phosphorylated c-Jun protein (p-c-Jun) and Caspase-3 (Cas-3) expressed in substantia nigra (SN) region of hemiparkinsonian rats. Results PC-12 cells under SP-GNP treatment showed better cell viability and lower degree of apoptosis than those under SP solution treatment. Hemiparkinsonian rats under intranasal SP-GNP administration demonstrated better behavioral improvement, higher level of TH in SN along with much lower extent of p-c-Jun and Cas-3 than those under intranasal SP solution administration and intravenous SP-GNP administration. Conclusions With the advantages of GNP and nose-to-brain pathway, SP can be effectively delivered into the damaged SN region and exhibit its neuro-recovery function through the inhibition on JNK pathway and dopaminergic neuron apoptosis. PMID:26894626

  14. In vivo toxicity and immunogenicity of wheat germ agglutinin conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal delivery to the brain

    SciTech Connect

    Liu Qingfeng; Shao Xiayan; Chen Jie; Shen Yehong; Feng Chengcheng; Gao Xiaoling; Zhao Yue; Li Jingwei; Zhang Qizhi Jiang, Xinguo

    2011-02-15

    Biodegradable polymer-based nanoparticles have been widely studied to deliver therapeutic agents to the brain after intranasal administration. However, knowledge as to the side effects of nanoparticle delivery system to the brain is limited. The aim of this study was to investigate the in vivo toxicity and immunogenicity of wheat germ agglutinin (WGA) conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (WGA-NP) after intranasal instillation. Sprague-Dawley rats were intranasally given WGA-NP for 7 continuous days. Amino acid neurotransmitters, lactate dehydrogenase (LDH) activity, reduced glutathione (GSH), acetylcholine, acetylcholinesterase activity, tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin-8 (IL-8) in rat olfactory bulb (OB) and brain were measured to estimate the in vivo toxicity of WGA-NP. Balb/C mice were intranasally immunized by WGA-NP and then WGA-specific antibodies in serum and nasal wash were detected by indirect ELISA. WGA-NP showed slight toxicity to brain tissue, as evidenced by increased glutamate level in rat brain and enhanced LDH activity in rat OB. No significant changes in acetylcholine level, acetylcholinesterase activity, GSH level, TNF-{alpha} level and IL-8 level were observed in rat OB and brain for the WGA-NP group. WGA-specific antibodies in mice serum and nasal wash were not increased after two intranasal immunizations of WGA-NP. These results demonstrate that WGA-NP is a safe carrier system for intranasal delivery of therapeutic agents to the brain.

  15. Development of siRNA-loaded chitosan nanoparticles targeting Galectin-1 for the treatment of glioblastoma multiforme via intranasal administration.

    PubMed

    Van Woensel, Matthias; Wauthoz, Nathalie; Rosière, Rémi; Mathieu, Véronique; Kiss, Robert; Lefranc, Florence; Steelant, Brecht; Dilissen, Ellen; Van Gool, Stefaan W; Mathivet, Thomas; Gerhardt, Holger; Amighi, Karim; De Vleeschouwer, Steven

    2016-04-10

    Galectin-1 (Gal-1) is a naturally occurring galactose-binding lectin, which is overexpressed in glioblastoma multiforme (GBM). Gal-1 is associated with tumor progression, and is a potent immune suppressor in the tumor micro-environment. To inhibit Gal-1 in GBM, an effective therapy is required that reaches the central nervous system tumor, with limited systemic effects. In this study, we report for the first time that concentrated chitosan nanoparticle suspensions can deliver small interfering RNA (siRNA) into the central nervous system tumor within hours after intranasal administration. These nanoparticles are able to complex siRNA targeting Gal-1 to a high percentage, and protect them from RNAse degradation. Moreover, a successful intracellular delivery of anti-Gal-1 siRNA resulted in a decreased expression of Gal-1 in both murine and human GBM cells. Sequence specific RNAinterference, resulted in more than 50% Gal-1 reduction in tumor bearing mice. This study indicates that the intranasal pathway is an underexplored transport route for delivering siRNA-based therapies targeting Gal-1 in the treatment of GBM. PMID:26902800

  16. Robust neuroprotective effects of intranasally delivered iNOS siRNA encapsulated in gelatin nanoparticles in the postischemic brain.

    PubMed

    Kim, Il-Doo; Sawicki, Elizabeth; Lee, Hye-Kyung; Lee, Eun-Hwa; Park, Heon Joo; Han, Pyung-Lim; Kim, Kyekyoon Kevin; Choi, Hyungsoo; Lee, Ja-Kyeong

    2016-07-01

    The therapeutic efficacy of intranasal iNOS siRNA delivery was investigated in the postischemic rat brain after encapsulating on in gelatin nanoparticles (GNPs; diameter 188.0 ± 60.9 nm) cross-linked with 0.0667% glutaraldehyde (GA). Intranasally delivered GNPs were found in extracellular and intracellular compartments of many brain regions, including the olfactory bulb, cerebral cortex, and striatum at 1 hour after infusion and continued to be detected for days. Infarct volumes were markedly suppressed (maximal reduction to 42.1 ± 2.6%) at 2 days after 60 minutes of middle cerebral artery occlusion (MCAO) when iNOS siRNA/GNPs were delivered at 6 hours post-MCAO. In addition, this protective effect was manifested by reductions in neurological and behavioral deficits that were sustained for 2 weeks. Therapeutic potency of iNOS siRNA/GNPs was significantly greater and sustained longer than that of bare siRNA and prolonged and efficient iNOS by iNOS siRNA/GNP is responsible for the robust neuroprotective effect. PMID:26945975

  17. Induction of mucosal immune responses and protection of cattle against direct-contact challenge by intranasal delivery with foot-and-mouth disease virus antigen mediated by nanoparticles.

    PubMed

    Pan, Li; Zhang, Zhongwang; Lv, Jianliang; Zhou, Peng; Hu, Wenfa; Fang, Yuzhen; Chen, Haotai; Liu, Xinsheng; Shao, Junjun; Zhao, Furong; Ding, Yaozhong; Lin, Tong; Chang, Huiyun; Zhang, Jie; Zhang, Yongguang; Wang, Yonglu

    2014-01-01

    The aim of this study was to enhance specific mucosal, systemic, and cell-mediated immunity and to induce earlier onset of protection against direct-contact challenge in cattle by intranasal delivery of a nanoparticle-based nasal vaccine against type A foot-and-mouth disease (FMD). In this study, two kinds of nanoparticle-based nasal vaccines against type A FMD were designed: (1) chitosan-coated poly(lactic-co-glycolic acid) (PLGA) loaded with plasmid DNA (Chi-PLGA-DNA) and (2) chitosan-trehalose and inactivated foot-and-mouth disease virus (FMDV) (Chi-Tre-Inactivated). Cattle were immunized by an intranasal route with nanoparticles and then challenged for 48 hours by direct contact with two infected donor cattle per pen. Donors were inoculated intradermally in the tongue 48 hours before challenge, with 0.2 mL cattle-passaged FMDV. Serological and mucosal antibody responses were evaluated, and virus excretion and the number of contact infections were quantified. FMDV-specific secretory immunoglobulin (Ig)A (sIgA) antibodies in nasal washes were initially detected at 4 days postvaccination (dpv) with two kinds of nanoparticles. The highest levels of sIgA expression were observed in nasal washes, at 10 dpv, from animals with Chi-PLGA-DNA nanoparticles, followed by animals immunized once by intranasal route with a double dose of Chi-Tre-Inactivated nanoparticles and animals immunized by intranasal route three times with Chi-Tre-Inactivated nanoparticles (P<0.05). FMDV-specific IgA antibodies in serum showed a similar pattern. All animals immunized by intranasal route developed low levels of detectable IgG in serum at 10 dpv. Following stimulation with FMDV, the highest levels of proliferation were observed in splenocytes harvested from Chi-PLGA-DNA-immunized animals, followed by proliferation of cells harvested from Chi-Tre-Inactivated nanoparticle-immunized animals (P<0.05). Higher protection rates were associated with the highest sIgA antibody responses induced in

  18. Gelatin nanoparticles for use as a vaccine adjuvant in intranasal immunizations

    NASA Astrophysics Data System (ADS)

    Washington, Tara D.

    Vaccine adjuvants are used to increase the immune response in the delivery of subunit antigens. Currently the only FDA approved adjuvants are aluminum based and must be delivered parenterally. Nasal mucoadhesive vaccine administration can decrease cost, increase efficiency and increase patient compliance. The purpose of this study was to develop a mucoadhesive gelatin nanoparticle >500 nm in diameter that can be used to encapsulate a model protein antigen. The particles were prepared by nanoprecipitation of a gelatin solution with acetone. Thiol groups were incubated with gelatin to increase mucoadhesivness at 20, 40, and 80 mg per 1 gram of gelatin. The thiolation chemistry was characterized using UV-Vis and x-ray photoelectron spectroscopy (XPS). The total amount of sulfur present in the gelatin was determined to be 7.48, 30.53, and 46.75 mmol/gram respectively. However XPS analysis revealed that there was no substantial difference between surface sulfur content of the unmodified gelatin nanoparticles and the gelatin nanoparticles modified with 80 mg of iminothiolane. Particle size, charge and morphology were determined using laser light diffraction, atomic force microscopy microscopy and electron microscopy. The average diameter of the unmodified gelatin was 171 nm. The average diameter of the thiolated gelatin nanoparticles was 275 nm. The polydispersity index was approximately 0.61 +/- 0 .04 for all nanoparticles. The zeta (zeta) potential of the unmodified gelatin nanoparticles was -21.5 +/- 2.0 mV and the zeta-potential of the modified gelatin nanoparticles was -25.2 +/- 1.5, -27.3 +/- 0.8, and -28.6 +/- 3.0 mV for the 20, 40, and 80 thiolated gelatin nanoparticles. Particle encapsulation efficiency (EE) and release kinetics were conducted using fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) as a model antigen. The EE of the nanoparticles increased from 35.0% (unmodified gelatin) to 82.5% (highest modified gelatin). Particles encapsulated with

  19. The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticles.

    PubMed

    Zhang, Lili; Bai, Ru; Liu, Ying; Meng, Li; Li, Bai; Wang, Liming; Xu, Ligeng; Le Guyader, Laurent; Chen, Chunying

    2012-08-01

    Increasing production and application of metallic nanomaterials are likely to result in the release of these particles into the environment. These released nanoparticles may enter into the lungs and the central nervous system (CNS) directly through inhalation, which therefore poses a potential risk to human health. Herein, we focus on the systemic toxicity and potential influence on the neurotransmitter secretion of intranasally instilled copper nanoparticles (23.5 nm) at three different doses. Copper nanoparticle-exposed mice exhibit pathological lesions at different degrees in certain tissues and especially in lung tissue as revealed by histopathology and transmission electron microscopy (TEM) observations. Inductively-coupled plasma mass spectrometry (ICP-MS) results show that the liver, lung and olfactory bulb are the main tissues in which the copper concentrations increased significantly after exposure to a higher level of Cu nanoparticles (40 mg/kg of body weight). The secretion levels of various neurotransmitters changed as well in some brain regions, especially in the olfactory bulb. Our results indicate that the intranasally instilled copper nanoparticles not only cause the lesions where the copper accumulates, but also affect the neurotransmitter levels in the brain. PMID:21657985

  20. Intranasal Piperine-Loaded Chitosan Nanoparticles as Brain-Targeted Therapy in Alzheimer's Disease: Optimization, Biological Efficacy, and Potential Toxicity.

    PubMed

    Elnaggar, Yosra S R; Etman, Samar M; Abdelmonsif, Doaa A; Abdallah, Ossama Y

    2015-10-01

    Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity. PMID:26147711

  1. Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity

    PubMed Central

    Phua, Kyle K. L.; Staats, Herman F.; Leong, Kam W.; Nair, Smita K.

    2014-01-01

    Direct in vivo administration of messenger RNA (mRNA) delivered in both naked and nanoparticle formats are actively investigated because the use of dendritic cells transfected ex vivo with mRNA for cancer therapy is expensive and needs significant infrastructure. Notably, intravenous and subcutaneous injections are the only routes of administration tested for mRNA nanoparticle tumor vaccination. In this report, we demonstrate that tumor immunity can be achieved via nasal administration of mRNA. Mice nasally immunized with mRNA delivered in nanoparticle format demonstrate delayed tumor progression in both prophylactic and therapeutic immunization models. The observed tumor immunity correlates with splenic antigen-specific CD8+ T cells and is achieved only when mRNA is delivered in nanoparticle but not in naked format. In conclusion, we demonstrate, as a proof-of-concept, a non-invasive approach to mRNA tumor vaccination, increasing its potential as a broadly applicable and off-the-shelf therapy for cancer treatment. PMID:24894817

  2. "Application of Box-Behnken design for optimization and development of quetiapine fumarate loaded chitosan nanoparticles for brain delivery via intranasal route* ".

    PubMed

    Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

    2016-08-01

    The objective of the present investigation was to optimize and develop quetiapine fumarate (QF) loaded chitosan nanoparticles (QF-NP) by ionic gelation method using Box-Behnken design. Three independent variables viz., X1-Concentration of chitosan, X2-Concentration of sodium tripolyphosphate and X3-Volume of sodium tripolyphosphate were taken to investigate their effect on dependent variables (Y1-Size, Y2-PDI and Y3-%EE). Optimized formula of QF-NP was selected from the design space which was further evaluated for physicochemical, morphological, solid state characterization, nasal diffusion and in-vivo distribution for brain targeting following non-invasive intranasal administration. The average particle size, PDI, %EE and nasal diffusion were found to be 131.08±7.45nm, 0.252±0.064, 89.93±3.85% and 65.24±5.26% respectively. Neither toxicity nor structural damage on nasal mucosa was observed upon histopathological examination. Significantly higher brain/blood ratio and 2 folds higher nasal bioavailability in brain with QF-NP in comparison to drug solution following intranasal administration revealed preferential nose to brain transport bypassing blood-brain barrier and prolonged retention of QF at site of action suggesting superiority of chitosan as permeability enhancer. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery. PMID:27130654

  3. Brain Transit and Ameliorative Effects of Intranasally Delivered Anti-Amyloid-β Oligomer Antibody in 5XFAD Mice

    PubMed Central

    Xiao, Chun; Davis, Francesca J.; Chauhan, Balwantsinh C.; Viola, Kirsten L.; Lacor, Pascale N.; Velasco, Pauline T.; Klein, William L.; Chauhan, Neelima B.

    2013-01-01

    Alzheimer’s disease (AD) is a global health crisis with limited treatment options. Despite major advances in neurotherapeutics, poor brain penetration due to the blood-brain barrier continues to pose a big challenge in overcoming the access of therapeutics to the central nervous system. In that regard, the non-invasive intranasal route of brain targeting is gaining considerable attention. The nasal mucosa offers a large surface area, rapid absorption, and avoidance of first-pass metabolism increasing drug bioavailability with less systemic side effects. Intranasal delivery is known to utilize olfactory, rostral migratory stream, and trigeminal routes to reach the brain. This investigation confirmed that intranasal delivery of oligomeric amyloid-β antibody (NU4) utilized all three routes to enter the brain with a resident time of 96 hours post single bolus intranasal administration, and showed evidence of perikaryal and parenchymal uptake of NU4 in 5XFAD mouse brain, confirming the intranasal route as a non-invasive and efficient way of delivering therapeutics to the brain. In addition, this study demonstrated that intranasal delivery of NU4 antibody lowered cerebral amyloid-β and improved spatial learning in 5XFAD mice. PMID:23542865

  4. Brain-targeted distribution and high retention of silver by chronic intranasal instillation of silver nanoparticles and ions in Sprague-Dawley rats.

    PubMed

    Wen, Ruoxi; Yang, Xiaoxi; Hu, Ligang; Sun, Cheng; Zhou, Qunfang; Jiang, Guibin

    2016-03-01

    The wide applications of silver nanoparticles (AgNPs) have been concerned regarding their unintentional toxicities. Different exposure modes may cause distinct accumulation, retention and elimination profiles, which are closely related with their toxicities. Unlike silver accumulation profiles through other regular administration modes, the biodistribution, accumulation and elimination of AgNPs by intranasal instillation are not fully understood. This study conducted intranasal instillation of polyvinylpyrrolidone-coated AgNPs in neonatal Sprague-Dawley rats at doses of 1 and 0.1 mg kg(-1) day(-1) for 4 and 12 weeks, respectively. The 4-week recovery was also designed after the 12-week exposure. Silver concentrations in the main tissues or organs were periodically monitored. Parallel exposures using silver ion were performed for the comparative studies. No physiological alterations were observed in AgNP exposures. In comparison, 1 mg kg(-1) day(-1) silver ions decreased body weight gain and caused mortality of 18.2%, showing ionic silver had a relatively higher toxicity than AgNPs. A relatively higher silver accumulation was observed in silver ion groups than AgNP groups. The silver ion release could not fully explain silver accumulation in AgNP exposures, showing silver distribution caused by particulate silver occurred in vivo. The highest silver concentration was in the liver at week 4, while it shifted to the brain after a 12-week exposure. Dose-related silver accumulation occurred for both AgNP and silver ion groups. The time course revealed a uniquely high concentration and retention of brain silver, implying chronic intranasal instillation caused brain-targeted silver accumulation. These findings provided substantial evidence on the potential neuronal threat from the intranasal administration of AgNPs or silver colloid-based products. PMID:26584724

  5. Gelatin nanoparticle-mediated intranasal delivery of substance P protects against 6-hydroxydopamine-induced apoptosis: an in vitro and in vivo study

    PubMed Central

    Lu, Cui-Tao; Jin, Rong-Rong; Jiang, Yi-Na; Lin, Qian; Yu, Wen-Ze; Mao, Kai-Li; Tian, Fu-Rong; Zhao, Ya-Ping; Zhao, Ying-Zheng

    2015-01-01

    Background The aim of this study was to investigate the protective role of intranasally administered substance P-loaded gelatin nanoparticles (SP-GNPs) against 6-hydroxydopamine (6-OHDA)-induced apoptosis in vitro and in vivo, and to provide a new strategy for treating brain pathology, such as Parkinson’s disease. Methods SP-GNPs were prepared by a water-in-water emulsion method, and their stability, encapsulating efficiency, and loading capacity were evaluated. PC-12 cells were used to examine the enhancement of growth and inhibition of apoptosis by SP-GNPs in vitro using MTT assays. In the in vivo study, hemiparkinsonian rats were created by intracerebroventricular injection of 6-OHDA. The rats then received intranasal SP-GNPs daily for 2 weeks. Functional improvement was assessed by quantifying rotational behavior, and the degree of apoptosis was assessed by immunohistochemical staining for caspase-3 in the substantia nigra region. Results PC-12 cells with 6-OHDA-induced disease treated with SP-GNPs showed higher cell viability than their untreated counterparts, and cell viability increased as the concentration of substance P (SP) increased, indicating that SP could enhance cell growth and inhibit the cell apoptosis induced by 6-OHDA. Rats with 6-OHDA-induced hemiparkinsonism treated with SP-GNPs made fewer rotations and showed less staining for caspase-3 than their counterparts not treated with SP, indicating that SP protects rats with 6-OHDA-induced hemiparkinsonism from apoptosis and therefore demonstrates their functional improvement. Conclusion Intranasal delivery of SP-GNPs protects against 6-OHDA-induced apoptosis both in vitro and in vivo. PMID:25897205

  6. Intranasal Glucagon

    PubMed Central

    2014-01-01

    Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia. PMID:25385946

  7. Immune response elicited by an intranasally delivered HBsAg low-dose adsorbed to poly-ε-caprolactone based nanoparticles.

    PubMed

    Jesus, Sandra; Soares, Edna; Costa, João; Borchard, Gerrit; Borges, Olga

    2016-05-17

    Among new strategies to increase hepatitis B virus (HBV) vaccination, especially in developing countries, the development of self-administered vaccines is considered one of the most valuable. Nasal vaccination using polymeric nanoparticles (NPs) constitutes a valid approach to this issue. In detail, poly-ε-caprolactone (PCL)/chitosan NPs present advantages as a mucosal vaccine delivery system: the high resistance of PCL against degradation in biological fluids and the mucoadhesive and immunostimulatory properties of chitosan. In vitro studies revealed these NPs were retained in a mucus-secreting pulmonary epithelial cell line and were capable of entering into differentiated epithelial cells. The intranasal (IN) administration of 3 different doses of HBsAg (1.5μg, 5μg and 10μg) adsorbed on a fixed amount of PCL/chitosan NPs (1614μg) generated identical titers of serum anti-HBsAg IgG and anti-HBsAg sIgA in mice nasal secretions. Besides other factors, the NP surface characteristics, particularly, zeta potential differences among the administered formulations are believed to be implicated in the outcome of the immune response generated. PMID:26976502

  8. Application of quality by design approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles: Effect on formulation and characterization parameters.

    PubMed

    Shah, Brijesh; Khunt, Dignesh; Bhatt, Himanshu; Misra, Manju; Padh, Harish

    2015-10-12

    In the present investigation, Quality by Design (QbD) approach was applied on the development and optimization of solid lipid nanoparticle (SLN) formulation of hydrophilic drug rivastigmine (RHT). RHT SLN were formulated by homogenization and ultrasonication method using Compritol 888 ATO, tween-80 and poloxamer-188 as lipid, surfactant and stabilizer respectively. The effect of independent variables (X1 - drug: lipid ratio, X2 - surfactant concentration and X3 - homogenization time) on quality attributes of SLN i.e. dependent variables (Y1 - size, Y2 - PDI and Y3 - %entrapment efficiency (%EE)) were investigated using 3(3) factorial design. Multiple linear regression analysis and ANOVA were employed to indentify and estimate the main effect, 2FI, quadratic and cubic effect. Optimized RHT SLN formula was derived from an overlay plot on which further effect of probe sonication was evaluated. Final RHT SLN showed narrow size distribution (PDI- 0.132±0.016) with particle size of 82.5±4.07 nm and %EE of 66.84±2.49. DSC and XRD study showed incorporation of RHT into imperfect crystal lattice of Compritol 888 ATO. In comparison to RHT solution, RHT SLN showed higher in-vitro and ex-vivo diffusion. The diffusion followed Higuchi model indicating drug diffusion from the lipid matrix due to erosion. Histopathology study showed intact nasal mucosa with RHT SLN indicating safety of RHT SLN for intranasal administration. PMID:26143262

  9. Nanoparticle conjugation enhances the immunomodulatory effects of intranasally delivered CpG in house dust mite-allergic mice

    SciTech Connect

    Ballester, Marie; Jeanbart, Laura; de Titta, Alexandre; Nembrini, Chiara; Marsland, Benjamin J.; Hubbell, Jeffrey A.; Swartz, Melody A.

    2015-09-21

    An emerging strategy in preventing and treating airway allergy consists of modulating the immune response induced against allergens in the lungs. CpG oligodeoxynucleotides have been investigated in airway allergy studies, but even if promising, efficacy requires further substantiation. We investigated the effect of pulmonary delivery of nanoparticle (NP)-conjugated CpG on lung immunity and found that NP-CpG led to enhanced recruitment of activated dendritic cells and to Th1 immunity compared to free CpG. We then evaluated if pulmonary delivery of NP-CpG could prevent and treat house dust mite-induced allergy by modulating immunity directly in lungs. When CpG was administered as immunomodulatory therapy prior to allergen sensitization, we found that NP-CpG significantly reduced eosinophilia, IgE levels, mucus production and Th2 cytokines, while free CpG had only a moderate effect on these parameters. In a therapeutic setting where CpG was administered after allergen sensitization, we found that although both free CpG and NP-CpG reduced eosinophilia and IgE levels to the same extent, NP conjugation of CpG significantly enhanced reduction of Th2 cytokines in lungs of allergic mice. Taken together, these data highlight benefits of NP conjugation and the relevance of NP-CpG as allergen-free therapy to modulate lung immunity and treat airway allergy.

  10. Nanoparticle conjugation enhances the immunomodulatory effects of intranasally delivered CpG in house dust mite-allergic mice.

    PubMed

    Ballester, Marie; Jeanbart, Laura; de Titta, Alexandre; Nembrini, Chiara; Marsland, Benjamin J; Hubbell, Jeffrey A; Swartz, Melody A

    2015-01-01

    An emerging strategy in preventing and treating airway allergy consists of modulating the immune response induced against allergens in the lungs. CpG oligodeoxynucleotides have been investigated in airway allergy studies, but even if promising, efficacy requires further substantiation. We investigated the effect of pulmonary delivery of nanoparticle (NP)-conjugated CpG on lung immunity and found that NP-CpG led to enhanced recruitment of activated dendritic cells and to Th1 immunity compared to free CpG. We then evaluated if pulmonary delivery of NP-CpG could prevent and treat house dust mite-induced allergy by modulating immunity directly in lungs. When CpG was administered as immunomodulatory therapy prior to allergen sensitization, we found that NP-CpG significantly reduced eosinophilia, IgE levels, mucus production and Th2 cytokines, while free CpG had only a moderate effect on these parameters. In a therapeutic setting where CpG was administered after allergen sensitization, we found that although both free CpG and NP-CpG reduced eosinophilia and IgE levels to the same extent, NP conjugation of CpG significantly enhanced reduction of Th2 cytokines in lungs of allergic mice. Taken together, these data highlight benefits of NP conjugation and the relevance of NP-CpG as allergen-free therapy to modulate lung immunity and treat airway allergy. PMID:26387548

  11. Nanoparticle conjugation enhances the immunomodulatory effects of intranasally delivered CpG in house dust mite-allergic mice

    PubMed Central

    Ballester, Marie; Jeanbart, Laura; de Titta, Alexandre; Nembrini, Chiara; Marsland, Benjamin J.; Hubbell, Jeffrey A.; Swartz, Melody A.

    2015-01-01

    An emerging strategy in preventing and treating airway allergy consists of modulating the immune response induced against allergens in the lungs. CpG oligodeoxynucleotides have been investigated in airway allergy studies, but even if promising, efficacy requires further substantiation. We investigated the effect of pulmonary delivery of nanoparticle (NP)-conjugated CpG on lung immunity and found that NP-CpG led to enhanced recruitment of activated dendritic cells and to Th1 immunity compared to free CpG. We then evaluated if pulmonary delivery of NP-CpG could prevent and treat house dust mite-induced allergy by modulating immunity directly in lungs. When CpG was administered as immunomodulatory therapy prior to allergen sensitization, we found that NP-CpG significantly reduced eosinophilia, IgE levels, mucus production and Th2 cytokines, while free CpG had only a moderate effect on these parameters. In a therapeutic setting where CpG was administered after allergen sensitization, we found that although both free CpG and NP-CpG reduced eosinophilia and IgE levels to the same extent, NP conjugation of CpG significantly enhanced reduction of Th2 cytokines in lungs of allergic mice. Taken together, these data highlight benefits of NP conjugation and the relevance of NP-CpG as allergen-free therapy to modulate lung immunity and treat airway allergy. PMID:26387548

  12. Nanoparticle conjugation enhances the immunomodulatory effects of intranasally delivered CpG in house dust mite-allergic mice

    DOE PAGESBeta

    Ballester, Marie; Jeanbart, Laura; de Titta, Alexandre; Nembrini, Chiara; Marsland, Benjamin J.; Hubbell, Jeffrey A.; Swartz, Melody A.

    2015-09-21

    An emerging strategy in preventing and treating airway allergy consists of modulating the immune response induced against allergens in the lungs. CpG oligodeoxynucleotides have been investigated in airway allergy studies, but even if promising, efficacy requires further substantiation. We investigated the effect of pulmonary delivery of nanoparticle (NP)-conjugated CpG on lung immunity and found that NP-CpG led to enhanced recruitment of activated dendritic cells and to Th1 immunity compared to free CpG. We then evaluated if pulmonary delivery of NP-CpG could prevent and treat house dust mite-induced allergy by modulating immunity directly in lungs. When CpG was administered as immunomodulatorymore » therapy prior to allergen sensitization, we found that NP-CpG significantly reduced eosinophilia, IgE levels, mucus production and Th2 cytokines, while free CpG had only a moderate effect on these parameters. In a therapeutic setting where CpG was administered after allergen sensitization, we found that although both free CpG and NP-CpG reduced eosinophilia and IgE levels to the same extent, NP conjugation of CpG significantly enhanced reduction of Th2 cytokines in lungs of allergic mice. Taken together, these data highlight benefits of NP conjugation and the relevance of NP-CpG as allergen-free therapy to modulate lung immunity and treat airway allergy.« less

  13. Aqueous medium induced optical transitions in cerium oxide nanoparticles

    SciTech Connect

    Inerbaev, Talgat M.; Karakoti, Ajay S.; Kuchibhatla, S. V. N. T.; Kumar, Amit; Masunov, Artem E.; Seal, Sudipta

    2015-03-07

    Experimental and theoretical investigations were performed to investigate the effect of water on optical properties of nanoceria as a function of Ce3+ concentration. Theoretical studies based on density functional plane-wave calculations reveal that the indirect optical transitions in bare ceria nanoparticles are red-shifted with an increase in the concentration of Ce3+. However, ceria nanoparticles model with adsorbed water molecules show a blue shift in the indirect optical spectra under identical conditions. Direct optical transitions are almost independent of Ce3+ concentration but show a pronounced blue shift in the aqueous environment relative to the bare nanoparticles. The theoretical study is consistent with our experimental observation in difference of shift behaviour in bare and aqueous suspended ceria nanoparticles. This change from red- to blue-shift in indirect optical transitions is associated with the polarization effect of water molecules on f-electron states.

  14. Transition metal-substituted cobalt ferrite nanoparticles for biomedical applications.

    PubMed

    Sanpo, Noppakun; Berndt, Christopher C; Wen, Cuie; Wang, James

    2013-03-01

    Transition metals of copper, zinc, chromium and nickel were substituted into cobalt ferrite nanoparticles via a sol-gel route using citric acid as a chelating agent. The microstructure and elemental composition were characterized using scanning electron microscopy combined with energy-dispersive X-ray spectroscopy. Phase analysis of transition metal-substituted cobalt ferrite nanoparticles was performed via X-ray diffraction. Surface wettability was measured using the water contact angle technique. The surface roughness of all nanoparticles was measured using profilometry. Moreover, thermogravimetric analysis and differential scanning calorimetry were performed to determine the temperature at which the decomposition and oxidation of the chelating agents took place. Results indicated that the substitution of transition metals influences strongly the microstructure, crystal structure and antibacterial property of the cobalt ferrite nanoparticles. PMID:23137676

  15. Order-disorder transition of aragonite nanoparticles in nacre.

    PubMed

    Huang, Zaiwang; Li, Xiaodong

    2012-07-13

    Understanding nacre's bottom-up biomineralization mechanism, particularly, how individual aragonite platelets are formed, has long remained elusive due to its crystallographic peculiarity and structural complexity. Here we report that crystallographic order-disorder transition can be triggered within individual aragonite platelets in pristine nacre by means of heat treatment and/or inelastic deformation, offering a unique opportunity to discriminate mysterious aragonite nanoparticles in transmission electron microscopy. Our findings unambiguously uncover why aragonite nanoparticles in pristine nacre have long been inaccessible under TEM observation, which is attributed to the monocrystal-polycrystal duality of the aragonite platelet. The underlying physical mechanism for why an individual aragonite platelet adopts a highly oriented attachment of aragonite nanoparticles as its crystallization pathway is, for the first time, explained in terms of the thermodynamics. The finding of an order-disorder transition in nacre provides a new perspective for understanding the formation for other biominerals. PMID:23030176

  16. Semimetal to Semiconductor Transition in Carbon Nanoparticles

    SciTech Connect

    Lopinski, G.P.; Merkulov, V.I.; Lannin, J.S.

    1998-05-01

    Electron energy loss spectroscopy (EELS) has been used to observe size dependent changes in the electronic states of isolated, nanocrystalline carbon particles supported on SiO{sub 2} substrates. The structure and size distribution of the particles have been characterized by Raman scattering, Auger electron spectroscopy, and electron microscopy. EELS observations indicate that a semimetal to semiconductor transition occurs for particles smaller than 1nm. In addition, hydrogen adsorption is found to significantly alter the electronic states, demonstrating that both finite size and dangling bond effects modify the properties of small carbon nanocrystallites. {copyright} {ital 1998} {ital The American Physical Society}

  17. Size dependence of phase transitions in aerosol nanoparticles

    PubMed Central

    Cheng, Yafang; Su, Hang; Koop, Thomas; Mikhailov, Eugene; Pöschl, Ulrich

    2015-01-01

    Phase transitions of nanoparticles are of fundamental importance in atmospheric sciences, but current understanding is insufficient to explain observations at the nano-scale. In particular, discrepancies exist between observations and model predictions of deliquescence and efflorescence transitions and the hygroscopic growth of salt nanoparticles. Here we show that these discrepancies can be resolved by consideration of particle size effects with consistent thermodynamic data. We present a new method for the determination of water and solute activities and interfacial energies in highly supersaturated aqueous solution droplets (Differential Köhler Analysis). Our analysis reveals that particle size can strongly alter the characteristic concentration of phase separation in mixed systems, resembling the influence of temperature. Owing to similar effects, atmospheric secondary organic aerosol particles at room temperature are expected to be always liquid at diameters below ~20 nm. We thus propose and demonstrate that particle size should be included as an additional dimension in the equilibrium phase diagram of aerosol nanoparticles. PMID:25586967

  18. The superspin glass transition in zinc ferrite nanoparticles

    NASA Astrophysics Data System (ADS)

    Kaman, O.; Kořínková, T.; Jirák, Z.; Maryško, M.; Veverka, M.

    2015-05-01

    Nanoparticles of the ZnxFe3-xO4 (x = 0.3-0.4) spinel phase having 5 and 15 nm size were synthesized by thermal decomposition of the respective acetylacetonates in a high boiling-point solvent employing surfactants. The collective behaviour of the nanoparticles was probed by dc and ac magnetic measurements of tightly compressed pellets of the particles and silica coated products which were prepared by reverse microemulsion technique. The assembly of bare 5 nm particles remains in the superparamagnetic state with Curie-Weiss characteristics down to 35 K when a rather sharp freezing of superspins is detected. The larger particles show a similar but more diffusive transition at 250 K. The cores encapsulated into the diamagnetic silica do not exhibit glassy freezing.

  19. Structural transitions in alumina nanoparticles by heat treatment

    NASA Astrophysics Data System (ADS)

    Kaur, Nirmal; Khanna, Atul; Chen, Banghao; González, Fernando

    2016-05-01

    γ-alumina nanoparticles were annealed sequentially at 800°C, 950°C and 1100°C and structural transitions as a function of heat treatment were studied by X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and 27Al Magic Angle Spinning Nuclear Magnetic Resonance (MAS-NMR) methods.. XRD studies found that γ-Al2O3 is stable upto a temperature of at least 950°C and transforms to the thermodynamically stable α-phase after annealing at 1100°C. MAS-NMR revealed that γ-alumina contains AlO4 and AlO6 structural units in the ratio 1: 2, while α-phase contains only AlO6 units. DSC confirmed that γ → α transition initiates at 1060°C.

  20. Pitfalls of intranasal naloxone.

    PubMed

    Zuckerman, Matthew; Weisberg, Stacy N; Boyer, Edward W

    2014-01-01

    We present a case of failed prehospital treatment of fentanyl induced apnea with intranasal (IN) naloxone. While IN administration of naloxone is becoming more common in both lay and pre-hospital settings, older EMS protocols utilized intravenous (IV) administration. Longer-acting, higher potency opioids, such as fentanyl, may not be as easily reversed as heroin, and studies evaluating IN administration in this population are lacking. In order to contribute to our understanding of the strengths and limitations of IN administration of naloxone, we present a case where it failed to restore ventilation. We also describe peer reviewed literature that supports the use of IV naloxone following heroin overdose and explore possible limitations of generalizing this literature to opioids other than heroin and to IN routes of administration. PMID:24830404

  1. Intranasal scopolamine preparation and method

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi (Inventor); Cintron, Nitza M. (Inventor)

    1991-01-01

    A new method and preparation for intranasal delivery of scopolamine provides a safe and effective treatment for motion sickness and other conditions requiring anticholinergic therapy. The preparation can be in the form of aqueous nasal drops, mist spray, gel or oinment. Intranasal delivery of scopolamine has similar bioavailability and effect of intravenous delivery and is far superior to oral dosage. Scopolamine is prepared in a buffered saline solution at the desired dosage rate for effective anticholinergic response.

  2. Intranasal therapies for acute seizures.

    PubMed

    Kälviäinen, Reetta

    2015-08-01

    Most seizure emergencies occur outside of the hospital, and there is a need for treatment interventions that can be administered quickly and safely by nonclinical caregivers. Intranasal benzodiazepine administration does not require intravenous access and offers rapid seizure cessation. Intranasal midazolam is faster at aborting seizure activity than rectal diazepam and quicker to administer than intravenous diazepam. Although time to seizure cessation varies from study to study, intranasal midazolam is efficacious when administered not only by emergency department personnel but also by paramedics and caregivers in out-of-hospital and home settings. Absorption of midazolam intranasal formulations appears to be relatively rapid compared to diazepam formulations. Its shorter elimination half-life may also be beneficial in that patients may more quickly return to normal function because of rapid offset of effect. On the other hand, the faster rate of elimination of midazolam may expose patients to a higher rate of seizure recurrence compared with diazepam. Two diazepam formulations and one midazolam formulation are being currently developed for intranasal use. This article is part of a Special Issue entitled "Status Epilepticus". PMID:26022649

  3. Formulation and Optimization of Polymeric Nanoparticles for Intranasal Delivery of Lorazepam Using Box-Behnken Design: In Vitro and In Vivo Evaluation

    PubMed Central

    Sharma, Deepak; Maheshwari, Dipika; Rana, Ravish; Bhatia, Shanu; Singh, Manisha; Gabrani, Reema; Sharma, Sanjeev K.; Ali, Javed; Sharma, Rakesh Kumar; Dang, Shweta

    2014-01-01

    The aim of the present study was to optimize lorazepam loaded PLGA nanoparticles (Lzp-PLGA-NPs) by investigating the effect of process variables on the response using Box-Behnken design. Effect of four independent factors, that is, polymer, surfactant, drug, and aqueous/organic ratio, was studied on two dependent responses, that is, z-average and % drug entrapment. Lzp-PLGA-NPs were successfully developed by nanoprecipitation method using PLGA as polymer, poloxamer as surfactant and acetone as organic phase. NPs were characterized for particle size, zeta potential, % drug entrapment, drug release behavior, TEM, and cell viability. Lzp-PLGA-NPs were characterized for drug polymer interaction using FTIR. The developed NPs showed nearly spherical shape with z-average 167–318 d·nm, PDI below 0.441, and −18.4 mV zeta potential with maximum % drug entrapment of 90.1%. In vitro drug release behavior followed Korsmeyer-Peppas model and showed initial burst release of 21.7 ± 1.3% with prolonged drug release of 69.5 ± 0.8% from optimized NPs up to 24 h. In vitro drug release data was found in agreement with ex vivo permeation data through sheep nasal mucosa. In vitro cell viability study on Vero cell line confirmed the safety of optimized NPs. Optimized Lzp-PLGA-NPs were radiolabelled with Technitium-99m for scintigraphy imaging and biodistribution studies in Sprague-Dawley rats to establish nose-to-brain pathway. PMID:25126544

  4. Electric field effects on phase transitions in the 8CB liquid crystal doped with ferroelectric nanoparticles

    NASA Astrophysics Data System (ADS)

    Lin, Y.; Daoudi, A.; Segovia-Mera, A.; Dubois, F.; Legrand, C.; Douali, R.

    2016-06-01

    The influence of a low ac electric field on phase transitions is discussed in the case of a nematic liquid crystal 4 -n -octyl-4 '-cyanobiphenyl (8CB) doped with Sn2P2S6 ferroelectric nanoparticles. The phase-transition temperatures obtained from temperature-dependent dielectric measurements were higher than those determined by the calorimetric method. This difference is explained by the presence of the measuring electric field which induces two effects. The first one is the amplification of the interactions between the nanoparticle polarization and the liquid-crystal order parameter. The second one is the field-induced disaggregation or aggregation process at high nanoparticle concentrations.

  5. Surface free energy of alkali and transition metal nanoparticles

    NASA Astrophysics Data System (ADS)

    Aqra, Fathi; Ayyad, Ahmed

    2014-09-01

    This paper addresses an interesting issue on the surface free energy of metallic nanoparticles as compared to the bulk material. Starting from a previously reported equation, a theoretical model, that involves a specific term for calculating the cohesive energy of nanoparticle, is established in a view to describe the behavior of surface free energy of metallic nanoparticles (using different shapes of particle: sphere, cube and disc). The results indicate that the behavior of surface energy is very appropriate for spherical nanoparticle, and thus, it is the most realistic shape of a nanoparticle. The surface energy of copper, silver, gold, platinum, tungsten, molybdenum, tantalum, paladium and alkali metallic nanoparticles is only prominent in the nanoscale size, and it decreases with the decrease of nanoparticle size. Thus, the surface free energy plays a more important role in determining the properties of nanoparticles than in bulk materials. It differs from shape to another, and falls down as the number of atoms (nanoparticle size) decreases. In the case of spherical nanoparticles, the onset of the sharp decrease in surface energy is observed at about 110 atom. A decrease of 16% and 45% in surface energy is found by moving from bulk to 110 atom and from bulk to 5 atom, respectively. The predictions are consistent with the reported data.

  6. Calcitonin intranasal--unigene: Salcatonin intranasal--unigene.

    PubMed

    2004-01-01

    An intranasal spray formulation of recombinant salmon calcitonin [salcatonin] is in development with Unigene Laboratories as therapy for postmenopausal osteoporosis. Calcitonin is an endogenous polypeptide hormone that regulates calcium and bone metabolism. It is produced by the parafollicular cells of the thyroid gland in humans and other species. Calcitonin inhibits bone loss through the suppression of osteoclast activity. Salmon calcitonin is approximately 40-50 times more potent than natural human calcitonin at inhibiting osteoclast function. It can be obtained naturally from salmon or can be synthesised with the same chemical structure. Calcitonin was originally available only as an injectable formulation, but in recent years more convenient formulations have become available. Unigene is actively seeking to license its intranasal calcitonin product in Europe and other territories outside the US. nigene licensed its intranasal calcitonin product to Upsher-Smith Laboratories in December 2002, under a $US10 million exclusive US licensing agreement. Under the terms of the agreement, Unigene received an upfront payment of $US3 million from Upsher-Smith and will be eligible to receive milestone payments and royalty payments on product sales. Unigene will be responsible for manufacturing the product at its Boonton facility in New Jersey, USA, and will sell finished calcitonin product to Upsher-Smith. Upsher-Smith will package, market and distribute the product nationwide. Unigene granted an exclusive license to Faran Laboratories in September 2003 for its intranasal calcitonin osteoporosis product in Greece. Unigene will sell the finished product to Faran, who will promote and market it throughout the country after Unigene obtains European regulatory approval and local pricing approval. Unigene will receive an upfront payment and is eligible to receive milestone payments prior to product launch. Faran will pay Unigene a fixed price for each unit of product received

  7. Effect of a dimer of nanoparticles on the linewidth of forbidden E2 transitions

    NASA Astrophysics Data System (ADS)

    Guzatov, D. V.; Klimov, V. V.

    2016-07-01

    In the framework of classical electrodynamics we have obtained and investigated analytical expressions for the radiation linewidth of forbidden E2 transitions in an atom located near a dimer of spherical particles. It is shown that the material of particles, their location and size have a significant effect on the linewidth of the E2 transition in the atom. It is found that in the gap between metal spherical nanoparticles, the linewidth of E2 transitions in the atom can take on substantially larger values than in the case of an atom near a single metal nanoparticle.

  8. [Intranasal opioids for acute pain].

    PubMed

    Añez Simón, C; Rull Bartomeu, M; Rodríguez Pérez, A; Fuentes Baena, A

    2006-12-01

    Intranasal drug administration is an easy, well-tolerated, noninvasive transmucosal route that avoids first-pass metabolism in the liver. The nasal mucosa provides an extensive, highly vascularized surface of pseudostratified ciliated epithelium. It secretes mucus that is subjected to mucociliary movement that can affect the time of contact between the drug and the surface. Absorption is influenced by anatomical and physiological factors as well as by properties of the drug and the delivery system. We review the literature on intranasal administration of fentanyl, meperidine, diamorphine, and butorphanol to treat acute pain. The adverse systemic effects are similar to those described for intravenous administration, the most common being drowsiness, nausea, and vomiting. Local effects reported are a burning sensation with meperidine and a bad taste. PMID:17302079

  9. Silver nanoparticles enhanced multichannel transition luminescence of Pr3+ in heavy metal germanium tellurite glasses

    NASA Astrophysics Data System (ADS)

    Du, Y. Y.; Chen, B. J.; Pun, E. Y. B.; Wang, Z. Q.; Zhao, X.; Lin, H.

    2015-01-01

    Enhanced luminescence of Pr3+ was observed in heavy metal germanium tellurite (NZPGT) glasses containing silver nanoparticles. Long-time annealing at 300 °C yield spherical and well-dispersed Ag nanoparticles with ~4 nm diameter as evidenced by transmission electron microscope (TEM). Multichannel transition luminescence intensity of Pr3+ in Ag nanoparticles embedded glasses grows by ~36% in comparison with the glasses without silver doping, which provides a new approach to improve energy conversion efficiency of GaAsAl solar cells. Hypersensitive probe Eu3+ reveals that electric field around rare-earth ions is remarkably enhanced due to the presence of Ag nanoparticles in the glass matrix, resulting in the luminescence intensification of Pr3+ in NZPGT glasses embedded with Ag nanoparticles.

  10. Pressure-induced Phase Transition in Thiol-capped CdTe Nanoparticles

    SciTech Connect

    Wu, F; Zaug, J; Young, C; Zhang, J Z

    2006-11-29

    Phase transitions for CdTe nanoparticles (NPs) under high pressure up to 37.0 GPa have been studied using fluorescence measurements. The phase transition from cinnarbar to rocksalt phase has been observed in CdTe NPs solution at 5.8 GPa, which is much higher than the phase transition pressure of bulk CdTe (3.8 GPa) and that of CdTe NPs in solid form (0.8 GPa). CdTe NPs solution therefore shows elevated phase transition pressure and enhanced stability against pressure compared with bulk CdTe and CdTe NPs in solid forms. The enhanced stability of CdTe NPs solution has been attributed to possible shape change in the phase transition and/or inhomogeneous strains in nanoparticle solutions.

  11. Thermally induced solid-solid structural transition of copper nanoparticles through direct geometrical conversion

    NASA Astrophysics Data System (ADS)

    Cheng, Bingqing; Ngan, Alfonso H. W.

    2013-04-01

    Molecular dynamics simulations of small Cu nanoparticles using three different interatomic potentials at rising temperature indicate that small nanoparticles can undergo solid-solid structural transitions through a direct geometrical conversion route. The direct geometrical conversion can happen for cuboctahedral nanoparticles, which turn into an icosahedra shape: one diagonal of the square faces contracts, and the faces are folded along the diagonal to give rise to two equilateral triangles. The transition is a kinetic process that cannot be fully explained through an energetic point of view. It has low activation energy and fast reaction time in the simulations. The transition mechanism is via the transmission of shear waves initiated from the particle surface and does not involve dislocation activity.

  12. Thermally induced solid-solid structural transition of copper nanoparticles through direct geometrical conversion.

    PubMed

    Cheng, Bingqing; Ngan, Alfonso H W

    2013-04-28

    Molecular dynamics simulations of small Cu nanoparticles using three different interatomic potentials at rising temperature indicate that small nanoparticles can undergo solid-solid structural transitions through a direct geometrical conversion route. The direct geometrical conversion can happen for cuboctahedral nanoparticles, which turn into an icosahedra shape: one diagonal of the square faces contracts, and the faces are folded along the diagonal to give rise to two equilateral triangles. The transition is a kinetic process that cannot be fully explained through an energetic point of view. It has low activation energy and fast reaction time in the simulations. The transition mechanism is via the transmission of shear waves initiated from the particle surface and does not involve dislocation activity. PMID:23635145

  13. Preparation of transition metal nanoparticles and surfaces modified with (CO) polymers synthesized by RAFT

    DOEpatents

    McCormick, III, Charles L.; Lowe, Andrew B.; Sumerlin, Brent S.

    2006-10-25

    A new, facile, general one-phase method of generating thiol-functionalized transition metal nanoparticles and surface modified by (co)polymers synthesized by the RAFT method is described. The method includes the steps of forming a (co)polymer in aqueous solution using the RAFT methodology, forming a collidal transition metal precursor solution from an appropriate transition metal; adding the metal precursor solution or surface to the (co)polymer solution, adding a reducing agent into the solution to reduce the metal colloid in situ to produce the stabilized nanoparticles or surface, and isolating the stabilized nanoparticles or surface in a manner such that aggregation is minimized. The functionalized surfaces generated using these methods can further undergo planar surface modifications, such as fuctionalization with a variety of different chemical groups, expanding their utility and application.

  14. Preparation of transition metal nanoparticles and surfaces modified with (co)polymers synthesized by RAFT

    DOEpatents

    McCormick, III, Charles L.; Lowe, Andrew B.; Sumerlin, Brent S.

    2011-12-27

    A new, facile, general one-phase method of generating thiol-functionalized transition metal nanoparticles and surfaces modified by (co)polymers synthesized by the RAFT method is described. The method includes the steps of forming a (co)polymer in aqueous solution using the RAFT methodology, forming a colloidal transition metal precursor solution from an appropriate transition metal; adding the metal precursor solution or surface to the (co)polymer solution, adding a reducing agent into the solution to reduce the metal colloid in situ to produce the stabilized nanoparticles or surface, and isolating the stabilized nanoparticles or surface in a manner such that aggregation is minimized. The functionalized surfaces generated using these methods can further undergo planar surface modifications, such as functionalization with a variety of different chemical groups, expanding their utility and application.

  15. Preparation of transition metal nanoparticles and surfaces modified with (CO)polymers synthesized by RAFT

    DOEpatents

    McCormick, III., Charles L.; Lowe, Andrew B.; Sumerlin, Brent S.

    2006-11-21

    A new, facile, general one-phase method of generating thio-functionalized transition metal nanoparticles and surfaces modified by (co)polymers synthesized by the RAFT method is described. The method includes the stops of forming a (co)polymer in aqueous solution using the RAFT methodology, forming a colloidal transition metal precursor solution from an appropriate transition metal; adding the metal precursor solution or surface to the (co)polymer solution, adding a reducing agent into the solution to reduce the metal colloid in situ to produce the stabilized nanoparticles or surface, and isolating the stabilized nanoparticles or surface in a manner such that aggregation is minimized. The functionalized surfaces generated using these methods can further undergo planar surface modifications, such as functionalization with a variety of different chemical groups, expanding their utility and application.

  16. Charge Transfer Stabilization of Late Transition Metal Oxide Nanoparticles on a Layered Niobate Support.

    PubMed

    Strayer, Megan E; Senftle, Thomas P; Winterstein, Jonathan P; Vargas-Barbosa, Nella M; Sharma, Renu; Rioux, Robert M; Janik, Michael J; Mallouk, Thomas E

    2015-12-30

    Interfacial interactions between late transition metal/metal oxide nanoparticles and oxide supports impact catalytic activity and stability. Here, we report the use of isothermal titration calorimetry (ITC), electron microscopy and density functional theory (DFT) to explore periodic trends in the heats of nanoparticle-support interactions for late transition metal and metal oxide nanoparticles on layered niobate and silicate supports. Data for Co(OH)2, hydroxyiridate-capped IrOx·nH2O, Ni(OH)2, CuO, and Ag2O nanoparticles were added to previously reported data for Rh(OH)3 grown on nanosheets of TBA0.24H0.76Ca2Nb3O10 and a layered silicate. ITC measurements showed stronger bonding energies in the order Ag < Cu ≈ Ni ≈ Co < Rh < Ir on the niobate support, as expected from trends in M-O bond energies. Nanoparticles with exothermic heats of interaction were stabilized against sintering. In contrast, ITC measurements showed endothermic interactions of Cu, Ni, and Rh oxide/hydroxide nanoparticles with the silicate and poor resistance to sintering. These trends in interfacial energies were corroborated by DFT calculations using single-atom and four-atom cluster models of metal/metal oxide nanoparticles. Density of states and charge density difference calculations reveal that strongly bonded metals (Rh, Ir) transfer d-electron density from the adsorbed cluster to niobium atoms in the support; this mixing is absent in weakly binding metals, such as Ag and Au, and in all metals on the layered silicate support. The large differences between the behavior of nanoparticles on niobate and silicate supports highlight the importance of d-orbital interactions between the nanoparticle and support in controlling the nanoparticles' stability. PMID:26651875

  17. Cu nanoshells: effects of interband transitions on the nanoparticle plasmon resonance.

    PubMed

    Wang, Hui; Tam, Felicia; Grady, Nathaniel K; Halas, Naomi J

    2005-10-01

    The optical properties of metals arise both from optical excitation of interband transitions and their collective electronic, or plasmon, response. Here, we examine the optical properties of Cu, whose strong interband transitions dominate its optical response in the visible region of the spectrum, in a nanoshell geometry. This nanostructure permits the geometrical tuning of the nanoparticle plasmon energy relative to the onset of interband transitions in the metal. Spectral overlap of the interband transitions of Cu with the nanoshell plasmon resonance results in a striking double-peaked plasmon resonance, a unique phenomenon previously unobserved in other noble or coinage metal nanostructures. PMID:16853342

  18. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  19. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  20. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  1. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  2. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  3. Size effect on order-disorder transition kinetics of FePt nanoparticles.

    PubMed

    Zhang, Shuaidi; Qi, Weihong; Huang, Baiyun

    2014-01-28

    The kinetics of order-disorder transition of FePt nanoparticles during high temperature annealing is theoretically investigated. A model is developed to address the influence of large surface to volume ratio of nanoparticles on both the thermodynamic and kinetic aspect of the ordering process; specifically, the nucleation and growth of L10 ordered domain within disordered nanoparticles. The size- and shape-dependence of transition kinetics are quantitatively addressed by a revised Johnson-Mehl-Avrami equation that included corrections for deviations caused by the domination of surface nucleation in nanoscale systems and the non-negligible size of the ordered nuclei. Calculation results based on the model suggested that smaller nanoparticles are kinetically more active but thermodynamically less transformable. The major obstacle in obtaining completely ordered nanoparticles is the elimination of antiphase boundaries. The results also quantitatively confirmed the existence of a size-limit in ordering, beyond which, inducing order-disorder transitions through annealing is impossible. A good agreement is observed between theory, experiment, and computer simulation results. PMID:25669544

  4. Size effect on order-disorder transition kinetics of FePt nanoparticles

    SciTech Connect

    Zhang, Shuaidi; Qi, Weihong; Huang, Baiyun

    2014-01-28

    The kinetics of order-disorder transition of FePt nanoparticles during high temperature annealing is theoretically investigated. A model is developed to address the influence of large surface to volume ratio of nanoparticles on both the thermodynamic and kinetic aspect of the ordering process; specifically, the nucleation and growth of L1{sub 0} ordered domain within disordered nanoparticles. The size- and shape-dependence of transition kinetics are quantitatively addressed by a revised Johnson-Mehl-Avrami equation that included corrections for deviations caused by the domination of surface nucleation in nanoscale systems and the non-negligible size of the ordered nuclei. Calculation results based on the model suggested that smaller nanoparticles are kinetically more active but thermodynamically less transformable. The major obstacle in obtaining completely ordered nanoparticles is the elimination of antiphase boundaries. The results also quantitatively confirmed the existence of a size-limit in ordering, beyond which, inducing order-disorder transitions through annealing is impossible. A good agreement is observed between theory, experiment, and computer simulation results.

  5. Silver and oxygen: Transition from clusters to nanoparticles

    NASA Astrophysics Data System (ADS)

    Schmidt, Martin; Bréchignac, Catherine

    2016-03-01

    By varying the sizes of isolated and charged silver particles, we may observe a wide range of reactions from weak molecular-oxygen physisorption to strong oxygen chemisorption. The global electron configuration dominates the stability of the silver-oxygen complexes. Our experimental studies at 77 K show a cluster regime below 40 free valence electrons in the system. Here each atom of silver added to the complex cause strong alternations of the oxygen binding by quantum effects. Bigger silver-oxygen complexes show smoother size dependence. As is rather typical for nanoparticles, the quantum effects are here less important, while the system size still matters. The electrostatic interaction between the charge state of the nanoparticle and the charge transfer of the reaction accounts for the general trends observed at silver, as it is in related oxygen-metal complexes. xml:lang="fr"

  6. Transition of temperature coefficient of conductance in weakly coupled gold nanoparticle arrays

    NASA Astrophysics Data System (ADS)

    Wang, Ying; Guan, Changrong; Sun, Jinling; Peng, Lianmao; Liao, Jianhui

    2014-12-01

    A unique positive-to-negative transition of temperature coefficient of conductance (TCC) was observed in self-assembled close-packed Au nanoparticle (AuNP) arrays. The transition of TCC can be interpreted properly with a diffusive hopping model, in which the Coulomb charging energy Ea plays a significant role. Two parameters of AuNP arrays, the nearest neighboring number and the particle core size, have been varied to tune Ea. Our data show that the positive-to-negative transitions of TCC are relevant to both parameters, which confirms the validity of the diffusive hopping model.

  7. Template-induced structure transition in sub-10 nm self-assembling nanoparticles.

    PubMed

    Asbahi, Mohamed; Mehraeen, Shafigh; Lim, Kevin T P; Wang, Fuke; Cao, Jianshu; Tan, Mei Chee; Yang, Joel K W

    2014-05-14

    We report on the directed self-assembly of sub-10 nm gold nanoparticles confined within a template comprising channels of gradually varying widths. When the colloidal lattice parameter is mismatched with the channel width, the nanoparticles rearrange and break their natural close-packed ordering, transiting through a range of structural configurations according to the constraints imposed by the channel. While much work has been done in assembling ordered configurations, studies of the transition regime between ordered states have been limited to microparticles under applied compression. Here, with coordinated experiments and Monte Carlo simulations we show that particles transit through a more diverse set of self-assembled configurations than observed for compressed systems. The new insight from this work could lead to the control and design of complex self-assembled patterns other than periodic arrays of ordered particles. PMID:24702584

  8. The Ligand Shell as an Energy Barrier in Surface Reactions on Transition Metal Nanoparticles.

    PubMed

    Smith, Jeremy G; Jain, Prashant K

    2016-06-01

    Transition metal nanoparticles, including those employed in catalytic, electrocatalytic, and photocatalytic conversions, have surfaces that are typically coated with a layer of short or long-chain ligands. There is little systematic understanding of how much this ligand layer affects the reactivity of the underlying surface. We show for Ag nanoparticles that a surface-adsorbed thiol layer greatly impedes the kinetics of an ionic chemical reaction taking place on the Ag surface. The model reaction studied is the galvanic exchange of Ag with Au(3+) ions, the kinetics of which is measured on individual thiol-coated nanoparticles using in situ optical scattering spectroscopy. We observe a systematic lowering of the reactivity of the nanoparticle as the chain length of the thiol is increased, from which we deduce that the ligand layer serves as an energy barrier to the transport of incoming/outgoing reactive ions. This barrier effect can be decreased by light irradiation, resulting from weakened binding of the thiol layer to the metal surface. We find that the influence of the surface ligand layer on reactivity is much stronger than factors such as nanoparticle size, shape, or crystallinity. These findings provide improved understanding of the role of ligand or adsorbates in colloidal catalysis and photocatalysis and have important implications for the transport of reactants and ions to surfaces and for engineering the reactivity of nanoparticles using surface passivation. PMID:27152595

  9. Phase transition method to form Group 6A nanoparticles on carbonaceous templates.

    PubMed

    Youn, Hee-Chang; Jegal, Jong-Pil; Park, Sang-Hoon; Kim, Hyun-Kyung; Park, Ho Seok; Roh, Kwang Chul; Kim, Kwang-Bum

    2014-03-25

    Considerable effort has been made to develop unique methods of preparing and characterizing nanoparticles and nanocomposites in order to exploit the true potential of nanotechnology. We used a facile, versatile phase-transition method for forming Group 6A nanoparticles on carbonaceous templates to produce homogeneous 5-10 nm diameter Group 6A nanoparticles on carbon nanotubes (CNTs) and reduced graphene oxide (RGO), to obtain nanocomposites. The method involved melting and recrystallizing mixtures of elemental sulfur and either CNTs or RGO on carbonaceous templates. The surface tension and hydrophilicity of the molten Group 6A species surfaces and the oxygen functional groups on the carbonaceous template surfaces were considered in depth to provide important guidelines for forming Group 6A nanoparticles on carbonaceous templates. The surface tension of the molten Group 6A species should be intrinsically low, leading to effective wetting on the carbonaceous template. In addition, the molten Group 6A species hydrophilic surfaces were essential for enabling hydrophilic-hydrophilic interaction for selective wetting at the oxygen functional groups on the carbonaceous template, leading to the heterogeneous nucleation of nanoparticles. Furthermore, the size and morphology (isolated vs layer-like) of the Group 6A nanoparticles were tuned by adjusting the oxidation state of the carbonaceous template. We investigated the potential application of the nanocomposites prepared using this method to cathode materials in lithium-sulfur secondary batteries. PMID:24499384

  10. Semiconductor-metal transition of Se in Ru-Se Catalyst Nanoparticles

    NASA Astrophysics Data System (ADS)

    Babu, P. K.; Lewera, Adam; Oldfield, Eric; Wieckowski, Andrzej

    2009-03-01

    Ru-Se composite nanoparticles are promising catalysts for the oxygen reduction reaction (ORR) in fuel cells. Though the role of Se in enhancing the chemical stability of Ru nanoparticles is well established, the microscopic nature of Ru-Se interaction was not clearly understood. We carried out a combined investigation of ^77Se NMR and XPS on Ru-Se nanoparticles and our results indicate that Se, a semiconductor in elemental form, becomes metallic when interacting with Ru. ^77Se spin-lattice relaxation rates are found to be proportional to T, the well-known Korringa behavior characteristic of metals. The NMR results are supported by the XPS binding energy shifts which suggest that a possible Ru->Se charge transfer could be responsible for the semiconductor->metal transition of Se which also makes Ru less susceptible to oxidation during ORR.

  11. Alkaline transition of horse heart cytochrome c in the presence of ZnO nanoparticles

    NASA Astrophysics Data System (ADS)

    Šimšíková, Michaela; Antalík, Marián

    2013-01-01

    The effect of zinc oxide nanoparticles (ZnO NPs) on cytochrome c (cyt c) in alkaline pH was studied with absorption spectroscopy and UV circular dichroism (CD). Spectral data from UV-vis spectroscopy and circular dichroism indicate only small changes in the native structure of the protein at neutral pH after the interaction with ZnO nanoparticles. The stability around the heme crevice of cyt c and therefore the switch of the axial ligand Met80 to Lys which occurs in conditions of higher pH was proven following the interaction of cytochrome c with ZnO nanoparticles. The formation of cyt c-ZnO NPs complex based on electrostatic attraction was accompanied by a significant increase in the apparent pKa constant of the alkaline transition of cyt c.

  12. [Development of formulations of desmopressin intranasal drops].

    PubMed

    Gerbutaviciene, Rima; Klimas, Rimantas; Savickas, Arūnas; Maciulevicius, Jonas

    2002-01-01

    In recent years synthetic vasopressin analogues (particularly desmopressin) emerged as safe and effective representatives of this class of drugs for same clinical indications as natural hormone. It was imperative to create intranasal drug form using synthetic desmopressin compound. The purpose of this work was to develop formulations of intranasal desmopressin drug using synthetic active compound with optimal composition. Aquatic desmopressin intranasal solution was prepared in 0.05 mg/ml concentration using phosphate buffer (pH 4.5-5.5) and following preservatives: nipagin-nipazol 7:3--0.1% or benzalkonium chloride 0.01%. Sterility is the main condition for intranasal drops and hormones as a raw material are thermolabile so it is not possible to apply a thermic sterilisation. Polymeric membrane filters of 0.22 micron pore size were employed as sterilizing filters. In order to control the quality, to determine the stability of desmopressin intranasal drops at long-lasting storage (24 months) and to evaluate the influence of the technological factors we have developed the analytical methods of quality control. According to our quality control data, desmopressin intranasal drops are stable for two years and remain sterile during storage and administration of the drug. PMID:12474688

  13. Upconverting nanoparticles for the near infrared photoactivation of transition metal complexes: new opportunities and challenges in medicinal inorganic photochemistry.

    PubMed

    Ruggiero, Emmanuel; Alonso-de Castro, Silvia; Habtemariam, Abraha; Salassa, Luca

    2016-08-16

    The article highlights the emergent use of upconverting nanoparticles as tools for the near infrared photoactivation of transition metal complexes, identifying opportunities and challenges of this approach in the context of medicinal inorganic chemistry. PMID:27482656

  14. BaTiO3 supercages: unusual oriented nanoparticle aggregation and continuous ordering transition in morphology.

    PubMed

    Li, Juan; Hietala, Sami; Tian, Xuelin

    2015-01-27

    Here we report the organic-free mesocrystalline superstructured cages of BaTiO3, i.e., the BaTiO3 supercages, which are synthesized by a one-step templateless and additive-free route using molten hydrated salt as the reaction medium. An unusual three-dimensional oriented aggregation of primary BaTiO3 nanoparticles in the medium of high ionic strength, which normally favors random aggregation, is identified to take place at the early stage of the synthesis. The spherical BaTiO3 aggregates further experience a remarkable continuous ordering transition in morphology, consisting of nanoparticle faceting and nanosheet formation steps. This ordering transition in conjunction with Ostwald ripening-induced solid evacuation leads to the formation of unique supercage structure of BaTiO3. Benefiting from their structure, the BaTiO3 supercages exhibit improved microwave absorption property. PMID:25514033

  15. Adhesion and Wetting of Soft Nanoparticles on Textured Surfaces: Transition between Wenzel and Cassie-Baxter States

    DOE PAGESBeta

    Cao, Zhen; Stevens, Mark J.; Carrillo, Jan-Michael Y.; Dobrynin, Andrey V.

    2015-01-16

    We use a combination of the molecular dynamics simulations and scaling analysis to study interactions between gel-like nanoparticles and substrates covered with rectangular shape posts. Our simulations have shown that nanoparticle in contact with substrate undergo first order transition between Wenzel and Cassie-Baxter state which location depends on nanoparticle shear modulus, the strength of nanoparticle-substrate interactions, height of the substrate posts and nanoparticle size, Rp. There is a range of system parameters where these two states coexist such that the average indentation δ produced by substrate posts changes monotonically with nanoparticle shear modulus, Gp. We have developed a scaling modelmore » that describes deformation of nanoparticle in contact with patterned substrate. In the framework of this model the effect of the patterned substrate can be taken into account by introducing an effective work of adhesion, Weff, which describes the first order transition between Wenzel and Cassie-Baxter states. There are two different shape deformation regimes for nanoparticles with shear modulus Gp and surface tension γp. Shape of small nanoparticles with size Rp < γp 3/2Gp-1 Weff-1/2 is controlled by capillary forces while deformation of large nanoparticles, Rp > γp 3/2Gp-1 Weff-1/2« less

  16. Phase Transitions and Spatial Organization in Nanoparticle-Block Copolymer Mixtures

    NASA Astrophysics Data System (ADS)

    Kim, Jaeup

    2005-03-01

    Introducing nanoparticles into nanostructured block copolymer phases can dramatically influence the polymer host. Computer simulations [Balazs et al., PRL, 89, 155503 (2002)] suggest inclusions can actually trigger transitions from one polymer phase to another. Simultaneously, the nanoparticles can be organized into complex superstructures, giving composite materials with novel mechanical, electrical and optical properties. Potential applications include catalysts, selective membranes and optical filters. We have developed a first principles theory predicting polymer phases and nanoparticle distributions. We find modification by nanoinclusions of the free energy of stretched polymer domains in lamellar, cylindrical or spherical geometries triggers structural changes and determines particle distributions. Our framework builds on Semenov's description of AB copolymers in the strongly stretched limit by incorporating nanoinclusions. Energy favors segregation into particle-rich regions, while entropy favors particle mixing into the energetically preferred block, say A. When entropy wins (small particles), an A-core cylindrical-to-lamellar phase transition is induced. Interestingly, large particles by contrast microphase separate into copolymer domains (analogous to Semenov's conclusions for homopolymer-copolymer mixtures) triggering reverse phase transitions (e.g. lamellar to A-core cylindrical). We present our results as a complete phase diagram.

  17. Influenza (Flu) vaccine (Live, Intranasal): What you need to know

    MedlinePlus

    ... is taken in its entirety from the CDC Influenza Live, Intranasal Flu Vaccine Information Statement (VIS): www.cdc.gov/vaccines/ ... flulive.html . CDC review information for Live, Intranasal Influenza VIS: Vaccine Information Statement Influenza Page last reviewed: ...

  18. Population Pharmacokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  19. Spin-glass transition in Ni carbide single crystal nanoparticles with Ni3C - type structure

    NASA Astrophysics Data System (ADS)

    Fujieda, S.; Kuboniwa, T.; Shinoda, K.; Suzuki, S.; Echigoya, J.

    2016-05-01

    Hexagonal shaped nanoparticles about 60 nm in size were successfully synthesized in tetraethylene glycol solution containing polyvinylpyrrolidone. By the analysis of the electron diffraction pattern, these were identified as a single crystal of Ni carbide with Ni3C - type structure. Their magnetization curve at 5 K was not completely saturated under a magnetic field of 5 T. The thermomagnetization curves after zero-field cooling and after field cooling exhibited the magnetic cooling effect at low temperatures. Furthermore, the 2nd order nonlinear term of AC magnetic susceptibility exhibited a negative divergence at about 17 K. It is concluded that Ni carbide single crystal nanoparticles with the Ni3C - type structure exhibit spin-glass transition at low temperatures.

  20. Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

    PubMed

    El-Setouhy, Doaa Ahmed; Ahmed, Sami; Badawi, Alia Abd El-Latif; El-Nabarawi, Mohamed Ahmed; Sallam, Nada

    2015-08-30

    Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well. PMID:25917526

  1. Formation of Superlattices of Gold Nanoparticles Using Ostwald Ripening in Emulsions: Transition from fcc to bcc Structure.

    PubMed

    Schmitt, Julien; Hajiw, Stéphanie; Lecchi, Amélie; Degrouard, Jéril; Salonen, Anniina; Impéror-Clerc, Marianne; Pansu, Brigitte

    2016-06-30

    An efficient method to form 3D superlattices of gold nanoparticles inside oil emulsion droplets is presented. We demonstrate that this method relies on Ostwald ripening, a well-known phenomenon occurring during the aging of emulsions. The key point is that the nanoparticle concentration inside the smaller droplets is increasing very slowly with time, thus inducing the crystallization of the nanoparticles into superlattices. Using oil-in-water emulsions doped with hydrophobic gold nanoparticles, we demonstrate that this method is efficient for different types of oils (toluene, cyclohexane, dodecane, and hexadecane). 3D superlattices of the nanoparticles are obtained, with dimensions reaching a hundred nanometers. The kinetics of the crystallization depends on the solubility of the oil in water but also on the initial concentration of the gold nanoparticles in oil. This method also provides an innovative way to obtain the complete phase diagram of nanoparticle suspensions with concentration. Indeed, during this slow crystallization process, a transition from a disordered suspension to a fcc structure is observed, followed by a transition toward a bcc structure. This evolution with time provides key results to understand the role played by the ligands located at the surface of the nanoparticles in order to control the type of superlattices which are formed. PMID:27267312

  2. Determination of phenolic compounds using spectral and color transitions of rhodium nanoparticles.

    PubMed

    Gatselou, Vasiliki; Christodouleas, Dionysios C; Kouloumpis, Antonios; Gournis, Dimitrios; Giokas, Dimosthenis L

    2016-08-17

    This work reports a new approach for the determination of phenolic compounds based on their interaction with citrate-capped rhodium nanoparticles. Phenolic compounds (i.e., catechins, gallates, cinnamates, and dihydroxybenzoic acids) were found to cause changes in the size and localized surface plasmon resonance of rhodium nanoparticles, and therefore, give rise to analyte-specific spectral and color transitions in the rhodium nanoparticle suspensions. Upon reaction with phenolic compounds (mainly dithydroxybenzoate derivatives, and trihydroxybenzoate derivatives), new absorbance peaks at 350 nm and 450 nm were observed. Upon reaction with trihydroxybenzoate derivatives, however, an additional absorbance peak at 580 nm was observed facilitating the speciation of phenolic compounds in the sample. Both absorbance peaks at 450 nm and 580 nm increased with increasing concentration of phenolic compounds over a linear range of 0-500 μM. Detection limits at the mid-micromolar levels were achieved, depending on the phenolic compound involved, and with satisfactory reproducibility (<7.3%). On the basis of these findings, two rhodium nanoparticles-based assays for the determination of the total phenolic content and total catechin content were developed and applied in tea samples. The obtained results correlated favorably with commonly used methods (i.e., Folin-Ciocalteu and aluminum complexation assay). Not the least, the finding that rhodium nanoparticles can react with analytes and exhibit unique localized surface plasmon resonance bands in the visible region, can open new opportunities for developing new optical and sensing analytical applications. PMID:27286772

  3. Adhesion and Wetting of Soft Nanoparticles on Textured Surfaces: Transition between Wenzel and Cassie-Baxter States

    SciTech Connect

    Cao, Zhen; Stevens, Mark J.; Carrillo, Jan-Michael Y.; Dobrynin, Andrey V.

    2015-01-16

    We use a combination of the molecular dynamics simulations and scaling analysis to study interactions between gel-like nanoparticles and substrates covered with rectangular shape posts. Our simulations have shown that nanoparticle in contact with substrate undergo first order transition between Wenzel and Cassie-Baxter state which location depends on nanoparticle shear modulus, the strength of nanoparticle-substrate interactions, height of the substrate posts and nanoparticle size, Rp. There is a range of system parameters where these two states coexist such that the average indentation δ produced by substrate posts changes monotonically with nanoparticle shear modulus, Gp. We have developed a scaling model that describes deformation of nanoparticle in contact with patterned substrate. In the framework of this model the effect of the patterned substrate can be taken into account by introducing an effective work of adhesion, Weff, which describes the first order transition between Wenzel and Cassie-Baxter states. There are two different shape deformation regimes for nanoparticles with shear modulus Gp and surface tension γp. Shape of small nanoparticles with size Rp < γp 3/2Gp-1 Weff-1/2 is controlled by capillary forces while deformation of large nanoparticles, Rp > γp 3/2Gp-1 Weff-1/2nanoparticle elastic and contact free energies. The model predictions are in a good agreement with simulation results.

  4. Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment.

    PubMed

    Kaur, Prabhjot; Garg, Tarun; Vaidya, Bhuvaneshwar; Prakash, Atish; Rath, Goutam; Goyal, Amit K

    2015-04-01

    This study was aimed for brain delivery of Tramadol HCl (centrally acting synthetic opioid) following intranasal administration for treatment of depression. Chitosan nanoparticles (NPs) were prepared by ionic gelation method followed by the addition of developed NPs with in the Pluronic and HPMC-based mucoadhesive thermo-reversible gel. Developed formulation optimized based on the various parameters such as particle size, entrapment efficiency, in vitro release study. Depression induction was done by forced swim test and evaluated by various behavioral and biochemical parameters. Furthermore, results showed significantly increased in locomotors activity, body weight as compared to control group. It also showed alteration in biochemical parameters such glutathione level and catalase levels significantly increased other than lipid peroxidation and nitrite level was found to be decreased after intranasal administration of formulation. Thus, intranasal TRM HCl NP-loaded in situ gel was found to be a promising formulation for the treatment of depression. PMID:25539073

  5. Size-controlled synthesis of transition metal nanoparticles through chemical and photo-chemical routes

    NASA Astrophysics Data System (ADS)

    Tangeysh, Behzad

    The central objective of this work is developing convenient general procedures for controlling the formation and stabilization of nanoscale transition metal particles. Contemporary interest in developing alternative synthetic approaches for producing nanoparticles arises in large part from expanding applications of the nanomaterials in areas such as catalysis, electronics and medicine. This research focuses on advancing the existing nanoparticle synthetic routes by using a new class of polymer colloid materials as a chemical approach, and the laser irradiation of metal salt solution as a photo-chemical method to attain size and shape selectivity. Controlled synthesis of small metal nanoparticles with sizes ranging from 1 to 5nm is still a continuing challenge in nanomaterial synthesis. This research utilizes a new class of polymer colloid materials as nano-reactors and protective agents for controlling the formation of small transition metal nanoparticles. The polymer colloid particles were formed from cross-linking of dinegatively charged metal precursors with partially protonated poly dimethylaminoethylmethacrylate (PDMAEMA). Incorporation of [PtCl6]2- species into the colloidal particles prior to the chemical reduction was effectively employed as a new strategy for synthesis of unusually small platinum nanoparticles with narrow size distributions (1.12 +/-0.25nm). To explore the generality of this approach, in a series of proof-of-concept studies, this method was successfully employed for the synthesis of small palladium (1.4 +/-0.2nm) and copper nanoparticles (1.5 +/-0.6nm). The polymer colloid materials developed in this research are pH responsive, and are designed to self-assemble and/or disassemble by varying the levels of protonation of the polymer chains. This unique feature was used to tune the size of palladium nanoparticles in a small range from 1nm to 5nm. The procedure presented in this work is a new convenient room temperature route for synthesis of

  6. Reactive Gas Environment Induced Structural Modification of Noble-Transition Metal Alloy Nanoparticles

    NASA Astrophysics Data System (ADS)

    Petkov, V.; Yang, L.; Yin, J.; Loukrakpam, R.; Shan, S.; Wanjala, B.; Luo, J.; Chapman, K. W.; Zhong, C. J.

    2012-09-01

    Noble-transition metal (noble=Pt,Au; transition=Co,Ni,Cu) alloy particles with sizes of about 5 nm have been studied by in situ high-energy x-ray diffraction while subjected to oxidizing (O2) and reducing (H2) gas atmospheres at elevated temperatures. The different gas atmospheres do not affect substantially the random alloy, face-centered-cubic structure type of the particles but do affect the way the metal atoms pack together. In an O2 atmosphere, atoms get extra separated from each other, whereas, in an H2 atmosphere, they come closer together. The effect is substantial, amounting to 0.1 Å difference in the first neighbor atomic distances, and concurs with a dramatic change of the particle catalytic properties. It is argued that such reactive gas induced “expansion shrinking” is a common phenomenon that may be employed for the engineering of “smart” nanoparticles responding advantageously to envisaged gas environments.

  7. Synthesis and study of optical properties of transition metals doped ZnS nanoparticles.

    PubMed

    Ramasamy, V; Praba, K; Murugadoss, G

    2012-10-01

    ZnS and transition metal (Mn, Co, Ni, Cu, Ag and Cd) doped ZnS were synthesized using chemical precipitation method in an air atmosphere. The structural and optical properties were studied using various techniques. The X-ray diffraction (XRD) analysis show that the particles are in cubic structure. The mean size of the nanoparticles calculated through Scherrer equation is in the range of 4-6.1 nm. Elemental dispersive (EDX) analysis of doped samples reveals the presence of doping ions. The scanning electron microscopic (SEM) and transmission electron microscopic (TEM) studies show that the synthesized particles are in spherical shape. Optical characterization of both undoped and doped samples was carried out by ultraviolet-visible (UV-Vis) and photoluminescence (PL) spectroscopy. The absorption spectra of all the samples are blue shifted from the bulk ZnS. An optimum doping level of the transition metals for enhanced PL properties are found through optical study. PMID:22938741

  8. Understanding the Enhanced Catalytic Performance of Ultrafine Transition Metal Nanoparticles-Graphene Composites

    NASA Astrophysics Data System (ADS)

    Liu, Xin; Meng, Changgong; Han, Yu

    2015-09-01

    Catalysis, as the key to minimize the energy requirement and environmental impact of today's chemical industry, plays a vital role in many fields directly related to our daily life and economy, including energy generation, environment control, manufacture of chemicals, medicine synthesis, etc. Rational design and fabrication of highly efficient catalysts have become the ultimate goal of today's catalysis research. For the purpose of handling and product separation, heterogeneous catalysts are highly preferred for industrial applications and a large part of which are the composites of transition metal nanoparticles (TMNPs). With the fast development of nanoscience and nanotechnology and assisted with theoretical investigations, basic understanding on tailoring the electronic structure of these nanocomposites has been gained, mainly by precise control of the composition, morphology, interfacial structure and electronic states. With the rise of graphene, chemical routes to prepare graphene were developed and various graphene-based composites were fabricated. Transition metal nanoparticles-reduced graphene oxide (TMNPs-rGO) composites have attracted considerable attention, because of their intriguing catalytic performance which have been extensively explored for energy- and environment-related applications to date. This review summarizes our recent experimental and theoretical efforts on understanding the superior catalytic performance of subnanosized TMNPs-rGO composites.

  9. Size-Dependent Infrared Phonon Modes and Ferroelectric Phase Transition in BiFe03 Nanoparticles

    SciTech Connect

    Chen, P.; Wong, S.; Xu, X.; Koenigsmann, C.; Santulli, A.C.; Musfeldt, J.L.

    2010-11-01

    One emergent property of ferroelectric nanoparticles is the sized-induced structural distortion to a high-symmetry paraelectric phase at small particle sizes. Finite length scale effects can thus be advantageously employed to elucidate ferroelectric transition mechanisms. In this work, we combine infrared spectroscopy with group theory and lattice dynamics calculations to reveal the displacive nature of the ferroelectric transition in BiFeO{sub 3}, a room temperature multiferroic. Systematic intensity and frequency trends in selected vibrational modes show that the paraelectric phase is Pm{sub 3}m and the lowest frequency A{sub 1} feature is the soft mode that drives the first order transition. Finite length scale effects are also evident in the electronic structure with a red-shifted band gap in nanoscale BiFeO{sub 3} compared with that of the rhombohedral film, a result that can impact the development of ferroelectric photovoltaics and oxide-based electronics. Taken together, these findings demonstrate the foundational importance of size effects for enhancing the rich functionality and broad utility of transition metal oxides.

  10. Structure, bonding, and catalytic activity of monodisperse, transition-metal-substituted CeO2 nanoparticles.

    PubMed

    Elias, Joseph S; Risch, Marcel; Giordano, Livia; Mansour, Azzam N; Shao-Horn, Yang

    2014-12-10

    We present a simple and generalizable synthetic route toward phase-pure, monodisperse transition-metal-substituted ceria nanoparticles (M0.1Ce0.9O2-x, M = Mn, Fe, Co, Ni, Cu). The solution-based pyrolysis of a series of heterobimetallic Schiff base complexes ensures a rigorous control of the size, morphology and composition of 3 nm M0.1Ce0.9O2-x crystallites for CO oxidation catalysis and other applications. X-ray absorption spectroscopy confirms the dispersion of aliovalent (M(3+) and M(2+)) transition metal ions into the ceria matrix without the formation of any bulk transition metal oxide phases, while steady-state CO oxidation catalysis reveals an order of magnitude increase in catalytic activity with copper substitution. Density functional calculations of model slabs of these compounds confirm the stabilization of M(3+) and M(2+) in the lattice of CeO2. These results highlight the role of the host CeO2 lattice in stabilizing high oxidation states of aliovalent transition metal dopants that ordinarily would be intractable, such as Cu(3+), as well as demonstrating a rational approach to catalyst design. The current work demonstrates, for the first time, a generalizable approach for the preparation of transition-metal-substituted CeO2 for a broad range of transition metals with unparalleled synthetic control and illustrates that Cu(3+) is implicated in the mechanism for CO oxidation on CuO-CeO2 catalysts. PMID:25406101

  11. Intranasal Osteopontin for Rodent Germinal Matrix Hemorrhage.

    PubMed

    Malaguit, Jay; Casel, Darlene; Dixon, Brandon; Doycheva, Desislava; Tang, Jiping; Zhang, John H; Lekic, Tim

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most common and devastating neurological problem of premature infants. Current treatment is largely ineffective and GMH has been nonpreventable. Osteopontin (OPN) is an endogenous protein that has been shown to be neuroprotective, however, it has not been tested in GMH. P7 neonatal rats were subjected to stereotactic ganglionic eminence collagenase infusion. Groups were as follows: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal OPN. Seventy-two hours later, the animals were evaluated using righting reflex, blood-brain barrier (BBB) permeability by Evans blue dye leakage, brain water content, and hemoglobin assay. Intranasal OPN improved outcomes after GMH by attenuation of brain swelling, BBB function, re-bleeding, and neurological outcomes. OPN may play an important role in enhancing neuroprotective brain signaling following GMH. These observed effects may offer novel possibilities for therapy in this patient population. PMID:26463952

  12. Drug development of intranasally delivered peptides.

    PubMed

    Campbell, Catherine; Morimoto, Bruce H; Nenciu, Daniela; Fox, Anthony W

    2012-04-01

    Intranasal drug delivery has attracted increasing attention as a noninvasive route of administration for therapeutic proteins and peptides. The delivery of therapeutic peptides through the nasal route provides an alternative to intravenous or subcutaneous injections. This review highlights the drug-development considerations unique to nasal therapeutics and discusses some of the factors and strategies that affect and can improve nasal absorption of peptides. The selectivity and good safety profile typical of peptide therapeutics, along with the dose limitation for intranasal administration, can provide challenges in drug development. Therefore, nasal peptide therapeutics often require special considerations in the nonclinical safety evaluations, such as determining drug exposure in the context of the maximum feasible dose in order to adequately prepare nasal products for clinical studies. PMID:22834082

  13. A detailed study on the transition from the blocked to the superparamagnetic state of reduction-precipitated iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Witte, K.; Bodnar, W.; Mix, T.; Schell, N.; Fulda, G.; Woodcock, T. G.; Burkel, E.

    2016-04-01

    Magnetic iron oxide nanoparticles were prepared by salt-assisted solid-state chemical precipitation method with alternating fractions of the ferric iron content. The physical properties of the precipitated nanoparticles mainly consisting of magnetite were investigated by means of transmission electron microscopy, high energy X-ray diffraction, vibrating sample magnetometry and Mössbauer spectroscopy. With particle sizes ranging from 16.3 nm to 2.1 nm, a gradual transition from the blocked state to the superparamagnetic state was observed. The transition was described as a dependence of the ferric iron content used during the precipitation. Composition, mean particle size, coercivity, saturation polarisation, as well as hyperfine interaction parameters and their evolution were studied systematically over the whole series of iron oxide nanoparticles.

  14. Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts

    NASA Astrophysics Data System (ADS)

    Tonga, Gulen Yesilbag; Jeong, Youngdo; Duncan, Bradley; Mizuhara, Tsukasa; Mout, Rubul; Das, Riddha; Kim, Sung Tae; Yeh, Yi-Cheun; Yan, Bo; Hou, Singyuk; Rotello, Vincent M.

    2015-07-01

    Bioorthogonal catalysis broadens the functional possibilities of intracellular chemistry. Effective delivery and regulation of synthetic catalytic systems in cells are challenging due to the complex intracellular environment and catalyst instability. Here, we report the fabrication of protein-sized bioorthogonal nanozymes through the encapsulation of hydrophobic transition metal catalysts into the monolayer of water-soluble gold nanoparticles. The activity of these catalysts can be reversibly controlled by binding a supramolecular cucurbit[7]uril ‘gate-keeper’ onto the monolayer surface, providing a biomimetic control mechanism that mimics the allosteric regulation of enzymes. The potential of this gated nanozyme for use in imaging and therapeutic applications was demonstrated through triggered cleavage of allylcarbamates for pro-fluorophore activation and propargyl groups for prodrug activation inside living cells.

  15. Multiscale theory on energy transfer for nanosystems and structural transitions in vault nanoparticles

    NASA Astrophysics Data System (ADS)

    Espinosa Duran, John Michael

    Recently, insights about nanoscale phenomena have been gained from theoretical and computational studies, filling gaps due to the lack of temporal and spatial resolution of some experimental characterization techniques to study dynamic phenomena. In this work, initially, two multiscale simulation approaches filling this gap are presented for studying the heat transfer problem between a system and its bath at nano/meso scale. In the first approach, an exploratory study, the internal energy of the system is used as a coarse-grained variable to study time evolution in biological nanosystems. In the second approach, the spatial profile of the energy density of the composite system is considered a field variable and it is evaluated at the nodes of a 3D grid to validate whether this variable varies slowly; the systems considered are some nanocrystals and a protein. Finally, some dynamic features of the temperature triggered structural transitions in Vault nanoparticles are revealed using classical molecular dynamics simulations.

  16. Noble-transition metal nanoparticle breathing in a reactive gas atmosphere.

    PubMed

    Petkov, Valeri; Shan, Shiyao; Chupas, Peter; Yin, Jun; Yang, Lefu; Luo, Jin; Zhong, Chuan-Jian

    2013-08-21

    In situ high-energy X-ray diffraction coupled to atomic pair distribution function analysis is used to obtain fundamental insight into the effect of the reactive gas environment on the atomic-scale structure of metallic particles less than 10 nm in size. To substantiate our recent discovery we investigate a wide range of noble-transition metal nanoparticles and confirm that they expand and contract radially when treated in oxidizing (O2) and reducing (H2) atmospheres, respectively. The results are confirmed by supplementary XAFS experiments. Using computer simulations guided by the experimental diffraction data we quantify the effect in terms of both relative lattice strain and absolute atomic displacements. In particular, we show that the effect leads to a small percent of extra surface strain corresponding to several tenths of Ångström displacements of the atoms at the outmost layer of the particles. The effect then gradually decays to zero within 4 atomic layers inside the particles. We also show that, reminiscent of a breathing type structural transformation, the effect is reproducible and reversible. We argue that because of its significance and widespread occurrence the effect should be taken into account in nanoparticle research. PMID:23828235

  17. Effects of NiO nanoparticles on the magnetic properties and diffuse phase transition of BZT/NiO composites

    PubMed Central

    2012-01-01

    A new composite system, Ba(Zr0.07Ti0.93)O3 (BZT93) ceramic/NiO nanoparticles, was fabricated to investigate the effect of NiO nanoparticles on the properties of these composites. M-H hysteresis loops showed an improvement in the magnetic behavior for higher NiO content samples plus modified ferroelectric properties. However, the 1 vol.% samples showed the optimum ferroelectric and ferromagnetic properties. Examination of the dielectric spectra showed that the NiO additive promoted a diffuse phase transition, and the two phase transition temperatures, as observed for BZT93, merged into a single phase transition temperature for the composite samples. PMID:22221698

  18. Metal-Insulator Transition in nanoparticle solids: a kinetic Monte Carlo study

    NASA Astrophysics Data System (ADS)

    Zimanyi, Gergely; Qu, Luman; Voros, Marton

    Nanoparticle (NP) solids recently emerged as a promising platform for high performance electronic/optoelectronic devices, including third generation solar cells, light emitting diodes and field effect transistors. A challenge of NP films is that their charge transport is in the unfavorable hopping/insulating regime. Recent experiments showed that it is possible to tune the NP solids through a Metal-Insulator Transition (MIT) via ligand engineering and ALD matrix infilling. However, the microscopic understanding of this transition is not yet clear. To address this challenge, we developed a Kinetic Monte Carlo transport modeling framework that builds on determining NP parameters from ab initio-based calculations of the energy level structures, charging energies and overlaps, and then uses these to compute the hopping mobility across a disordered NP array by the Marcus and Miller-Abrahams mechanisms. We reproduced and explained the observed non-monotonous dependence of the mobility on the NP diameter. Centrally, we extended our platform to be able to capture the MIT. We determined the MIT phase boundary on the (NP-NP overlap - Electron density) plane. We demonstrated that all mobilities fall on a universal scaling curve, allowing us to determine the critical behavior across the MIT. Supported by: UC Davis Office of Research RISE ANSWER Grant.

  19. Effect of superparamagnetic iron oxide nanoparticles on fluidity and phase transition of phosphatidylcholine liposomal membranes

    PubMed Central

    Santhosh, Poornima Budime; Drašler, Barbara; Drobne, Damjana; Kreft, Mateja Erdani; Kralj, Slavko; Makovec, Darko; Ulrih, Nataša Poklar

    2015-01-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) with multifunctional properties have shown great promise in theranostics. The aim of our work was to compare the effects of SPIONs on the fluidity and phase transition of the liposomal membranes prepared with zwitterionic phosphatidylcholine lipids. In order to study if the surface modification of SPIONs has any influence on these membrane properties, we have used four types of differently functionalized SPIONs, such as: plain SPIONs (primary size was shown to bê11 nm), silica-coated SPIONs, SPIONs coated with silica and functionalized with positively charged amino groups or negatively charged carboxyl groups (the primary size of all the surface-modified SPIONs was ~20 nm). Small unilamellar vesicles prepared with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipids and multilamellar vesicles prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine lipids were encapsulated or incubated with the plain and surface-modified SPIONs to determine the fluidity and phase transition temperature of the bilayer lipids, respectively. Fluorescent anisotropy and differential scanning calorimetric measurements of the liposomes that were either encapsulated or incubated with the suspension of SPIONs did not show a significant difference in the lipid ordering and fluidity; though the encapsulated SPIONs showed a slightly increased effect on the fluidity of the model membranes in comparison with the incubated SPIONs. This indicates the low potential of the SPIONs to interact with the nontargeted cell membranes, which is a desirable factor for in vivo applications. PMID:26491286

  20. Anti-ferromagnetic/ferromagnetic transition in half-metallic Co9Se8 nanoparticles

    NASA Astrophysics Data System (ADS)

    Singh, Jai; Kumar, Pushpendra

    2015-09-01

    The size, shape and defects of the half-metallic Co9Se8 nanoparticles (NPs) play a crucial role in the magnetic transition at the local magnetic regime at low temperatures. A general, non-injection, one-pot reaction route without toxic reagents, such as TOPO/TOPSe, surfactant and/or chelating agent, were used to synthesize gram scale of well-dispersed, high-quality Co9Se8 NPs. The calculated mean crystallite size of the NPs was ∼10 nm, which is consistent with the transmission electron microscope data. This study reveals an unusual anti-ferromagnetic/ferromagnetic transition with some super-paramagnetic character in the low temperature region of Co9Se8 NPs. These investigations are expected not only to help the observed phenomenon, but also help in identifying new half-metallic magnetic NPs for spintronics devices. The outcome provides better understanding of the occurrence of superparamagnetism at low temperatures in the nano-regime, for half-metallic systems.

  1. Effect of superparamagnetic iron oxide nanoparticles on fluidity and phase transition of phosphatidylcholine liposomal membranes.

    PubMed

    Santhosh, Poornima Budime; Drašler, Barbara; Drobne, Damjana; Kreft, Mateja Erdani; Kralj, Slavko; Makovec, Darko; Ulrih, Nataša Poklar

    2015-01-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) with multifunctional properties have shown great promise in theranostics. The aim of our work was to compare the effects of SPIONs on the fluidity and phase transition of the liposomal membranes prepared with zwitterionic phosphatidylcholine lipids. In order to study if the surface modification of SPIONs has any influence on these membrane properties, we have used four types of differently functionalized SPIONs, such as: plain SPIONs (primary size was shown to bê11 nm), silica-coated SPIONs, SPIONs coated with silica and functionalized with positively charged amino groups or negatively charged carboxyl groups (the primary size of all the surface-modified SPIONs was ~20 nm). Small unilamellar vesicles prepared with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipids and multilamellar vesicles prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine lipids were encapsulated or incubated with the plain and surface-modified SPIONs to determine the fluidity and phase transition temperature of the bilayer lipids, respectively. Fluorescent anisotropy and differential scanning calorimetric measurements of the liposomes that were either encapsulated or incubated with the suspension of SPIONs did not show a significant difference in the lipid ordering and fluidity; though the encapsulated SPIONs showed a slightly increased effect on the fluidity of the model membranes in comparison with the incubated SPIONs. This indicates the low potential of the SPIONs to interact with the nontargeted cell membranes, which is a desirable factor for in vivo applications. PMID:26491286

  2. Pressure-dependent Transition from Atoms to Nanoparticles in Magnetron Sputtering: Effect on WSi2 Film Roughness and Stress

    SciTech Connect

    Zhou, L.; Wang, Y; Zhou, H; Li, M; Headrick, R; MacArthur, K; Shi, B; Conley, R; Macrander, A

    2010-01-01

    We report on the transition between two regimes from several-atom clusters to much larger nanoparticles in Ar magnetron sputter deposition of WSi{sub 2}, and the effect of nanoparticles on the properties of amorphous thin films and multilayers. Sputter deposition of thin films is monitored by in situ x-ray scattering, including x-ray reflectivity and grazing incidence small-angle x-ray scattering. The results show an abrupt transition at an Ar background pressure P{sub c}; the transition is associated with the threshold for energetic particle thermalization, which is known to scale as the product of the Ar pressure and the working distance between the magnetron source and the substrate surface. Below P{sub c} smooth films are produced while above P{sub c} roughness increases abruptly, consistent with a model in which particles aggregate in the deposition flux before reaching the growth surface. The results from WSi{sub 2} films are correlated with in situ measurement of stress in WSi{sub 2}/Si multilayers, which exhibits a corresponding transition from compressive to tensile stress at P{sub c}. The tensile stress is attributed to coalescence of nanoparticles and the elimination of nanovoids.

  3. Sedation in pediatric imaging using intranasal midazolam.

    PubMed

    Harcke, H T; Grissom, L E; Meister, M A

    1995-01-01

    Intranasal midazolam offers an attractive alternative for use as a sedative agent for medical imaging studies in children. Its convenient administration and rapid onset are significant advantages over intravenous and oral agents. Because of its short duration, it is effective only for short procedures and as an adjunct to other sedative agents. When younger children present with such requirements, a dose of 0.2 mg/kg has been safe and effective in our experience. We advocate its use with adherence to guidelines for sedation published by the American Academy of Pediatrics. PMID:7567258

  4. [Development of intranasal lactocin (oxytocin) drops technology].

    PubMed

    Klimas, Rimantas; Baranauskas, Algirdas; Gendrolis, Antanas

    2002-01-01

    Pure oxytocin substance was obtained from posterior part of cattle pituitary gland by high pressure liquid chromatography. Biological activity of the substance--450-500 IU/mg. Chromatographically pure Oxytocin substance was used in developing two different compositions of Lactocin intranasal drops (40 IU/ml). Stability evaluation was performed for 2 year period. The technical documentation was prepared on the basis of the research results. Lactocin is active preparation helping lactation and is indicated for lactostasis treatment and its prophylaxis after delivery. PMID:12474675

  5. High Content Screening in Zebrafish Speeds up Hazard Ranking of Transition Metal Oxide Nanoparticles

    PubMed Central

    Lin, Sijie; Zhao, Yan; Xia, Tian; Meng, Huan; Zhaoxia, Ji; Liu, Rong; George, Saji; Xiong, Sijing; Wang, Xiang; Zhang, Haiyuan; Pokhrel, Suman; Mädler, Lutz; Damoiseaux, Robert; Lin, Shuo; Nel, Andre E.

    2014-01-01

    Zebrafish is an aquatic organism that can be used for high content safety screening of engineered nanomaterials (ENMs). We demonstrate, for the first time, the use of high content bright-field and fluorescence-based imaging to compare the toxicological effect of transition metal oxide (CuO, ZnO, NiO and Co3O4) nanoparticles in zebrafish embryos and larvae. High content bright-field imaging demonstrated potent and dose-dependant hatching interference in the embryos, with the exception of Co3O4 which was relatively inert. We propose that the hatching interference was due to the shedding of Cu and Ni ions, compromising the activity of the hatching enzyme, ZHE1, similar to what we previously proposed for Zn2+. This hypothesis is based on the presence of metal–sensitive histidines in the catalytic center of this enzyme. Co-introduction of a metal ion chelator, diethylene triamine pentaacetic acid (DTPA), reversed the hatching interference of Cu, Zn and Ni. While neither the embryos nor larvae demonstrated morphological abnormalities, high content fluorescence-based imaging demonstrated that CuO, ZnO and NiO could induce increased expression of the heat shock protein 70:enhanced green fluorescence protein (hsp70:eGFP) in transgenic zebrafish larvae. Induction of this response by CuO required a higher nanoparticle dose than the amount leading to hatching interference. This response was also DTPA sensitive. In conclusion, we demonstrate that high content imaging of embryo development, morphological abnormalities and HSP70 expression can be used for hazard ranking and determining the dose-response relationships leading to ENM effects on the development of the zebrafish embryo. PMID:21851096

  6. Transition metal-chelating surfactant micelle templates for facile synthesis of mesoporous silica nanoparticles

    SciTech Connect

    Lee, Hye Sun; Kim, Won Hee; Lee, Jin Hyung; Choi, Doo Jin; Jeong, Young-Keun; Chang, Jeong Ho

    2012-01-15

    Highly ordered mesoporous silica nanoparticles with tunable morphology and pore-size are prepared by the use of a transition metal-chelating surfactant micelle complex using Co{sup 2+}, Ni{sup 2+}, Cu{sup 2+}, and Zn{sup 2+} ions. These metal ions formed a metal-P123 micelle complex in an aqueous solution, while the metal ions are chelated to the hydrophilic domain such as the poly(ethylene oxide) group of a P123 surfactant. The different complexation abilities of the utilized transition metal ions play an important role in determining the formation of nano-sized ordered MSNs due to the different stabilization constant of the metal-P123 complex. Consequently, from a particle length of 1700 nm in the original mesoporous silica materials, the particle length of ordered MSNs through the metal-chelating P123 micelle templates can be reduced to a range of 180-800 nm. Furthermore, the variation of pore size shows a slight change from 8.8 to 6.6 nm. In particular, the Cu{sup 2+}-chelated MSNs show only decreased particle size to 180 nm. The stability constants for the metal-P123 complex are calculated on the basis of molar conductance measurements in order to elucidate the formation mechanism of MSNs by the metal-chelating P123 complex templates. In addition, solid-state {sup 29}Si, {sup 13}C-NMR and ICP-OES measurements are used for quantitative characterization reveal that the utilized metal ions affect only the formation of a metal-P123 complex in a micelle as a template. - Graphical abstract: Metal-chelating surfactant micelle templates support a simple and facile preparations of size-tunable ordered MSNs. Black-Small-Square Highlights: Black-Right-Pointing-Pointer Facile preparation of mesoporous silica nanoparticles (MSNs) was achieved by metal-chelating surfactant micelle complex using Co{sup 2+}, Ni{sup 2+}, Cu{sup 2+}, and Zn{sup 2+} ions. Black-Right-Pointing-Pointer Different complexation of metal ions plays an important role in determining the formation of

  7. Effect of annealing temperature on magnetic phase transition in Fe3O4 nanoparticles

    NASA Astrophysics Data System (ADS)

    Jafari, A.; Farjami Shayesteh, S.; Salouti, M.; Boustani, K.

    2015-04-01

    Fe3O4 (magnetite) nanoparticles (NPs) were synthesized using a co-precipitation method, and then annealed at various temperatures between 50 and 850 °C for 1 h in air. After annealing, the NPs were characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy and vibrating sample magnetometer (VSM). The FTIR and XRD results indicated that Fe3O4 NPs were converted to γ-Fe2O3 (maghemite) by annealing at 250 °C for 1 h and then to α-Fe2O3 (hematite) on annealing in the range of 550-650 °C. The average crystallite size of the NPs estimated by the Debye-Scherrer equation increased from 6.6 to 37.6 nm by increasing annealing temperature from 50 to 850 °C. According to VSM results, the magnetite NPs were superparamagnetic and converted to the maghemite with superparamagnetic phase by annealing up to 550 °C. A phase transition from soft to hard ferromagnetic was occurred at annealing temperature 650 and 850 °C, respectively °C. This phase transition was attributed to the conversion of magnetite to hematite. The VSM analysis confirmed the XRD and FTIR results. The saturation magnetization (Ms) of Fe3O4 NPs was increased from 41.69 to 53.61 emu/g by increasing annealing temperature from 50 to 550 °C, and then decreased intensively to 0.49 emu/g after annealing at 850 °C. By increasing annealing temperature from 50 to 550, the crystallite size of NPs was increased from 6.6 to 12.7 and the coercive force (Hc) was reached to 4.20 Oe after annealing at 550 °C and then intensively increased to 1459.02 Oe for any further increasing of particle size up to 850 °C.

  8. Seeded growth of ferrite nanoparticles from Mn oxides: observation of anomalies in magnetic transitions.

    PubMed

    Song, Hyon-Min; Zink, Jeffrey I; Khashab, Niveen M

    2015-07-28

    A series of magnetically active ferrite nanoparticles (NPs) are prepared by using Mn oxide NPs as seeds. A Verwey transition is identified in Fe3O4 NPs with an average diameter of 14.5 nm at 96 K, where a sharp drop of magnetic susceptibility occurs. In MnFe2O4 NPs, a spin glass-like state is observed with the decrease in magnetization below the blocking temperature due to the disordered spins during the freezing process. From these MnFe2O4 NPs, MnFe2O4@Mn(x)Fe(1-x)O core-shell NPs are prepared by seeded growth. The structure of the core is cubic spinel (Fd3¯m), and the shell is composed of iron-manganese oxide (Mn(x)Fe(1-x)O) with a rock salt structure (Fm3¯m). Moiré fringes appear perpendicular to the 〈110〉 directions on the cubic shape NPs through the plane-matched epitaxial growth. These fringes are due to the difference in the lattice spacings between MnFe2O4 and Mn(x)Fe(1-x)O. Exchange bias is observed in these MnFe2O4@Mn(x)Fe(1-x)O core-shell NPs with an enhanced coercivity, as well as the shift of hysteresis along the field direction. PMID:26123580

  9. ENERGY CONVERSION FOR THE TRANSITION FROM Al TO γ-Al2O3 NANOPARTICLES

    NASA Astrophysics Data System (ADS)

    Wang, Shulin; Li, Shengjuan; Xu, Bo; Jian, Dunliang; Zhu, Yufang

    2013-07-01

    We have successfully converted large volume Al particles into γ-Al2O3 nanostructures by vibration milling at room temperature and successive treatment. We show that there exist special relationships among stacking fault energy (SFE), strain energy (SRE), and surface energy (SE) of the materials, including interdependence, intercompetition, and interconversion during the phase transition. SFE and SRE perform the same changing tendency, while SE just does the opposite. However, it is not the particle size but the energy state that determines the reactivity of the materials. And it is the SE that can directly determine the physical chemical reaction and the conversion into the end product rather than SFE and SRE. When SE goes up, the material reactivity and the product yield will be enhanced; and when SE goes down, the reaction and the product yield will decay. However, the state of SE depends closely on the change tendency of the SFE and SRE. That is, when SFE and SRE goes up, SE will goes down; if SFE and SRE goes down, SE will goes up. It seems that energy conservation law may be followed in a sense in the particle system if the external input keeps constant. The work may be significant for energy conversion in nano-scale and mechanosynthesis of oxide nanoparticles.

  10. Plasmon coupling between silver nanoparticles: Transition from the classical to the quantum regime.

    PubMed

    Cha, Hoon; Lee, Daedu; Yoon, Jun Hee; Yoon, Sangwoon

    2016-02-15

    We explore plasmon coupling between silver nanoparticles (AgNPs) as two AgNPs approach each other within a subnanometer distance. We prepare AgNP dimers with two 21-nm AgNPs separated by alkanedithiol linkers in high yield. Changing the length of the alkanedithiol linkers enables us to control the interparticle distance down to the subnanometer level on the molecular scale. We observe that the longitudinal plasmon coupling band, which is sensitive to the interaction between AgNPs, gradually redshifts as the interparticle distance decreases. This observation is fully consistent with the classical electromagnetic model. The redshift of the plasmon coupling, however, undergoes a drastic change when the interparticle distance reaches ∼1nm. The longitudinal plasmon coupling band vanishes and a new intense band appears at a shorter wavelength. This band redshifts as the nanogap further narrows, but crosses over to a blueshift at ∼0.7nm. A comparison of our observation with finite-difference time-domain simulations reveals that this band arises from quantum effects. Controlled assembly of AgNP dimers in combination with simulations allows us to observe the transition of the plasmon coupling from the classical to the quantum regime at the ensemble level. PMID:26606377

  11. Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression.

    PubMed

    Andrade, Chittaranjan

    2015-05-01

    Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression. PMID:26035196

  12. Intranasal medications for the treatment of migraine and cluster headache.

    PubMed

    Rapoport, Alan M; Bigal, Marcelo E; Tepper, Stewart J; Sheftell, Fred D

    2004-01-01

    Intranasal medications for the treatment of headache have recently received increased attention. This paper reviews intranasal formulations of a variety of available medications (dihydroergotamine mesylate [dihydroergotamine mesilate], sumatriptan, zolmitriptan, butorphanol, capsaicin and lidocaine [lignocaine]) and one experimental medication (civamide, a cis-isomer of capsaicin) for the treatment of migraine and cluster headache. Although the efficacy of intranasal agents varies with the product used, intranasal delivery may be both convenient and more effective than other modes of drug delivery for a variety of reasons: (i) intranasal administration bypasses small bowel gastrointestinal tract absorption, which is often significantly delayed during the acute phase of a migraine attack; (ii) nauseated patients may prefer non-oral formulations as they decrease the chance of vomiting and are more rapidly effective; (iii) intranasal administration causes no pain or injection site reaction and is easier and more convenient to administer than injection or suppository and so may be used earlier in a migraine attack, resulting in better efficacy; (iv) intranasal medication produces the same number or fewer adverse events than injections; and (v) intranasal formulations offer a more rapid onset of action than oral medications, for some of the above reasons and, as such, may be more useful in patients with cluster headache, although this needs to be verified. However, it is important to emphasise that a preference study showed that most patients prefer oral tablets to an intranasal formulation. Also, some nasal preparations have significant adverse effects or are not well absorbed and therefore do not work consistently; others are more challenging to administer as a result of their delivery apparatus. Nevertheless, it is our opinion that nasal preparations increase therapeutic options and may result in faster response times and better efficacy than oral formulations and

  13. Electrocatalytic reduction of carbon dioxide on post-transition metal and metal oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    White, James L.

    The electroreduction of carbon dioxide to liquid products is an important component in the utilization of CO2 and in the high-density storage of intermittent renewable energy in the form of chemical bonds. Materials based on indium and tin, which yield predominantly formic acid, have been investigated in order to gain a greater understanding of the electrochemically active species and the mechanism of CO2 reduction on these heavy post-transition metals, since prior studies on the bulk metals did not provide thermodynamically sensible reaction pathways. Nanoparticles of the oxides and hydroxides of tin and indium have been prepared and characterized by transmission electron microscopy, X-ray diffractometry, X-ray photoelectron spectroscopy, and various electrochemical methods in order to obtain structural information and analyze the role of various surface species on the CO2 reduction pathway. On both indium and tin, metastable surface-bound hydroxides bound CO2 and formed metal carbonates, which can then be reduced electrochemically. The relevant oxidation state of tin was suggested to be SnII rather than SnIV, necessitating a pre reduction to generate the CO2-binding species. Metallic indium nanoparticles partially oxidized in air and became highly efficient CO2 reduction electrocatalysts. Unit Faradaic efficiencies for formate, much higher than on bulk indium, were achieved with only 300 mV of overpotential on these particles, which possessed an oxyhydroxide shell surrounding a conductive metallic core. Alloys and mixed-metal oxide and hydroxide particles of tin and indium have also been studied for their carbon dioxide electrocatalytic capabilities, especially in comparison to the pure metal species. Additionally, a solar-driven indium-based CO2 electrolyzer was developed to investigate the overall efficiency for intermittent energy storage. The three flow cells were powered by a commercial photovoltaic array and had a maximum conversion efficiency of incident

  14. Direct Observation of Amorphous to Crystalline Phase Transitions in Nano-Particle Arrays of Phase Change Materials

    SciTech Connect

    Raoux,S.; Rettner, C.; Jordan-Sweet, J.; Kellock, A.; Topuria, T.; Rice, P.; Miller, D.

    2007-01-01

    We have used time-resolved x-ray diffraction to study the amorphous-crystalline phase transition in 20-80?nm particles of the phase change materials Ge2Sb2Te5, nitrogen-doped Ge2Sb2Te5, Ge15Sb85, Sb2Te, and Sb2Te doped with Ag and In. We find that all samples undergo the phase transition with crystallization temperatures close to those of similarly prepared blanket films of the same materials with the exception of Sb2Te that shows the transition at a temperature that is about 40? C higher than that of blanket films. Some of the nanoparticles show a difference in crystallographic texture compared to thick films. Large area arrays of these nanoparticles were fabricated using electron-beam lithography, keeping the sample temperatures well below the crystallization temperatures so as to produce particles that were entirely in the amorphous phase. The observation that particles with diameters as small as 20?nm can still undergo this phase transition indicates that phase change solid-state memory technology should scale to these dimensions.

  15. Spin-flop transition, magnetic and microwave absorption properties of α-Fe2O4 spinel type ferrite nanoparticles

    NASA Astrophysics Data System (ADS)

    Yalçın, Orhan; Bayrakdar, Harun; Özüm, Songül

    2013-10-01

    We have prepared NiFe2O4, CoFe2O4, Ni0.6Zn0.4Fe2O4 and ZnFe2O4 spinel type ferrite nanoparticles by surfactant-assisted hydrothermal process using cetyltrimethylammonium bromide (CTAB). The spin-flop transition, magnetic, dielectric and permittivity characterizations have been investigated. The spin-flop transition occurs from antiferromagnetic state to mixed state and then ferromagnetic state for Zn doped samples. The spin-flop transition occurs in the temperature range of 50-250 K. The ionic conduction, dipolar relaxation, atomic polarization and electronic polarization are the main mechanisms that contribute to the permittivity of a dielectric material. The permittivity increases with increasing frequency. This suggests a resonance behavior, which is expected when the ferrite samples are highly conductive and skin effect become significant. These samples will provide great benefits for electromagnetic applications and electromagnetic interference shielding characteristics.

  16. Nanoparticle-Induced Ellipse-to-Vesicle Morphology Transition of Rod-Coil-Rod Triblock Copolymer Aggregates.

    PubMed

    Yang, Chaoying; Li, Qing; Cai, Chunhua; Lin, Jiaping

    2016-07-12

    Cooperative self-assembly behavior of rod-coil-rod poly(γ-benzyl-l-glutamate)-block-poly(ethylene glycol)-block-poly(γ-benzyl-l-glutamate) (PBLG-b-PEG-b-PBLG) amphiphilic triblock copolymers and hydrophobic gold nanoparticles (AuNPs) was investigated by both experiments and dissipative particle dynamics (DPD) simulations. It was discovered that pure PBLG-b-PEG-b-PBLG copolymers self-assemble into ellipse-like aggregates, and the morphology transforms into vesicles as AuNPs are introduced. When the hydrophobicity of AuNPs is close to that of the copolymers, AuNPs are homogeneously distributed in the vesicle wall. While for the AuNPs with higher hydrophobicity, they are embedded in the vesicle wall as clusters. In addition to the experimental observations, DPD simulations were performed on the self-assembly behavior of triblock copolymer/nanoparticle mixtures. Simulations well reproduced the morphology transition observed in the experiments and provided additional information such as chain packing mode in aggregates. It is deduced that the main reason for the ellipse-to-vesicle transition of the aggregates is attributed to the breakage of ordered and dense packing of PBLG rods in the aggregate core by encapsulating AuNPs. This study deepens our understanding of the self-assembly behavior of rod-coil copolymer/nanoparticle mixtures and provides strategy for designing hybrid polypeptide nanostructures. PMID:27314970

  17. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route.

    PubMed

    Jain, Darshana S; Bajaj, Amrita N; Athawale, Rajani B; Shikhande, Shruti S; Pandey, Abhijeet; Goel, Peeyush N; Gude, Rajiv P; Patil, Satish; Raut, Preeti

    2016-06-01

    Delivery of drugs to the brain via nasal route has been studied by many researchers. However, low residence time, mucociliary clearance and enzymatically active environment of nasal cavity pose many challenges to successful nasal delivery of drugs. We aim to deliver methotrexate by designing thermosensitive nanodispersion exhibiting enhanced residence time in nasal cavity and bypassing the blood brain barrier (BBB). PLA nanoparticles were developed using solvent evaporation technique. The developed nanoparticles were further dispersed in prepared thermosensitive vehicle of poloxamer 188 and Carbopol 934 to impart the property of increased residence time. The formulated nanoparticles demonstrated no interaction with the simulated nasal fluids (SNF), mucin, serum proteins and erythrocytes which demonstrate the safety of developed formulation for nasal administration. The penetration property of nanoparticles though the nasal mucosa was higher than the pure drug due to low mucociliary clearance. The developed nanoparticles diffused though the membrane pores and rapidly distributed into the brain portions compared to the pure drug. There was detectable and quantifiable amount of drug seen in the brain as demonstrated by in vivo brain distribution studies with considerably low amount of drug deposition in the lungs. The pharmacokinetic parameters demonstrated the enhancement in circulation half life, area under curve (AUC) and Cmax of the drug when administered intranasal in encapsulated form. Thus, the thermosensitive nanodispersions are surely promising delivery systems for delivering anticancer agents though the nasal route for potential treatment of brain tumors. PMID:27040235

  18. Phase Transition of Iron-Platinum Nanoparticles Prepared in Water-In-Oil Microemulsions

    NASA Astrophysics Data System (ADS)

    Hyie, Koay Mei; Yaacob, Iskandar Idris

    2009-06-01

    FePt nanoparticles were successfully prepared in water-in-oil microemulsions. Two different atmospheric conditions were used during annealing—argon and forming gas (95% argon+5% hydrogen). X-ray diffraction (XRD) result showed that fcc FePt nanoparticles annealed in forming gas atmosphere transformed into Pt3Fe phase. However, the as-synthesized fcc FePt could not be transformed to other phase in argon gas atmosphere. Variation of water/surfactant (w) ratio of 0.3, 0.5 and 0.65 were also investigated in order to produce fct FePt nanoparticles. After annealing at 700° C in forming gas atmosphere, FePt nanoparticles produced using w of 0.5 transformed into the ordered face centered tetragonal (fct) FePt structure while the nanoparticles formed using w of 0.3 and 0.65 turned into Pt3Fe phase.

  19. Non-Clinical Safety Evaluation of Intranasal Iota-Carrageenan

    PubMed Central

    Hebar, Alexandra; Koller, Christiane; Seifert, Jan-Marcus; Chabicovsky, Monika; Bodenteich, Angelika; Bernkop-Schnürch, Andreas; Grassauer, Andreas; Prieschl-Grassauer, Eva

    2015-01-01

    Carrageenan has been widely used as food additive for decades and therefore, an extended oral data set is available in the public domain. Less data are available for other routes of administration, especially intranasal administration. The current publication describes the non-clinical safety and toxicity of native (non-degraded) iota-carrageenan when applied intranasally or via inhalation. Intranasally applied iota-carrageenan is a topically applied, locally acting compound with no need of systemic bioavailability for the drug’s action. Animal experiments included repeated dose local tolerance and toxicity studies with intranasally applied 0.12% iota-carrageenan for 7 or 28 days in New Zealand White rabbits and nebulized 0.12% iota-carrageenan administered to F344 rats for 7 days. Permeation studies revealed no penetration of iota-carrageenan across nasal mucosa, demonstrating that iota-carrageenan does not reach the blood stream. Consistent with this, no relevant toxic or secondary pharmacological effects due to systemic exposure were observed in the rabbit or rat repeated dose toxicity studies. Data do not provide any evidence for local intolerance or toxicity, when carrageenan is applied intranasally or by inhalation. No signs for immunogenicity or immunotoxicity have been observed in the in vivo studies. This is substantiated by in vitro assays showing no stimulation of a panel of pro-inflammatory cytokines by iota-carrageenan. In conclusion, 0.12% iota-carrageenan is safe for clinical use via intranasal application. PMID:25875737

  20. Inside the brachycephalic nose: intranasal mucosal contact points.

    PubMed

    Schuenemann, Riccarda; Oechtering, Gerhard U

    2014-01-01

    The purpose of this study was to evaluate the prevalence of intranasal mucosal contact points in brachycephalic and normocephalic dogs. In total, 82 brachycephalic dogs (42 pugs and 40 French bulldogs) were evaluated by rhinoscopy for their intranasal mucosal contact and 25 normocephalic dogs were evaluated as a control group. Of those, 162 brachycephalic nasal cavities were evaluable and 140 had contact between intranasal structures (87%). Intraconchal and septoconchal mucosal contact points were the most commonly detected sites of contact. French bulldogs had a significantly higher prevalence of mucosal contact and had 3 mean contact points compared with 1.7 mean contact points per nasal cavity in pugs. Septal deviations were present in 62% of brachycephalic dogs. In the control group, mucosal contact points were present in only 7 of 50 nasal cavities (14%), and septal deviations occurred in 16% of those cases. Contact point average was 0.1 in large and 0.3 in small normocephalic dogs. Intranasal mucosal contact was identified as a common and previously unreported problem in brachycephalic dogs. Numerous contact points reduce the lumen of the intranasal passageways and indicate potential intranasal obstruction. Affected dogs might benefit from removal of obstructing conchae, potentially using laser-assisted turbinectomy. PMID:24659729

  1. Growth of Hollow Transition Metal (Fe, Co, Ni) Oxide Nanoparticles on Graphene Sheets through Kirkendall Effect as Anodes for High-Performance Lithium-Ion Batteries.

    PubMed

    Yu, Xianbo; Qu, Bin; Zhao, Yang; Li, Chunyan; Chen, Yujin; Sun, Chunwen; Gao, Peng; Zhu, Chunling

    2016-01-26

    A general strategy based on the nanoscale Kirkendall effect has been developed to grow hollow transition metal (Fe, Co or Ni) oxide nanoparticles on graphene sheets. When applied as lithium-ion battery anodes, these hollow transition metal oxide-based composites exhibit excellent electrochemical performance, with high reversible capacities and long-term stabilities at a high current density, superior to most transition metal oxides reported to date. PMID:26502895

  2. Size-Dependent Multi- to Single Domain Transition of UV Laser-Driven Ferromagnetic Co Nanoparticles Under External Magnetic Field.

    PubMed

    Lee, Jun Seok; Lee, Ja Bin; Yang, Jung Yup; Hong, Jin Pyo

    2015-06-01

    The magnetic domain of cobalt (Co) nanoparticles (NPs) was studied as a function of particle size. Various single crystalline and uniform Co NPs were prepared using a novel UV laser irradiation technique on ultra thin Co films under an external applied magnetic field. Structural and magnetic characteristics were analyzed with transmission electron microscopy and superconducting quantum interference devices. The experimental observations indicate that during Co NP growth, externally applied magnetic fields and size-dependent NP surface effects strongly facilitate multi-to-single domain transition at a critical diameter of about 10 nm, an extremely small NP size that is suitable for higher density storage applications. PMID:26369084

  3. Ultrafast Control of a Surface Plasmon Resonance via the Insulator to Metal Transition in V02 Nanoparticles

    SciTech Connect

    Rini, Matteo; Cavalleri, Andrea; Lopez, R.; Boatner, Lynn A; Haglund, Jr, Richard F; Haynes, Tony E; Feldman, Leonard C.

    2005-01-01

    We report on the study of the ultrafast insulator-to-metal transition in nanoparticles of strongly correlated VO2. The particles are grown by ion-implantation and self-assembly in a Silica matrix and can be switched between the insulating and metallic phase within less than 100 fs. The prompt formation of the metallic state results in the appearance of a surface-plasmon resonance that is absent in the bulk and can be further tailored by controlling the particle shape.

  4. Transitions.

    ERIC Educational Resources Information Center

    Nathanson, Jeanne H., Ed.

    1993-01-01

    This theme issue on transitions for individuals with disabilities contains nine papers discussing transition programs and issues. "Transition Issues for the 1990s," by Michael J. Ward and William D. Halloran, discusses self-determination, school responsibility for transition, continued educational engagement of at-risk students, and service…

  5. An expeditious synthesis of early transition metal carbide nanoparticles on graphitic carbons.

    PubMed

    Ressnig, Debora; Moldovan, Simona; Ersen, Ovidiu; Beaunier, Patricia; Portehault, David; Sanchez, Clément; Carenco, Sophie

    2016-08-01

    An expeditious synthesis of metal carbide nanoparticles onto various carbon supports is demonstrated. The procedure is versatile and readily yields TiC, VC, Mo2C and W2C nanoparticles on different types of carbons. The reaction is initiated at room temperature and proceeds within seconds. This novel synthetic route paves the way for a large variety of metal carbide-carbon nanocomposites that may be implemented in emerging nanotechnology fields. PMID:27383864

  6. Transition-metal-ion-mediated polymerization of dopamine: mussel-inspired approach for the facile synthesis of robust transition-metal nanoparticle-graphene hybrids.

    PubMed

    Yang, Liping; Kong, Junhua; Zhou, Dan; Ang, Jia Ming; Phua, Si Lei; Yee, Wu Aik; Liu, Hai; Huang, Yizhong; Lu, Xuehong

    2014-06-16

    Inspired by the high transition-metal-ion content in mussel glues, and the cross-linking and mechanical reinforcement effects of some transition-metal ions in mussel threads, high concentrations of nickel(II), cobalt(II), and manganese(II) ions have been purposely introduced into the reaction system for dopamine polymerization. Kinetics studies were conducted for the Ni(2+)-dopamine system to investigate the polymerization mechanism. The results show that the Ni(2+) ions could accelerate the assembly of dopamine oligomers in the polymerization process. Spectroscopic and electron microscopic studies reveal that the Ni(2+) ions are chelated with polydopamine (PDA) units, forming homogeneous Ni(2+)-PDA complexes. This facile one-pot approach is utilized to construct transition-metal-ion-PDA complex thin coatings on graphene oxide, which can be carbonized to produce robust hybrid nanosheets with well-dispersed metallic nickel/metallic cobalt/manganese(II) oxide nanoparticles embedded in PDA-derived thin graphitic carbon layers. The nickel-graphene hybrid prepared by using this approach shows good catalytic properties and recyclability for the reduction of p-nitrophenol. PMID:24862644

  7. Elimination of photon quenching by a transition layer to fabricate a quenching-shield sandwich structure for 800 nm excited upconversion luminescence of Nd3+-sensitized nanoparticles.

    PubMed

    Zhong, Yeteng; Tian, Gan; Gu, Zhanjun; Yang, Yijun; Gu, Lin; Zhao, Yuliang; Ma, Ying; Yao, Jiannian

    2014-05-01

    Nd3+-sensitized quenching-shield sandwich-structured upconversion nanoparticles are reported, which exhibit highly efficient upconversion photoluminescence under excitation by an 800 nm continuous-wave laser. The transition-layer structure is essential to bridge energy transfer from the sensitizer to the activator and simultaneously block energy back-transfer from the activator to the sensitizer. These 800 nm-excited upconversion nanoparticles are a key step toward the development of upconversion nanophosphors for biological applications. PMID:24338994

  8. Intranasal oxytocin effects on social cognition: a critique

    PubMed Central

    Evans, Simon L.; Monte, Olga Dal; Noble, Pamela; Averbeck, Bruno B.

    2014-01-01

    The last decade has seen a large number of published findings supporting the hypothesis that intranasally delivered oxytocin (OT) can enhance the processing of social stimuli and regulate social emotion-related behaviors such as trust, memory, fidelity, and anxiety. The use of nasal spray for administering OT in behavioral research has become a standard method, but many questions still exist regarding its action. OT is a peptide that cannot cross the blood-brain barrier, and it has yet to be shown that it does indeed reach the brain when delivered intranasally. Given the evidence, it seems highly likely that OT does affect behavior when delivered as a nasal spray. These effects may be driven by at least three possible mechanisms. First, the intranasally delivered OT may diffuse directly into the CNS where it directly engages OT receptors. Second, the intranasally delivered OT may trigger increased central release via an indirect peripheral mechanism. And third, the indirect peripheral effects may directly lead to behavioral effects via some mechanism other than increased central release. Although intranasally delivered OT likely affects behavior, there are conflicting reports as to the exact nature of those behavioral changes: some studies suggest that OT effects are not always “pro-social” and others suggest effects on social behaviors are due to a more general anxiolytic effect. In this critique, we draw from work in healthy human populations and the animal literature to review the mechanistic aspects of intranasal OT delivery, and to discuss intranasal OT effects on social cognition and behavior. We conclude that future work should control carefully for anxiolytic and gender effects, which could underlie inconsistencies in the existing literature. PMID:24239931

  9. 2D dynamical arrest transition in a mixed nanoparticle-phospholipid layer studied in real and momentum spaces.

    PubMed

    Orsi, Davide; Guzmán, Eduardo; Liggieri, Libero; Ravera, Francesca; Ruta, Beatrice; Chushkin, Yuriy; Rimoldi, Tiziano; Cristofolini, Luigi

    2015-01-01

    We investigate the interfacial dynamics of a 2D self-organized mixed layer made of silica nanoparticles interacting with phospholipid (DPPC) monolayers at the air/water interface. This system has biological relevance, allowing investigation of toxicological effects of nanoparticles on model membranes and lung surfactants. It might also provide bio-inspired technological solutions, exploiting the self-organization of DPPC to produce a non-trivial 2D structuration of nanoparticles. The characterization of interfacial dynamics yields information on the effects of NPs on the mechanical properties, important to improve performances of systems such as colloidosomes, foams, creams. For this, we combine micro-tracking in real-space with measurement in momentum-space via x-ray photon-correlation spectroscopy and Digital Fourier Microscopy. Using these complementary techniques, we extend the spatial range of investigation beyond the limits of each one. We find a dynamical transition from Brownian diffusion to an arrested state driven by compression, characterized by intermittent rearrangements, compatible with a repulsive glass phase. The rearrangement and relaxation of the monolayer structure results dramatically hindered by the presence of NPs, which is relevant to explain some the mechanical features observed for the dynamic surface pressure response of these systems and which can be relevant for the respiratory physiology and for future drug-delivery composite systems. PMID:26658474

  10. 2D dynamical arrest transition in a mixed nanoparticle-phospholipid layer studied in real and momentum spaces

    PubMed Central

    Orsi, Davide; Guzmán, Eduardo; Liggieri, Libero; Ravera, Francesca; Ruta, Beatrice; Chushkin, Yuriy; Rimoldi, Tiziano; Cristofolini, Luigi

    2015-01-01

    We investigate the interfacial dynamics of a 2D self-organized mixed layer made of silica nanoparticles interacting with phospholipid (DPPC) monolayers at the air/water interface. This system has biological relevance, allowing investigation of toxicological effects of nanoparticles on model membranes and lung surfactants. It might also provide bio-inspired technological solutions, exploiting the self-organization of DPPC to produce a non-trivial 2D structuration of nanoparticles. The characterization of interfacial dynamics yields information on the effects of NPs on the mechanical properties, important to improve performances of systems such as colloidosomes, foams, creams. For this, we combine micro-tracking in real-space with measurement in momentum-space via x-ray photon-correlation spectroscopy and Digital Fourier Microscopy. Using these complementary techniques, we extend the spatial range of investigation beyond the limits of each one. We find a dynamical transition from Brownian diffusion to an arrested state driven by compression, characterized by intermittent rearrangements, compatible with a repulsive glass phase. The rearrangement and relaxation of the monolayer structure results dramatically hindered by the presence of NPs, which is relevant to explain some the mechanical features observed for the dynamic surface pressure response of these systems and which can be relevant for the respiratory physiology and for future drug-delivery composite systems. PMID:26658474

  11. 2D dynamical arrest transition in a mixed nanoparticle-phospholipid layer studied in real and momentum spaces

    NASA Astrophysics Data System (ADS)

    Orsi, Davide; Guzmán, Eduardo; Liggieri, Libero; Ravera, Francesca; Ruta, Beatrice; Chushkin, Yuriy; Rimoldi, Tiziano; Cristofolini, Luigi

    2015-12-01

    We investigate the interfacial dynamics of a 2D self-organized mixed layer made of silica nanoparticles interacting with phospholipid (DPPC) monolayers at the air/water interface. This system has biological relevance, allowing investigation of toxicological effects of nanoparticles on model membranes and lung surfactants. It might also provide bio-inspired technological solutions, exploiting the self-organization of DPPC to produce a non-trivial 2D structuration of nanoparticles. The characterization of interfacial dynamics yields information on the effects of NPs on the mechanical properties, important to improve performances of systems such as colloidosomes, foams, creams. For this, we combine micro-tracking in real-space with measurement in momentum-space via x-ray photon-correlation spectroscopy and Digital Fourier Microscopy. Using these complementary techniques, we extend the spatial range of investigation beyond the limits of each one. We find a dynamical transition from Brownian diffusion to an arrested state driven by compression, characterized by intermittent rearrangements, compatible with a repulsive glass phase. The rearrangement and relaxation of the monolayer structure results dramatically hindered by the presence of NPs, which is relevant to explain some the mechanical features observed for the dynamic surface pressure response of these systems and which can be relevant for the respiratory physiology and for future drug-delivery composite systems.

  12. The use of Midazolam as an Intranasal Sedative in Dentistry.

    PubMed

    Greaves, Anwen

    2016-01-01

    The administration of midazolam intranasally exploits the unique structure of the nasopharynx thus ensuring rapid delivery to the systemic circulation (The Nose - Brain Pathway). The absorption of midazolam nasally is influenced by the volume and concentration of midazolam, its physicochemical properties and the characteristics of the nasal mucosa. Delivering midazolam intranasally is non-titratable. The level of conscious sedation may be equivalent to that achieved by intravenous routes but is approached in a less controlled manner. Randomised Control trials using intranasal sedation in children have shown the technique to be safe and effective in secondary care for dental procedures at concentrations varying from 0.2 mg/kg to 0.5 mg/kg. A combined technique of intranasal midazolam (to facilitate cannulation) and intravenous midazolam is used for adults with moderate to severe learning disabilities. This has revolutionised dental treatment for this group of patients as treatment under General Anaesthesia (GA) may be avoided. Intranasal delivery of midazolam is emerging as a significant tool in our dental armamentarium for the treatment of anxious children, phobic adult patients and patients with learning disabilities. PMID:27145560

  13. Transitions.

    ERIC Educational Resources Information Center

    Field, David; And Others

    1992-01-01

    Includes four articles: "Career Aspirations" (Field); "Making the Transition to a New Curriculum" (Baker, Householder); "How about a 'Work to School' Transition?" (Glasberg); and "Technological Improvisation: Bringing CNC to Woodworking" (Charles, McDuffie). (SK)

  14. Transition.

    ERIC Educational Resources Information Center

    Thompson, Sandy, Ed.; And Others

    1990-01-01

    This "feature issue" focuses on transition from school to adult life for persons with disabilities. Included are "success stories," brief program descriptions, and a list of resources. Individual articles include the following titles and authors: "Transition: An Energizing Concept" (Paul Bates); "Transition Issues for the 1990s" (William Halloran…

  15. Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)

    NASA Technical Reports Server (NTRS)

    Boyd, Jason L.; Du, Brian; Daniels, Vernie; Simmons, Rita; Buckey, Jay; Putcha, Lakshmi

    2009-01-01

    Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during early flight days of space missions. Orally administered scopolamine is commonly used by astronauts to prevent SMS. Bioavailability of oral (PO) SMS medications is often low and highly variable. Intranasal (IN) administration of medications achieves higher and more reliable bioavailability than from an equivalent PO dose. Methods: To test the safety and reliability of INSCOP, two clinical studies were performed, a dose escalation study and a comparison study administering INSCOP during normal ambulation and head down tilt bedrest. Efficacy was evaluated by testing INSCOP with two, different motion sickness inducing paradigms. Results: Preliminary results indicate that INSCOP demonstrates linear pharmacokinetics and a low side effect profile. In head down tilt bedrest, relative bioavailability of INSCOP was increased for females at both doses (0.2 and 0.4 mg) and for males at the higher dose (0.4 mg) but is reduced at the lower dose (0.2 mg) compared to normal ambulation. INSCOP displays gender specific differences during ABR. One of the treatment efficacy trials conducted at Dartmouth Hitchcock Medical Center demonstrated that INSCOP is efficacious at both doses (0.2 and 0.4 mg) in suppressing motion sickness symptoms as indicated by longer chair ride times with INSCOP administration than with placebo, and efficacy increases with dose. Similar results were seen using another motion sickness simulator, the motion simulator dome, at the Naval Aerospace Medical Research Laboratory, with significantly increased time in the dome in motion-susceptible subjects when using INSCOP compared to untreated controls. Conclusion: Higher bioavailability, linear pharmacokinetics, a low incidence of side effects, and a favorable efficacy profile make INSCOP a desirable formulation for prophylactic and rescue treatment of astronauts in space and military personnel on

  16. New strategies to improve the intranasal absorption of insulin.

    PubMed

    Duan, Xiaopin; Mao, Shirui

    2010-06-01

    Recently, intranasal delivery of insulin as an alternative route of parenteral administration has been widely studied because it bears close resemblance to the 'pulsatile' pattern of endogenous insulin secretion during meal time. However, insulin is not well absorbed through nasal mucosa because of its large molecular size, hydrophilicity and low permeability through the membrane. This review describes the main barriers preventing nasal insulin absorption, and special attention is given to new approaches to improve the intranasal absorption of insulin, including the application of new safe absorption enhancers and the use of appropriate delivery systems. It seems that bioadhesive delivery systems or water-insoluble powders with absorption enhancers are the most promising methods for intranasal delivery of insulin. PMID:20359545

  17. Intranasal curcumin and its evaluation in murine model of asthma.

    PubMed

    Subhashini; Chauhan, Preeti S; Kumari, Sharda; Kumar, Jarajana Pradeep; Chawla, Ruchi; Dash, D; Singh, Mandavi; Singh, Rashmi

    2013-11-01

    Curcumin, a phytochemical present in turmeric, rhizome of Curcuma longa, has been shown to have a wide variety of pharmacological activities including anti-inflammatory, anti-allergic and anti-asthmatic properties. Curcumin is known for its low systemic bioavailability and rapid metabolization through oral route and has limited its applications. Over the recent decades, the interest in intranasal delivery as a non-invasive route for drugs has increased as target tissue for drug delivery since nasal mucosa offers numerous benefits. In this study, we evaluated intranasal curcumin following its absorption through nasal mucosa by a sensitive and validated high-performance liquid chromatography (HPLC) method for the determination of intranasal curcumin in mouse blood plasma and lung tissue. Intranasal curcumin has been detected in plasma after 15 min to 3 h at pharmacological dose (5 mg/kg, i.n.), which has shown anti-asthmatic potential by inhibiting bronchoconstriction and inflammatory cell recruitment to the lungs. At considerably lower doses has proved better than standard drug disodium cromoglycate (DSCG 50 mg/kg, i.p.) by affecting inflammatory cell infiltration and histamine release in mouse model of asthma. HPLC detection revealed that curcumin absorption in lungs has started after 30 min following intranasal administration and retained till 3h then declines. Present investigations suggest that intranasal curcumin (5.0 mg/kg, i.n.) has effectively being absorbed and detected in plasma and lungs both and suppressed airway inflammations at lower doses than the earlier doses used for detection (100-200 mg/kg, i.p.) for pharmacological studies (10-20 mg/kg, i.p.) in mouse model of asthma. Present study may prove the possibility of curcumin as complementary medication in the development of nasal drops to prevent airway inflammations and bronchoconstrictions in asthma without any side effect. PMID:24021755

  18. Demystifying FluMist, a new intranasal, live influenza vaccine.

    PubMed

    Mossad, Sherif B

    2003-09-01

    FluMist--a cold-adapted, live-attenuated, trivalent, intranasal influenza virus vaccine approved by the US Food and Drug Administration on June 17, 2003--has been shown to be safe and effective, but its role in the general prevention of influenza is yet to be defined. Intranasal administration is expected to be more acceptable than parenteral, particularly in children, but the potential for the shedding of live virus may pose a risk to anyone with a compromised immune system. PMID:14518575

  19. Intranasal midazolam for rapid sedation of an agitated patient

    PubMed Central

    Shrestha, Gentle Sunder; Joshi, Pankaj; Bhattarai, Krishna; Chhetri, Santosh; Acharya, Subhash Prasad

    2015-01-01

    Rapidly, establishing a difficult intravenous access in a dangerously agitated patient is a real challenge. Intranasal midazolam has been shown to be effective and safe for rapidly sedating patients before anesthesia, for procedural sedation and for control of seizure. Here, we report a patient in intensive care unit who was on mechanical ventilation and on inotropic support for management of septic shock and who turned out extremely agitated after accidental catheter removal. Intravenous access was successfully established following sedation with intranasal midazolam, using ultrasound guidance. PMID:26195863

  20. Chronic invasive fungal sinusitis associated with intranasal drug use.

    PubMed

    Pekala, Kelly R; Clavenna, Matthew J; Shockley, Ross; Weiss, Vivian L; Turner, Justin H

    2015-12-01

    Chronic invasive fungal sinusitis (CIFS) is a rare but potentially aggressive form of invasive fungal disease that occurs in immunocompetent patients. We report a case of CIFS in an otherwise healthy young adult associated with intranasal illicit drug abuse. The patient presented with nonhealing nasal septal and palatal perforations. Biopsy demonstrated invasive Aspergillus flavus requiring surgical debridement and extended intravenous antifungal therapy. Tissue necrosis and ulceration related to intranasal drug use should be recognized as a potential risk factor for invasive fungal sinusitis. PMID:26153255

  1. Abnormal cubic-tetragonal phase transition of barium strontium titanate nanoparticles studied by in situ Raman spectroscopy and transmission electron microscopy heating experiments

    SciTech Connect

    Zhang, Yin; Chen, Chen; Gao, Ran; Xia, Feng; Li, YueSheng; Che, Renchao

    2015-11-02

    Phase stability of the ferroelectric materials at high temperature is extremely important to their device performance. Ba{sub x}Sr{sub 1−x}TiO{sub 3} (BST) nanoparticles with different Sr contents (x = 1, 0.91, 0.65, 0.4, and 0) are prepared by a facile hydrothermal method. Using Raman spectroscopy and transmission electron microscopy (TEM) analyses under in situ heating conditions (up to 300 °C), the phase transitions of BST nanoparticles between 25 °C and 280 °C are comprehensively investigated. The original Curie temperature of BST nanoparticles decreases abruptly with the increase in Sr content, which is more obvious than in the bulk or film material. Besides, an abnormal phase transition from cubic to tetragonal structure is observed from BST nanoparticles and the transition temperature rises along with the increase in Sr content. Direct TEM evidences including a slight lattice distortion have been provided. Differently, BaTiO{sub 3} nanoparticles remained in the tetragonal phase during the above temperature ranges.

  2. nanoparticles

    NASA Astrophysics Data System (ADS)

    Andreu-Cabedo, Patricia; Mondragon, Rosa; Hernandez, Leonor; Martinez-Cuenca, Raul; Cabedo, Luis; Julia, J. Enrique

    2014-10-01

    Thermal energy storage (TES) is extremely important in concentrated solar power (CSP) plants since it represents the main difference and advantage of CSP plants with respect to other renewable energy sources such as wind, photovoltaic, etc. CSP represents a low-carbon emission renewable source of energy, and TES allows CSP plants to have energy availability and dispatchability using available industrial technologies. Molten salts are used in CSP plants as a TES material because of their high operational temperature and stability of up to 500°C. Their main drawbacks are their relative poor thermal properties and energy storage density. A simple cost-effective way to improve thermal properties of fluids is to dope them with nanoparticles, thus obtaining the so-called salt-based nanofluids. In this work, solar salt used in CSP plants (60% NaNO3 + 40% KNO3) was doped with silica nanoparticles at different solid mass concentrations (from 0.5% to 2%). Specific heat was measured by means of differential scanning calorimetry (DSC). A maximum increase of 25.03% was found at an optimal concentration of 1 wt.% of nanoparticles. The size distribution of nanoparticle clusters present in the salt at each concentration was evaluated by means of scanning electron microscopy (SEM) and image processing, as well as by means of dynamic light scattering (DLS). The cluster size and the specific surface available depended on the solid content, and a relationship between the specific heat increment and the available particle surface area was obtained. It was proved that the mechanism involved in the specific heat increment is based on a surface phenomenon. Stability of samples was tested for several thermal cycles and thermogravimetric analysis at high temperature was carried out, the samples being stable.

  3. Effect of polymer-nanoparticle interactions on the glass transition dynamics and the conductivity mechanism in polyurethane titanium dioxide nanocomposites

    SciTech Connect

    Polyzos, Georgios; Tuncer, Enis; Agapov, Alexander L; Stevens, Derrick; Sokolov, Alexei P; Kidder, Michelle; Jacobs,; Koerner, Hilmar; Vaia, Richard; More, Karren Leslie; Sauers, Isidor

    2012-01-01

    We report on the glass transition dynamics and the conductivity properties of a nanodielectric system composed of pre-synthesized TiO{sub 2} nanoparticles embedded in thermoplastic polyurethane. Increase of TiO{sub 2} loading results in enhanced segmental mobility of the composites and less steep temperature dependence, i.e., lower fragility index. The decrease in the fragility index and glass transition temperature is discussed based on the FTIR results. We observe different behavior of conductivity for temperatures above and below the glass transition temperature. At high temperatures the composites exhibit conductivity values more than 2 orders of magnitude higher than those in the pristine matrix. At the same time, at sub-Tg temperatures composites are characterized by superior electrical insulation properties compared to pristine matrix material. Such drastic temperature dependence of the conductivity/insulating ability of the flexible and light-weight, low-Tg composite material can be utilized in various applications including sensing and temperature switching materials.

  4. Well-defined oxide core-polymer shell nanoparticles: interfacial interactions, peculiar dynamics, and transitions in polymer nanolayers.

    PubMed

    Bershtein, V A; Gun'ko, V M; Egorova, L M; Guzenko, N V; Pakhlov, E M; Ryzhov, V A; Zarko, V I

    2010-07-01

    Interfacial interactions, chain dynamics, and glass and melting transitions were studied in well-defined core-shell nanoparticles with amorphous silica or crystalline alumina cores and noncrystallizable poly(vinyl pyrrolidone) (PVP) or crystallizable poly(ethylene glycol) (PEG) shells. Varying particle composition caused regular changes in the shell thickness from 1 to 2 nm (monomolecular layer) up to 90 nm. Far- and mid-IR spectroscopy allowed us to register hydrogen bonding and, tentatively, Lewis/Brønsted (LB) interfacial interactions as well as changes in the dynamics and conformational state of the polymer chains as a function of the nanoshell thickness. Their most pronounced peculiarities were found for the monomolecular polymer layers. The LB interactions were stronger with the alumina substrate than silica. DSC analysis was performed, and the data obtained were in agreement with the spectroscopic data. Unlike the bulk polymer, the PVP monolayer was characterized with an extraordinarily large dynamic heterogeneity within the glass transition while broadening the transition range and varying the activation energy by an order of magnitude. The PEG monolayer adsorbed on silica was totally amorphous, whereas a highly crystalline one with the anomalously thin lamellae, down to 3 nm thick, was adsorbed on an alumina surface, presumably as a result of the quasi-heteroepitaxial crystallization process. PMID:20415443

  5. Nanoscale confinement and interfacial effects on the dynamics and glass transition/crystallinity of thin adsorbed films on silica nanoparticles

    NASA Astrophysics Data System (ADS)

    Madathingal, Rajesh Raman

    in the latter case bridging of PMMA between aggregates occurred. The anchoring point densities were comparable to the silanol densities, suggesting that PMMA adsorbed as trains rather than loops. For hydrophilic SiO2, Tg increased with [SiOH], as more carbonyl groups hydrogen bonded to the silanols, and was independent of particle morphology. For methylated silica, (CH3) 3-SiO2, the adsorption isotherms were identical for colloidal and fumed silica, but Tg was depressed for the former, and comparable to the bulk value for the latter. The increased Tg of PMMA adsorbed onto fumed (CH3)3-SiO2 was attributed to the larger loops formed by the bridging PMMA chains between the silica aggregates. For nanocomposites the interphase region becomes more important as the surface/volume ratio of the nanoparticles increases. Polymers have chain dimensions (characterized by the radius of gyration, Rg) similar to the nanoparticles (Rnanoparticle) themselves, so that chain conformation, mobility and crystallinity can be affected by Rg/Rnanoparticle. Here, both the glass transition temperature (Tg) and degree of crystallinity (Xc) of polyethylene oxide (PEO) on individual SiO 2 nanoparticles of nominal 15, 50 and 100 nm diameter (2 RSiO2 ) , in which Rg (PEO) was greater, equal to or less than RSiO2 was investigated. Plateau adsorption of PEO on SiO2 nanoparticles (PEO-SiO2) increased in the order PEO-SiO 2 (100 nm) > PEO-SiO2 (50 nm) > PEO-SiO2 (15 nm). At plateau adsorption after melting and solidification, the samples were completely amorphous. The Tg of the adsorbed PEO increased in the order PEO-SiO 2 (100 nm) > PEO-SiO2 (50 nm) > PEO-SiO2 (15 nm); since the Tgs were above 25°C in all cases, the PEO behaved more like a brittle solid than an elastomer. For comparable amounts of PEO that were adsorbed from solution but not melted, the melt endotherm increased in the order PEO-SiO2 (15 nm) > PEO-SiO2 (50 nm) > PEO-SiO 2 (100 nm). These trends were interpreted as due to an increase

  6. Intranasal H5N1 vaccines, adjuvanted with chitosan derivatives, protect ferrets against highly pathogenic influenza intranasal and intratracheal challenge.

    PubMed

    Mann, Alex J; Noulin, Nicolas; Catchpole, Andrew; Stittelaar, Koert J; de Waal, Leon; Veldhuis Kroeze, Edwin J B; Hinchcliffe, Michael; Smith, Alan; Montomoli, Emanuele; Piccirella, Simona; Osterhaus, Albert D M E; Knight, Alastair; Oxford, John S; Lapini, Giulia; Cox, Rebecca; Lambkin-Williams, Rob

    2014-01-01

    We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and

  7. Size dependence and phase transition during melting of fcc-Fe nanoparticles: A molecular dynamics simulation

    NASA Astrophysics Data System (ADS)

    Shen, Tong; Meng, Wenjian; Wu, Yongquan; Lu, Xionggang

    2013-07-01

    Continuous melting and cooling of isolated fcc-Fe nanoparticles with 59-9577 atoms are studied by Molecular Dynamics (MD) simulation with Sutton-Chen potential. An energy minimization process was employed to obtain the stable solid structure for simulation of melting. The energy-minimized nanoparticles show lower potential energy and radius compared with the counterparts without energy minimizing. The size dependence of melting point shows perfect linear variation with N-1/3 for particles above a limit of 113 atoms. The bulk melting temperature of 1833.3 K, which is close to the experimental data (1811 K for bcc and 1800.8 K for fcc), has been predicted by a linear relationship. Two different inner structures, including five-fold twinning and lamellar structures, have been found to be the initial stable configurations prior to melting, and both surface premelting and internal defects were verified as the origins for melting behavior.

  8. Protein Brownian Rotation at the Glass Transition Temperature of a Freeze-Concentrated Buffer Probed by Superparamagnetic Nanoparticles

    PubMed Central

    Eloi, J.-C.; Okuda, M.; Jones, S.E. Ward; Schwarzacher, W.

    2013-01-01

    For applications from food science to the freeze-thawing of proteins it is important to understand the often complex freezing behavior of solutions of biomolecules. Here we use a magnetic method to monitor the Brownian rotation of a quasi-spherical cage-shaped protein, apoferritin, approaching the glass transition Tg in a freeze-concentrated buffer (Tris-HCl). The protein incorporates a synthetic magnetic nanoparticle (Co-doped Fe3O4 (magnetite)). We use the magnetic signal from the nanoparticles to monitor the protein orientation. As T decreases toward Tg of the buffer solution the protein’s rotational relaxation time increases exponentially, taking values in the range from a few seconds up to thousands of seconds, i.e., orders of magnitude greater than usually accessed, e.g., by NMR. The longest relaxation times measured correspond to estimated viscosities >2 MPa s. As well as being a means to study low-temperature, high-viscosity environments, our method provides evidence that, for the cooling protocol used, the following applies: 1), the concentration of the freeze-concentrated buffer at Tg is independent of its initial concentration; 2), little protein adsorption takes place at the interface between ice and buffer; and 3), the protein is free to rotate even at temperatures as low as 207 K. PMID:23790376

  9. Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors

    PubMed Central

    Watson, Katherine D.; Lai, Chun-Yen; Qin, Shengping; Kruse, Dustin E.; Lin, Yueh-Chen; Seo, Jai Woong; Cardiff, Robert D.; Mahakian, Lisa M.; Beegle, Julie; Ingham, Elizabeth S.; Curry, Fitz-Roy; Reed, Rolf K.; Ferrara, Katherine W.

    2012-01-01

    Acquisition of the epithelial-mesenchymal transition (EMT) tumor phenotype is associated with impaired chemotherapeutic delivery and a poor prognosis. In this study, we investigated the application of therapeutic ultrasound methods available in the clinic to increase nanotherapeutic particle accumulation in epithelial and EMT tumors by labeling particles with a positron emission tomography tracer. Epithelial tumors were highly vascularized with tight cell-cell junctions, compared to EMT tumors where cells displayed an irregular, elongated shape with loosened cell-cell adhesions and a reduction in E-cadherin and cytokeratins 8/18 and 19. Without ultrasound, the accumulation of liposomal nanoparticles administered to tumors in vivo was ~1.5 times greater in epithelial tumors than EMT tumors. When ultrasound was applied, both nanoaccumulation and apparent tumor permeability were increased in both settings. Notably, ultrasound effects differed with thermal and mechanical indices, such that increasing the thermal ultrasound dose increased nanoaccumulation in EMT tumors. Taken together, our results illustrate how ultrasound can be used to enhance nanoparticle accumulation in tumors by reducing their intratumoral pressure and increasing their vascular permeability. PMID:22282664

  10. Colloidal Nanoparticle Interaction Transition during Solvent Evaporation Investigated by in-Situ Small-Angle X-ray Scattering.

    PubMed

    Bahadur, J; Sen, D; Mazumder, S; Santoro, G; Yu, S; Roth, S V; Melnichenko, Y B

    2015-04-28

    In-situ scanning small-angle X-ray scattering (SAXS) experiments have been performed to probe the drying of a single suspended droplet of silica colloids. It has been demonstrated that the formation of a nanoparticle shell during drying can be confirmed just by measuring the temporal evolution of the spatial transmission profile across the drying droplet. The shrinkage of the droplet stops once the shell is formed. The temporal dependence of the shell thickness and droplet radius has been estimated by quantitative analysis of the functionality of the transmission profiles. It is revealed that the position of the correlation peak originating from interactions between silica nanoparticles evolves linearly during the initial stage of drying and exhibits sigmoidal growth behavior in later stages. The interaction between colloidal particles in different drying stages has been investigated. We provide experimental confirmation of the transition from repulsive interaction to a capillary-driven short-range attraction during shell formation. The present work demonstrates that in-situ scanning SAXS on a suspended droplet is an invaluable technique for monitoring the dynamic self-organization of colloids as it probes the drying of complex fluids without the interference of a substrate. PMID:25839830

  11. Intranasal flunisolide treatment in children with adenoidal hypertrophy.

    PubMed

    Ciprandi, G; Varricchio, A; Capasso, M; Varricchio, A M; De Lucia, A; Ascione, E; Avvisati, F; Capristo, C; Marseglia, G L; Barillari, U

    2007-01-01

    Adenoidal hypertrophy (AH) represents one of the most frequent indications for surgery in children and it has been proposed that treatment with intranasal corticosteroids can decrease the size of AH. Therefore, the aim of the study is to evaluate the effect of the use of intranasal flunisolide among children affected by AH. 178 children with AH were evaluated in this randomised and controlled study. Inclusion criteria for the study required that each patient had to have a III or IV degree of AH on the initial endoscopic examination. Children were treated with intranasal flunisolide or isotonic saline solution for 8 weeks. After treatment, endoscopy was performed to re-evaluate AH degree. Flunisolide treatment was associated with significant (p less than 0.04) reduction of AH degree. There was moreover a consistent reduction of children (46 out of 58) proposed to adenoidectomy. No clinically important adverse events were reported. In conclusion, this preliminary study demonstrates that an 8-week treatment with intranasal flunisolide is significantly associated with reduction of AH, thus preventing the recurrence to adenoidectomy, and is safe. PMID:18179756

  12. Ready-to-use colloidal adjuvant systems for intranasal immunization.

    PubMed

    Lee, Jeong-Jun; Shim, Aeri; Lee, Song Yi; Kwon, Bo-Eun; Kim, Seong Ryeol; Ko, Hyun-Jeong; Cho, Hyun-Jong

    2016-04-01

    Adjuvant systems based on oil-in-water (o/w) microemulsions (MEs) for vaccination via intranasal administration were prepared and evaluated. A ready-to-use blank ME system composed of mineral oil (oil), Labrasol (surfactant), Tween 80 (cosurfactant), and water was prepared and blended with antigen (Ag) solution prior to use. The o/w ME system developed exhibited nano-size droplets within the tested range of Ag concentrations and dilution factors. The maintenance of primary, secondary, and tertiary structural stability of ovalbumin (OVA) in ME, compared with OVA in solution, was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), and fluorescence intensity measurements, respectively. The uptake efficiency in RAW 264.7 cells, evaluated by flow cytometry, of OVA in the ME group was significantly higher than that of the OVA solution group (p<0.05). In an intranasal immunization study with OVA ME in mice, elevated adjuvant effects in terms of mucosal immunization and Th1-dominant cell-mediated immune responses were identified. Given the convenience of use (simply mixing with Ag solution prior to use) and the adjuvant effects after intranasal immunization, the new o/w ME may be a practical and efficient adjuvant system for intranasal vaccination. PMID:26775242

  13. Pharmacodynamics and toxicity of vasoactive intestinal peptide for intranasal administration.

    PubMed

    Cui, Xu; Cao, De-Ying; Wang, Zhi-Min; Zheng, Ai-Ping

    2013-01-01

    The aim of this work was to study the nasal route for the delivery of vasoactive intestinal peptide (VIP) to the brain and to evaluate the toxicity of VIP nasal spray. Mice were injected intracerebroventricularly with the aggregated Abeta25-35 to mimic Alzheimer's disease. Following administration, different groups of mice were treated over one week, and their spatial learning and memory capacities were evaluated by the Morris water maze test. The toxicity of VIP nasal spray was evaluated by examining the morphology of individual rat nasal mucosa cilia and the pathology of rat nasal mucosa. Rats receiving intranasal VIP (40 microg/ml) showed good spatial memory relative to the Abeta25-35 model group, but the escape latency did not show any statistically significant difference. Intranasal administration of VIP nasal spray (200 microg/ml) improved deficits in spatial memory to the point that test animals receiving intranasal VIP showed no statistically significant differences from the normal control group in escape latency. This indicated that the nasal spray method could increase the quantity of VIP entering the brain and protect the central nervous systems of mice. Toxicity evaluation showed that the preparation could cause minor irritation, which resolved spontaneously within a week at the end of treatment. In conclusion, VIP can be delivered successfully to the brain using the intranasal route. PMID:23444784

  14. Acute Physiological and Behavioral Effects of Intranasal Methamphetamine in Humans

    PubMed Central

    Hart, Carl L; Gunderson, Erik W; Perez, Audrey; Kirkpatrick, Matthew G; Thurmond, Andrew; Comer, Sandra D; Foltin, Richard W

    2016-01-01

    Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and ‘positive’ subjective effects, with peaks occurring approximately 5–15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses. PMID:17851535

  15. On the origin of multi-step spin transition behaviour in 1D nanoparticles

    NASA Astrophysics Data System (ADS)

    Chiruta, Daniel; Jureschi, Catalin-Maricel; Linares, Jorge; Dahoo, Pierre Richard; Garcia, Yann; Rotaru, Aurelian

    2015-09-01

    To investigate the spin state switching mechanism in spin crossover (SCO) nanoparticles, a special attention is given to three-step thermally induced SCO behavior in 1D chains. An additional term is included in the standard Ising-like Hamiltonian to account for the border interaction between SCO molecules and its local environment. It is shown that this additional interaction, together with the short range interaction, drives the multi-steps thermal hysteretic behavior in 1D SCO systems. The relation between a polymeric matrix and this particular multi-step SCO phenomenon is discussed accordingly. Finally, the environmental influence on the SCO system's size is analyzed as well.

  16. Enhanced electron transport in Nb-doped TiO2 nanoparticles via pressure-induced phase transitions.

    PubMed

    Lü, Xujie; Yang, Wenge; Quan, Zewei; Lin, Tianquan; Bai, Ligang; Wang, Lin; Huang, Fuqiang; Zhao, Yusheng

    2014-01-01

    Anatase TiO2 is one of the most important energy materials but suffers from poor electrical conductivity. Nb doping has been considered as an effective way to improve its performance in the applications of photocatalysis, solar cells, Li batteries, and transparent conducting oxide films. Here, we report the further enhancement of electron transport in Nb-doped TiO2 nanoparticles via pressure-induced phase transitions. The phase transition behavior and influence of Nb doping in anatase Nb-TiO2 have been systematically investigated by in situ synchrotron X-ray diffraction and Raman spectroscopy. The bulk moduli are determined to be 179.5, 163.3, 148.3, and 139.0 GPa for 0, 2.5, 5.0, and 10.0 mol % Nb-doped TiO2, respectively. The Nb-concentration-dependent stiffness variation has been demonstrated: samples with higher Nb concentrations have lower stiffness. In situ resistance measurements reveal an increase of 40% in conductivity of quenched Nb-TiO2 in comparison to the pristine anatase phase. The pressure-induced conductivity evolution is discussed in detail in terms of the packing factor model, which provides direct evidence for the rationality of the correlation of packing factors with electron transport in semiconductors. Pressure-treated Nb-doped TiO2 with unique properties surpassing those in the anatase phase holds great promise for energy-related applications. PMID:24320708

  17. Data on energy-band-gap characteristics of composite nanoparticles obtained by modification of the amorphous potassium polytitanate in aqueous solutions of transition metal salts.

    PubMed

    Zimnyakov, D A; Sevrugin, A V; Yuvchenko, S A; Fedorov, F S; Tretyachenko, E V; Vikulova, M A; Kovaleva, D S; Krugova, E Y; Gorokhovsky, A V

    2016-06-01

    Here we present the data on the energy-band-gap characteristics of composite nanoparticles produced by modification of the amorphous potassium polytitanate in aqueous solutions of different transition metal salts. Band gap characteristics are investigated using diffuse reflection spectra of the obtained powders. Calculated logarithmic derivative quantity of the Kubelka-Munk function reveals a presence of local maxima in the regions 0.5-1.5 eV and 1.6-3.0 eV which correspond to band gap values of the investigated materials. The values might be related to the constituents of the composite nanoparticles and intermediate products of their chemical interaction. PMID:27158654

  18. Pressure-dependent transition from atoms to nanoparticles in magnetron sputtering: Effect on WSi{sub 2} film roughness and stress

    SciTech Connect

    Zhou Lan; Wang Yiping; Zhou Hua; Li Minghao; Headrick, Randall L.; MacArthur, Kimberly; Shi Bing; Conley, Ray; Macrander, Albert T.

    2010-08-15

    We report on the transition between two regimes from several-atom clusters to much larger nanoparticles in Ar magnetron sputter deposition of WSi{sub 2}, and the effect of nanoparticles on the properties of amorphous thin films and multilayers. Sputter deposition of thin films is monitored by in situ x-ray scattering, including x-ray reflectivity and grazing incidence small-angle x-ray scattering. The results show an abrupt transition at an Ar background pressure P{sub c}; the transition is associated with the threshold for energetic particle thermalization, which is known to scale as the product of the Ar pressure and the working distance between the magnetron source and the substrate surface. Below P{sub c} smooth films are produced while above P{sub c} roughness increases abruptly, consistent with a model in which particles aggregate in the deposition flux before reaching the growth surface. The results from WSi{sub 2} films are correlated with in situ measurement of stress in WSi{sub 2}/Si multilayers, which exhibits a corresponding transition from compressive to tensile stress at P{sub c}. The tensile stress is attributed to coalescence of nanoparticles and the elimination of nanovoids.

  19. Thermodynamics of a phase transition of silicon nanoparticles at the annealing and carbonization of porous silicon

    SciTech Connect

    Nagornov, Yu. S.

    2015-12-15

    The formation of SiC nanocrystals of the cubic modification in the process of high-temperature carbonization of porous silicon has been analyzed. A thermodynamic model has been proposed to describe the experimental data obtained by atomic-force microscopy, Raman scattering, spectral analysis, Auger spectroscopy, and X-ray diffraction spectroscopy. It has been shown that the surface energy of silicon nanoparticles and quantum filaments is released in the process of annealing and carbonization. The Monte Carlo simulation has shown that the released energy makes it possible to overcome the nucleation barrier and to form SiC nanocrystals. The processes of laser annealing and electron irradiation of carbonized porous silicon have been analyzed.

  20. Ethanol decomposition on transition metal nanoparticles during carbon nanotube growth: ab initio molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Shibuta, Yasushi; Shimamura, Kohei; Oguri, Tomoya; Arifin, Rizal; Shimojo, Fuyuki; Yamaguchi, Shu

    2015-03-01

    The growth mechanism of carbon nanotubes (CNT) has been widely discussed both from experimental and computational studies. Regarding the computational studies, most of the studies focuses on the aggregation of isolate carbon atoms on the catalytic metal nanoparticle, whereas the initial dissociation of carbon source molecules should affect the yield and quality of the products. On the other hand, we have studied the dissociation process of carbon source molecules on the metal surface by the ab initio molecular dynamics simulation. In the study, we investigate the ethanol dissociation on Pt and Ni clusters by ab initio MD simulations to discuss the initial stage of CNT growth by alcohol CVD technique. Part of this research is supported by the Grant-in-Aid for Young Scientists (a) (No. 24686026) from MEXT, Japan.

  1. Intranasal midazolam for seizure cessation in the community setting

    PubMed Central

    Zelcer, Michal; Goldman, Ran D.

    2016-01-01

    Question There are times when parents arrive to my clinic after their child has had a seizure and a second seizure takes place in the clinic. While waiting for transport to the hospital, are there ways to stop the seizures without the need to obtain intravenous access in the clinic? Answer Intravenous diazepam has been a first-line therapy to stop seizures in children for many years. Other routes of drug administration such as intramuscular, rectal, and buccal are available but have several limitations. More evidence suggests that the intranasal route to administer drugs is quick and effective in children, and the use of midazolam has been continuing to show promise in seizure cessation. With its good safety profile, intranasal midazolam can be used in the clinic and prehospital setting for seizure cessation in children. PMID:27412207

  2. Assessment of the pharmacodynamics of intranasal, intravenous and oral scopolamine

    NASA Technical Reports Server (NTRS)

    Tietze, Karen J.

    1990-01-01

    Space motion sickness is an important issue in the space medical sciences program. One of the objectives of the ongoing clinical experimental protocol Pharmacokinetics of Intranasal Scopolamine in Normal Subjects is to evaluate the pharmacodynamics of scopolamine using salivary flow rate and pH profiles and cognitive performance tests as pharmacodynamic parameters. Normal volunteers collected saliva and performed the NTI Multiresource Performance Battery tests at designed time intervals to establish control saliva flow rates, salivary pH profiles, and the characteristics of the learning curve for the performance program under normal conditions. In the clinical part of the study, saliva samples and performance test scores are collected from healthy nonsmoking subjects after receiving a single 0.4 mg dose of either intranasal, intravenous, or oral scopolamine.

  3. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    PubMed Central

    Dor-On, Eyal; Solomon, Beka

    2015-01-01

    Bacteriophages (phages) are ubiquitous viruses that control the growth and diversity of bacteria. Although they have no tropism to mammalian cells, accumulated evidence suggests that phages are not neutral to the mammalian macro-host and can promote immunomodulatory and anti-tumorigenic activities. Here we demonstrate that Ff phages that do not display any proteins or peptides could inhibit the growth of subcutaneous glioblastoma tumors in mice and that this activity is mediated in part by lipopolysaccharide molecules attached to their virion. Using the intranasal route, a non-invasive approach to deliver therapeutics directly to the CNS, we further show that phages rapidly accumulate in the brains of mice and could attenuate progression of orthotopic glioblastoma. Taken together, this study provides new insight into phages non-bacterial activities and demonstrates the feasibility of delivering Ff phages intranasally to treat brain malignancies. PMID:26074908

  4. Intranasal substituted cathinone "bath salts" psychosis potentially exacerbated by diphenhydramine.

    PubMed

    Gunderson, Erik W; Kirkpatrick, Matthew G; Willing, Laura M; Holstege, Christopher P

    2013-01-01

    In this report, we describe a case of intranasal "bath salts"-associated psychosis. Symptoms developed during a 3-week binge and were potentially exacerbated by oral diphenhydramine taken for insomnia. The clinical case conference includes expert discussion from 3 disciplines: emergency medicine toxicology, behavioral pharmacology, and addiction medicine. It is hoped that the discussion will provide insight into the clinical aspects and challenges of addressing acute substituted cathinone toxicity, including acute psychosis, a major adverse effect of bath salts consumption. PMID:23732955

  5. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Tam, V.; Chow, Diana S. L.; Putcha, Lakshmi

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP.

  6. Pharmaceutical Product Development: Intranasal Scopolamine (INSCOP) Metered Dose Spray

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Crady, Camille; Putcha, Lakshmi

    2012-01-01

    Motion sickness (MS) has been a problem associated with space flight, the modern military and commercial air and water transportation for many years. Clinical studies have shown that scopolamine is the most effective medication for the prevention of motion sickness (Dornhoffer et al, 2004); however, the two most common methods of administration (transdermal and oral) have performance limitations that compromise its utility. Intranasal administration offers a noninvasive treatment modality, and has been shown to counter many of the problems associated with oral and transdermal administration. With the elimination of the first pass effect by the liver, intranasal delivery achieves higher and more reliable bioavailability than an equivalent oral dose. This allows for the potential of enhanced efficacy at a reduced dose, thus minimizing the occurrence of untoward side effects. An Intranasal scopolamine (INSCOP) gel formulation was prepared and tested in four ground-based clinical trials under an active Investigational New Drug (IND) application with the Food and Drug Administration (FDA). Although there were early indicators that the intranasal gel formulation was effective, there were aspects of formulation viscosity and the delivery system that were less desirable. The INSCOP gel formulation has since been reformulated into an aqueous spray dosage form packaged in a precise, metered dose delivery system; thereby enhancing dose uniformity, increased user satisfaction and palatability, and a potentially more rapid onset of action. Recent reports of new therapeutic indications for scopolamine has prompted a wide spread interest in new scopolamine dosage forms. The novel dosage form and delivery system of INSCOP spray shows promise as an effective treatment for motion sickness targeted at the armed forces, spaceflight, and commercial sea, air, and space travel markets, as well as prospective psychotherapy for mental and emotional disorders.

  7. Best evidence topic report. Intranasal midazolam in patients with fits.

    PubMed

    Smith, Martin; Carley, Simon

    2005-06-01

    A short cut review was carried out to establish whether intranasal midazolam was effective for stopping fits. Altogether 36 papers were found using the reported search, of which four presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. A clinical bottom line is stated. PMID:15911956

  8. Phase stabilization of magnetite (Fe3O4) nanoparticles with B2O3 addition: A significant enhancement on the phase transition temperature

    NASA Astrophysics Data System (ADS)

    Topal, Uğur; Aksan, Mehmet Ali

    2016-05-01

    Magnetite nanoparticles (MNPs) are extensively investigated for biomedical applications, particularly as contrast agents for Magnetic Resonance Imaging and as drug delivery agent and heat mediators for cancer therapy. Tuning the magnetic properties of the magnetite nanoparticles with doping of foreign atoms has a crucial importance for determining the application areas of these materials and so attracts much interests. On the other hand the doping with foreign atoms requires high temperature annealing, and it causes a phase transition to the hematite phase above 400 °C. In this work the phase transition temperature from the magnetite to the hematite phase has been increased by 200 °C, which is the highest enhancement reported in literature. It was achieved by addition of the appropriate amounts of B2O3. Our experiments indicates that the 5.0 wt% of B2O3 addition stabilizes and keeps the existence of single phase magnetite up to 600 °C.

  9. Microdialysis pharmacokinetic study of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration.

    PubMed

    Wei, Yan; Ying, Mingzhen; Xu, Shuai; Wang, Feng; Zou, Aifeng; Cao, Shilei; Jiang, Xinguo; Wang, Yajie

    2016-01-01

    The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. Tmax plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8-70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery. PMID:24865285

  10. Dose escalation pharmacokinetics of intranasal scopolamine gel formulation.

    PubMed

    Wu, Lei; Boyd, Jason L; Daniels, Vernie; Wang, Zuwei; Chow, Diana S-L; Putcha, Lakshmi

    2015-02-01

    Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness. PMID:25187210

  11. Preparation and evaluation of fexofenadine microemulsion for intranasal delivery.

    PubMed

    Piao, Hong-Mei; Balakrishnan, Prabagar; Cho, Hyun Jong; Kim, Hyunjun; Kim, You Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

    2010-06-01

    To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol oleiqueCC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64mg/mL) and F2 (22.98mg/mL), compared to its intrinsic water solubility (1.51mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. T(max) was observed within 5min after intranasal administration at 1.0mg/kg dose, and the absolute bioavailability (0-4h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine. PMID:20685383

  12. Preparation and evaluation of fexofenadine microemulsions for intranasal delivery.

    PubMed

    Piao, Hong-Mei; Balakrishnan, Prabagar; Cho, Hyun-Jong; Kim, Hyunjun; Kim, You-Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

    2010-08-16

    To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol Oleique CC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64 mg/mL) and F2 (22.98 mg/mL), compared to its intrinsic water solubility (1.51 mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. Tmax was observed within 5 min after intranasal administration at 1.0 mg/kg dose, and the absolute bioavailability (0-4 h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine PMID:20635476

  13. Residual effects of intranasal methamphetamine on sleep, mood, and performance

    PubMed Central

    Perez, Audrey; Kirkpatrick, Matthew G.; Gunderson, Erik W.; Marrone, Gina; Silver, Rae; Foltin, Richard W.; Hart, Carl L.

    2008-01-01

    Although intranasal methamphetamine abuse has increased, there are no published data investigating the residual effects of the drug under controlled conditions. Thus, the current study examined the residual effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Non-treatment seeking methamphetamine abusers (n = 11) completed this two-week, in-patient, within-participant, double-blind study. The study consisted of 4 two-day blocks of sessions; each block was separated by at least 24 hrs. At approximately 1000 hrs, on the first day of each block, participants received one of four intranasal methamphetamine doses (0, 12, 25, 50 mg/70 kg). Lights were turned out at 2300 hrs that evening and sleep measures were assessed. On the morning of the second day of each block, methamphetamine plasma levels, cardiovascular measures, mood, subjective reports of the previous evening's sleep, and psychomotor performance were assessed to determine residual drug effects. The larger methamphetamine doses (25 and 50 mg) markedly disrupted subjective measures of that night's sleep and some indices of next-day mood, but only the largest dose (50 mg) dose decreased objective measures of that night's sleep and increased next-day physiological measures. Methamphetamine did not produce any negative residual effects on early next-day performance. Future studies should assess methamphetamine-related residual effects following repeated doses administered over consecutive days. PMID:18078723

  14. Magnetic phase transitions in ferrite nanoparticles characterized by electron spin resonance

    SciTech Connect

    Flores-Arias, Yesica Vázquez-Victorio, Gabriela; Ortega-Zempoalteca, Raul; Acevedo-Salas, Ulises; Valenzuela, Raul; Ammar, Souad

    2015-05-07

    Ferrite magnetic nanoparticles in the composition Zn{sub 0.7}Ni{sub 0.3}Fe{sub 2}O{sub 4} were synthesized by the polyol method, with an average size of 8 nm. Electron spin resonance (ESR) measurements were carried out at a frequency of 9.45 GHz in the 100–500 K temperature range. Obtained results exhibited a characteristic ESR signal in terms of resonance field, H{sub res}, linewidth, ΔH, and peak ratio, R, for each magnetic phase. At low temperatures, the ferrimagnetic phase showed low H{sub res}, broad ΔH, and asymmetric R. At high temperatures, these parameters exhibited opposite values: high H{sub res}, small ΔH, and R ∼ 1. For intermediate temperatures, a different phase was observed, which was identified as a superparamagnetic phase by means of zero-field cooling-field cooling and hysteresis loops measurements. The observed differences were explained in terms of the internal fields and especially due to the cubic anisotropy in the ordered phase.

  15. Electrocatalytic Hydrogenation of Oxygenates using Earth-Abundant Transition-Metal Nanoparticles under Mild Conditions.

    PubMed

    Carroll, Kyler J; Burger, Thomas; Langenegger, Lukas; Chavez, Steven; Hunt, Sean T; Román-Leshkov, Yuriy; Brushett, Fikile R

    2016-08-01

    Electrocatalytic hydrogenation (ECH) is a sustainable pathway for the synthesis of value-added organic compounds, provided affordable catalysts with high activity, selectivity and durability are developed. Here, we synthesize Cu/C, Ni/C, and CuNi/C nanoparticles and compare their performance to Pt/C, Ru/C, PtRu/C for the ECH of hydroxyacetone, a bio-derived feedstock surrogate containing a carbonyl and a hydroxyl functional group. The non-precious metal electrocatalysts show promising conversion-time behavior, product selectivities, and Faradaic efficiencies. Ni/C forms propylene glycol with a selectivity of 89 % (at 80 % conversion), while Cu/C catalyzes ECH (52 % selectivity) and hydrodeoxygenation (HDO, 48 % selectivity, accounting for evaporation). CuNi/C shows increased turnover frequencies but reduced ECH selectivity (80 % at 80 % conversion) as compared to the Ni/C catalyst. Importantly, stability studies show that the non-precious metal catalysts do not leach at operating conditions. PMID:27337680

  16. Photochemical Fabrication of Transition Metal Nanoparticles Using CdS Template and Their Co-Catalysis Effects for TiO2 Photocatalysis

    NASA Astrophysics Data System (ADS)

    Badhwar, Nidhi; Gupta, Nidhi; Pal, Bonamali

    2013-06-01

    Transition metal nanoparticles were prepared by chemical dissolution of CdS template from metal photodeposited CdS nanorod (length = 70-85 nm and width = 5-6 nm) heterocomposites. Size (9-10 nm) of metal nanoparticles obtained after CdS removal was larger than the size (4-6 nm) of metal nanodeposits over CdS template. The obtained Au nanoparticles displayed a broad red shifted absorption band at 660 nm, whereas Pt, Pd and Rh nanoparticles exhibit featureless absorption spectra. Elemental analysis confirms the complete removal of CdS template from Au-CdS (Au — 2.65 at.%) and Ag-CdS (Ag — 2.06 at.%) composites showing no Cd peak. These metal nanoparticles imparted dissimilar co-catalytic activity of TiO2 for photocatalytic degradation of salicylic acid in the order Au > Pt > Pd > Ag > Rh as a function of their nature, electronegativity, redox potential and work function.

  17. Self-healable and reversible liposome leakage by citrate-capped gold nanoparticles: probing the initial adsorption/desorption induced lipid phase transition

    NASA Astrophysics Data System (ADS)

    Wang, Feng; Liu, Juewen

    2015-09-01

    We herein report that the adsorption/desorption of citrate-capped gold nanoparticles (AuNPs) transiently causes leakage in fluid phase DOPC liposomes, while the liposomes do not leak with AuNPs capped with mercaptopropionic acid (MPA). Leakage also fails to occur for gel phase DPPC liposomes. Citrate-capped (but not MPA-capped) AuNPs raise the phase transition temperature of DPPC. We conclude that citrate-capped AuNPs interact with the PC liposomes very strongly, inducing a local fluid-to-gel lipid phase transition for DOPC. Leakage takes place during this transition, and the membrane integrity is resumed after the transition. Citrate-capped AuNPs allow stronger van der Waals forces than MPA-capped AuNPs with PC liposomes, since the latter are separated from the liposome surface by the ~0.3 nm MPA layer.We herein report that the adsorption/desorption of citrate-capped gold nanoparticles (AuNPs) transiently causes leakage in fluid phase DOPC liposomes, while the liposomes do not leak with AuNPs capped with mercaptopropionic acid (MPA). Leakage also fails to occur for gel phase DPPC liposomes. Citrate-capped (but not MPA-capped) AuNPs raise the phase transition temperature of DPPC. We conclude that citrate-capped AuNPs interact with the PC liposomes very strongly, inducing a local fluid-to-gel lipid phase transition for DOPC. Leakage takes place during this transition, and the membrane integrity is resumed after the transition. Citrate-capped AuNPs allow stronger van der Waals forces than MPA-capped AuNPs with PC liposomes, since the latter are separated from the liposome surface by the ~0.3 nm MPA layer. Electronic supplementary information (ESI) available: Methods, TEM, UV-vis and DLS data. See DOI: 10.1039/c5nr04805b

  18. Sol-gel transition of nanoparticles/polymer mixtures for sustained delivery of exenatide to treat type 2 diabetes mellitus.

    PubMed

    Oh, Keun Sang; Kim, Jae Yeon; Yoon, Byeong Deok; Lee, Minae; Kim, Heejoo; Kim, Michelle; Seo, Jae Hong; Yuk, Soon Hong

    2014-11-01

    The sol-gel transition of nanoparticles (NPs)/polymer mixture in aqueous medium was investigated for the sustained delivery of exenatide to treat type 2 diabetes mellitus. Exenatide-loaded multilayer NPs were prepared using a layer-by-layer approach which utilized the interaction between Pluronics and lipid bilayers as the main driving force for the construction of the multilayer. Pluronic F-127 was the polymer used, and it forms a gel at body temperature. Although the antidiabetic effects of exenatide-loaded multilayer NPs have been demonstrated previously in an animal model, in this work, the attempt was made to demonstrate the extended duration of antidiabetic effects, which was accomplished by localizing the exenatide-loaded NPs in muscular areas in the body through the gelation of Pluronic F-127. Transmittance electron microscopy and dynamic light scattering were used to examine the morphology of the multilayer NPs/polymer mixture. A change in the release pattern of exenatide was observed after gel formation at body temperature, and Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis was performed using native exenatide and a reference biomarker as control to observe whether exenatide extracted from the multilayer NPs and the multilayer NPs/Pluronic F-127 mixture degraded or not. We then observed the antidiabetic effect of exenatide-loaded multilayer NPs/Pluronic F-127 mixture by monitoring blood-glucose levels in db/db mice. In vitro and in vivo correlation was discussed regarding structural variation in the delivery vehicles. PMID:25152212

  19. Thermally-induced transition of lamellae orientation in block-copolymer films on ‘neutral’ nanoparticle-coated substrates

    DOE PAGESBeta

    Yager, Kevin G.; Forrey, Christopher; Singh, Gurpreet; Satija, Sushil K.; Page, Kirt A.; Patton, Derek L.; Jones, Ronald L.; Karin, Alamgir; Douglas, Jack F.

    2015-06-01

    Block-copolymer orientation in thin films is controlled by the complex balance between interfacial free energies, including the inter-block segregation strength, the surface tensions of the blocks, and the relative substrate interactions. While block-copolymer lamellae orient horizontally when there is any preferential affinity of one block for the substrate, we recently described how nanoparticle-roughened substrates can be used to modify substrate interactions. We demonstrate how such ‘neutral’ substrates can be combined with control of annealing temperature to generate vertical lamellae orientations throughout a sample, at all thicknesses. We observe an orientational transition from vertical to horizontal lamellae upon heating, as confirmedmore » using a combination of atomic force microscopy (AFM), neutron reflectometry (NR) and rotational small-angle neutron scattering (RSANS). Using molecular dynamics (MD) simulations, we identify substrate-localized distortions to the lamellar morphology as the physical basis of the novel behavior. In particular, under strong segregation conditions, bending of horizontal lamellae induce a large energetic cost. At higher temperatures, the energetic cost of conformal deformations of lamellae over the rough substrate is reduced, returning lamellae to the typical horizontal orientation. Thus, we find that both surface interactions and temperature play a crucial role in dictating block-copolymer lamellae orientation. As a result, our combined experimental and simulation findings suggest that controlling substrate roughness should provide a useful and robust platform for controlling block-copolymer orientation in applications of these materials.« less

  20. Thermally-induced transition of lamellae orientation in block-copolymer films on ‘neutral’ nanoparticle-coated substrates

    SciTech Connect

    Yager, Kevin G.; Forrey, Christopher; Singh, Gurpreet; Satija, Sushil K.; Page, Kirt A.; Patton, Derek L.; Jones, Ronald L.; Karin, Alamgir; Douglas, Jack F.

    2015-06-01

    Block-copolymer orientation in thin films is controlled by the complex balance between interfacial free energies, including the inter-block segregation strength, the surface tensions of the blocks, and the relative substrate interactions. While block-copolymer lamellae orient horizontally when there is any preferential affinity of one block for the substrate, we recently described how nanoparticle-roughened substrates can be used to modify substrate interactions. We demonstrate how such ‘neutral’ substrates can be combined with control of annealing temperature to generate vertical lamellae orientations throughout a sample, at all thicknesses. We observe an orientational transition from vertical to horizontal lamellae upon heating, as confirmed using a combination of atomic force microscopy (AFM), neutron reflectometry (NR) and rotational small-angle neutron scattering (RSANS). Using molecular dynamics (MD) simulations, we identify substrate-localized distortions to the lamellar morphology as the physical basis of the novel behavior. In particular, under strong segregation conditions, bending of horizontal lamellae induce a large energetic cost. At higher temperatures, the energetic cost of conformal deformations of lamellae over the rough substrate is reduced, returning lamellae to the typical horizontal orientation. Thus, we find that both surface interactions and temperature play a crucial role in dictating block-copolymer lamellae orientation. As a result, our combined experimental and simulation findings suggest that controlling substrate roughness should provide a useful and robust platform for controlling block-copolymer orientation in applications of these materials.

  1. Nanoparticle Loading Induced Morphological Transitions and Size Fractionation of Coassemblies from PS-b-PAA with Quantum Dots.

    PubMed

    Liu, Wei; Mao, Jun; Xue, Yanhu; Zhao, Ziliang; Zhang, Haishan; Ji, Xiangling

    2016-08-01

    Inorganic nanoparticles play a very important role in the fabrication and regulation of desirable hybrid structures with block copolymers. In this study, polystyrene-b-poly(acrylic acid) (PS48-b-PAA67) and oleic acid-capped CdSe/CdS core/shell quantum dots (QDs) are coassembled in tetrahydrofuran (THF) through gradual water addition. QDs are incorporated into the hydrophilic PAA blocks because of the strong coordination between PAA blocks and the surface of QDs. Increasing the weight fraction of QDs (ω = 0-0.44) leads to morphological transitions from hybrid spherical micelles to large compound micelles (LCMs) and then to bowl-shaped structures. The coassembly process is monitored using transmission electron microscopy (TEM). Formation mechanism of different morphologies is further proposed in which the PAA blocks bridging QDs manipulates the polymer chain mobility and the resulting morphology. Furthermore, the size and size distribution of assemblies serving as drug carriers will influence the circulation time, organ distribution and cell entry pathway of assemblies. Therefore, it is important to prepare or isolate assemblies with monodisperse or narrow size distribution for biomedical applications. Here, the centrifugation and membrane filtration techniques are applied to fractionate polydisperse coassemblies, and the results indicate that both techniques provide effective size fractionation. PMID:27447738

  2. Morphological transitions and buckling characteristics in a nanoparticle-laden sessile droplet resting on a heated hydrophobic substrate.

    PubMed

    Bansal, Lalit; Miglani, Ankur; Basu, Saptarshi

    2016-04-01

    In this work, we have established the evaporation-liquid flow coupling mechanism by which sessile nanofluid droplets on a hydrophobic substrate evaporate and agglomerate to form unique morphological features under controlled external heating. It is well understood that evaporation coupled with internal liquid flow controls particle transport in a spatiotemporal sense. Flow characteristics inside the heated droplet are investigated and found to be driven by the buoyancy effects. Velocity magnitudes are observed to increase by an order at higher temperatures with similar looking flow profiles. The recirculating flow induced particle transport coupled with collision of particles and shear interaction between them leads to the formation of dome shaped viscoelastic shells of different dimensions depending on the surface temperature. These shells undergo sol-gel transition and subsequently undergo buckling instability leading to the formation of daughter cavities. With an increase in the surface temperature, droplets exhibit buckling from multiple sites over a larger sector in the top half of the droplet. Irrespective of the initial nanoparticle concentration and substrate temperature, growth of a daughter cavity (subsequent to buckling) inside the droplet is found to be controlled by the solvent evaporation rate from the droplet periphery and is shown to exhibit a universal trend. PMID:27176350

  3. Morphological transitions and buckling characteristics in a nanoparticle-laden sessile droplet resting on a heated hydrophobic substrate

    NASA Astrophysics Data System (ADS)

    Bansal, Lalit; Miglani, Ankur; Basu, Saptarshi

    2016-04-01

    In this work, we have established the evaporation-liquid flow coupling mechanism by which sessile nanofluid droplets on a hydrophobic substrate evaporate and agglomerate to form unique morphological features under controlled external heating. It is well understood that evaporation coupled with internal liquid flow controls particle transport in a spatiotemporal sense. Flow characteristics inside the heated droplet are investigated and found to be driven by the buoyancy effects. Velocity magnitudes are observed to increase by an order at higher temperatures with similar looking flow profiles. The recirculating flow induced particle transport coupled with collision of particles and shear interaction between them leads to the formation of dome shaped viscoelastic shells of different dimensions depending on the surface temperature. These shells undergo sol-gel transition and subsequently undergo buckling instability leading to the formation of daughter cavities. With an increase in the surface temperature, droplets exhibit buckling from multiple sites over a larger sector in the top half of the droplet. Irrespective of the initial nanoparticle concentration and substrate temperature, growth of a daughter cavity (subsequent to buckling) inside the droplet is found to be controlled by the solvent evaporation rate from the droplet periphery and is shown to exhibit a universal trend.

  4. Renormalization of optical transition strengths in semiconductor nanoparticles due to band mixing

    DOE PAGESBeta

    Velizhanin, Kirill A.

    2016-05-25

    We report that unique optical properties of semiconductor nanoparticles (SN) make them very promising in the multitude of applications including lasing, light emission and photovoltaics. In many of these applications it is imperative to understand the physics of interaction of electrons in a SN with external electromagnetic fields on the quantitative level. In particular, the strength of electron–photon coupling determines such important SN parameters as the radiative lifetime and absorption cross section. This strength is often assumed to be fully encoded by the so called Kane momentum matrix element. This parameter, however, pertains to a bulk semiconductor material and, asmore » such, is not sensitive to the quantum confinement effects in SNs. In this work we demonstrate that the quantum confinement, via the so called band mixing, can result in a significant suppression of the strength of electron interaction with electromagnetic field. Within the envelope function formalism we show how this suppression can be described by introducing an effective energy-dependent Kane momentum. Then, the effect of band mixing on the efficiencies of various photoinduced processes can be fully captured by the conventional formulae (e.g., spontaneous emission rate), once the conventional Kane momentum is substituted with the renormalized energy-dependent Kane momentum introduced in here. Lastly, as an example, we evaluate the energy-dependent Kane momentum for spherical PbSe and PbS SNs (i.e., quantum dots) and show that neglecting band mixing in these systems can result in the overestimation of absorption cross sections and emission rates by a factor of ~2.« less

  5. Quantitatively probing propensity for structural transitions in engineered virus nanoparticles by single-molecule mechanical analysis

    NASA Astrophysics Data System (ADS)

    Castellanos, Milagros; Carrillo, Pablo J. P.; Mateu, Mauricio G.

    2015-03-01

    Viruses are increasingly being studied from the perspective of fundamental physics at the nanoscale as biologically evolved nanodevices with many technological applications. In viral particles of the minute virus of mice (MVM), folded segments of the single-stranded DNA genome are bound to the capsid inner wall and act as molecular buttresses that increase locally the mechanical stiffness of the particle. We have explored whether a quantitative linkage exists in MVM particles between their DNA-mediated stiffening and impairment of a heat-induced, virus-inactivating structural change. A series of structurally modified virus particles with disrupted capsid-DNA interactions and/or distorted capsid cavities close to the DNA-binding sites were engineered and characterized, both in classic kinetics assays and by single-molecule mechanical analysis using atomic force microscopy. The rate constant of the virus inactivation reaction was found to decrease exponentially with the increase in elastic constant (stiffness) of the regions closer to DNA-binding sites. The application of transition state theory suggests that the height of the free energy barrier of the virus-inactivating structural transition increases linearly with local mechanical stiffness. From a virological perspective, the results indicate that infectious MVM particles may have acquired the biological advantage of increased survival under thermal stress by evolving architectural elements that rigidify the particle and impair non-productive structural changes. From a nanotechnological perspective, this study provides proof of principle that determination of mechanical stiffness and its manipulation by protein engineering may be applied for quantitatively probing and tuning the conformational dynamics of virus-based and other protein-based nanoassemblies.Viruses are increasingly being studied from the perspective of fundamental physics at the nanoscale as biologically evolved nanodevices with many technological

  6. Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?

    PubMed Central

    van Woensel, Matthias; Wauthoz, Nathalie; Rosière, Rémi; Amighi, Karim; Mathieu, Véronique; Lefranc, Florence; van Gool, Stefaan W.; de Vleeschouwer, Steven

    2013-01-01

    Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma. PMID:24202332

  7. Nonaqueous synthesis of metal oxide nanoparticles: Short review and doped titanium dioxide as case study for the preparation of transition metal-doped oxide nanoparticles

    SciTech Connect

    Djerdj, Igor Arcon, Denis; Jaglicic, Zvonko; Niederberger, Markus

    2008-07-15

    The liquid-phase synthesis of metal oxide nanoparticles in organic solvents under exclusion of water is nowadays a well-established alternative to aqueous sol-gel chemistry. In this article, we highlight some of the advantages of these routes based on selected examples. The first part reviews some recent developments in the synthesis of ternary metal oxide nanoparticles by surfactant-free nonaqueous sol-gel routes, followed by the discussion of the morphology-controlled synthesis of lanthanum hydroxide nanoparticles, and the presentation of structural peculiarities of manganese oxide nanoparticles with an ordered Mn vacancy superstructure. These examples show that nonaqueous systems, on the one hand, allow the preparation of compositionally complex oxides, and, on the other hand, make use of the organic components (initially present or formed in situ) in the reaction mixture to tailor the morphology. Furthermore, obviously even the crystal structure can differ from the corresponding bulk material like in the case of MnO nanoparticles. In the second part of the paper we present original results regarding the synthesis of dilute magnetic semiconductor TiO{sub 2} nanoparticles doped with cobalt and iron. The structural characterization as well as the magnetic properties with special attention to the doping efficiency is discussed. - Graphical abstract: In the first part of this article, nonaqueous sol-gel routes to ternary metal oxide nanoparticles are briefly reviewed, followed by the discussion of the morphology-controlled synthesis of lanthanum hydroxide nanoparticles, and the appearance of an unprecedented superstructure in MnO nanoparticles. In the second part, doping experiments of TiO{sub 2} with Fe and Co are presented, along with their characterization including magnetic measurements.

  8. Reversible sol-gel transitions of aqueous dispersions of silica nanoparticles grafted with diblock copolymer brushes composed of a thermosensitive inner block and a charged outer block.

    PubMed

    Wright, Roger A E; Hu, Bin; Henn, Daniel M; Zhao, Bin

    2015-09-14

    We report in this article that aqueous dispersions of thermosensitive diblock copolymer brush-grafted 17 nm silica nanoparticles (hairy NPs) can undergo in situ, reversible sol-gel transitions in response to temperature changes. The brushes consisted of a thermosensitive poly(methoxydi(ethylene glycol) methacrylate) (PDEGMMA) inner block and a charge-carrying, poly(DEGMMA-co-2-(methacryloyloxy)ethyltrimethylammonium iodide) outer block, which were prepared by a one-pot, surface-initiated atom transfer radical polymerization and subsequent quaternization of tertiary amine moieties in the second block with iodomethane. Above a critical concentration, the aqueous dispersion of hairy NPs with an appropriate block copolymer composition exhibited a reversible transition from a free flowing liquid to a free standing hydrogel upon cooling from elevated temperatures, which was driven by the lower critical solution temperature transition of the thermosensitive inner block of hairy NPs as confirmed by dynamic light scattering study. At the same concentration of hairy NPs, the sol-gel transition temperature was higher when the highly hydrated, charged outer block was longer. The transition temperature decreased with decreasing the concentration of hairy NPs in the dispersion; reversible gelation was achieved with a concentration of hairy NPs in water as low as 5.5 wt%. Interestingly, the LCST transition of the inner thermosensitive PDEGMMA block disappeared and no sol-gel transition was observed in the studied temperature range when the charged outer block was sufficiently long. PMID:26223449

  9. In-situ, nanometer-scale visualization of nanoparticle phase transitions and light-matter interactions in 2- and 3-D

    NASA Astrophysics Data System (ADS)

    Dionne, Jennifer

    2015-03-01

    We present new spectroscopic techniques that enable visualization of nanoparticle phase transitions in reactive environments and light-matter interactions with nanometer-scale resolution. First, we directly monitor hydrogen absorption and desorption in individual palladium nanocrystals. Our approach is based on in-situ electron energy-loss spectroscopy (EELS) in an environmental transmission electron microscope. By probing hydrogen-induced shifts of the palladium plasmon resonance, we find that hydrogen loading and unloading isotherms are characterized by abrupt phase transitions and macroscopic hysteresis gaps. These results suggest that alpha and beta phases do not coexist in single-crystalline nanoparticles, in striking contrast with conventional phase transitions and ensemble measurements of Pd nanoparticles. Then, we then extend these techniques to monitor nanoparticle reactions in a liquid environment. By constructing a flow chamber, we directly monitor growth and assembly of colloidal plasmonic metamaterial constituents induced by chemical catalysts. Lastly, we introduce a novel tomographic technique, cathodoluminescence spectroscopic tomography, to probe optical properties in three dimensions with nanometer-scale spatial and spectral resolution. Particular attention is given to reconstructing a 3D metamaterial resonator supporting broadband electric and magnetic resonances at optical frequencies. Our tomograms allow us to locate regions of efficient cathodoluminescence across visible and near-infrared wavelengths, with contributions from material luminescence and radiative decay of electromagnetic eigenmodes. The experimental signal can further be correlated with the radiative local density of optical states in particular regions of the reconstruction. Our results provide a general framework for visualizing chemical reactions and light-matter interactions in plasmonic materials and metamaterials, with sub-nanometer-scale resolution, and in three-dimensions.

  10. Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening

    PubMed Central

    Ikeda, Gentaro; Matoba, Tetsuya; Nakano, Yasuhiro; Nagaoka, Kazuhiro; Ishikita, Ayako; Nakano, Kaku; Funamoto, Daiki; Sunagawa, Kenji; Egashira, Kensuke

    2016-01-01

    Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effects of early reperfusion therapy for acute myocardial infarction (MI), in which mitochondrial permeability transition pore (mPTP) opening plays a critical role. Our aim was to determine whether poly-lactic/glycolic acid (PLGA) nanoparticle-mediated mitochondrial targeting of a molecule that inhibits mPTP opening, cyclosporine A (CsA), enhances CsA-induced cardioprotection. In an in vivo murine IR model, intravenously injected PLGA nanoparticles were located at the IR myocardium mitochondria. Treatment with nanoparticles incorporated with CsA (CsA-NP) at the onset of reperfusion enhanced cardioprotection against IR injury by CsA alone (as indicated by the reduced MI size at a lower CsA concentration) through the inhibition of mPTP opening. Left ventricular remodeling was ameliorated 28 days after IR, but the treatment did not affect inflammatory monocyte recruitment to the IR heart. In cultured rat cardiomyocytes in vitro, mitochondrial PLGA nanoparticle-targeting was observed after the addition of hydrogen peroxide, which represents oxidative stress during IR, and was prevented by CsA. CsA-NP can be developed as an effective mPTP opening inhibitor and may protect organs from IR injury. PMID:26861678

  11. New intranasal formulations for the treatment of allergic rhinitis.

    PubMed

    Meltzer, Eli O; Bensch, Greg W; Storms, William W

    2014-01-01

    Intranasal corticosteroids (INSs) have been effectively used for >40 years for the treatment of seasonal allergic rhinitis (SAR) and perennial AR (PAR). Following the Montreal Protocol, the initial aerosol formulations using chlorofluorocarbon (CFC) propellants were phased out. For the past 20 years, aqueous solutions have been the only available option for INS treatment. In 2012, the U.S. Food and Drug Administration approved two new nonaqueous aerosol AR treatments that use a hydrofluoroalkane (HFA) propellant. In 2012, the first intranasal aqueous combination product was also approved. This article reviews the clinical profiles of HFA beclomethasone dipropionate (BDP) and HFA ciclesonide (CIC) and the aqueous combination intranasal antihistamine (INA)/INS formulation of azelastine hydrochloride/fluticasone propionate (AZE/FP). The medical literature was searched for clinical trials investigating the use of BDP, CIC, and AZE/FP in SAR and PAR. Clinical trials involving aqueous solutions and CFC propellant or HFA propellant delivery were included. Data from prescribing information and published efficacy and safety data were presented as part of the clinical profile for the reviewed agents. AZE/FP has shown efficacy and safety comparable or greater with the current AR treatment options. Although efficacy comparisons of new HFA formulations have not been investigated in head-to-head clinical trials with aqueous formulations, HFA formulations have shown similar efficacy rates. Furthermore, HFA formulations may have some additional benefits, including a preferable sensory profile for some patients. These new formulations will provide additional options for clinicians and patients to better individualize therapy for control of AR. PMID:25582157

  12. Computed Intranasal Spray Penetration: Comparisons Before and After Nasal Surgery

    PubMed Central

    Frank, Dennis O.; Kimbell, Julia S.; Cannon, Daniel; Rhee, John S.

    2012-01-01

    Background Quantitative methods for comparing intranasal drug delivery efficiencies pre- and postoperatively have not been fully utilized. The objective of this study is to use computational fluid dynamics techniques to evaluate aqueous nasal spray penetration efficiencies before and after surgical correction of intranasal anatomic deformities. Methods Ten three-dimensional models of the nasal cavities were created from pre- and postoperative computed tomography scans in five subjects. Spray simulations were conducted using a particle size distribution ranging from 10–110μm, a spray speed of 3m/s, plume angle of 68°, and with steady state, resting inspiratory airflow present. Two different nozzle positions were compared. Statistical analysis was conducted using Student T-test for matched pairs. Results On the obstructed side, posterior particle deposition after surgery increased by 118% and was statistically significant (p-value=0.036), while anterior particle deposition decreased by 13% and was also statistically significant (p-value=0.020). The fraction of particles that by-passed the airways either pre- or post-operatively was less than 5%. Posterior particle deposition differences between obstructed and contralateral sides of the airways were 113% and 30% for pre- and post-surgery, respectively. Results showed that nozzle positions can influence spray delivery. Conclusions Simulations predicted that surgical correction of nasal anatomic deformities can improve spray penetration to areas where medications can have greater effect. Particle deposition patterns between both sides of the airways are more evenly distributed after surgery. These findings suggest that correcting anatomic deformities may improve intranasal medication delivery. For enhanced particle penetration, patients with nasal deformities may explore different nozzle positions. PMID:22927179

  13. Serospecific protection of mice against intranasal infection with Bordetella pertussis.

    PubMed

    Robinson, A; Gorringe, A R; Funnell, S G; Fernandez, M

    1989-08-01

    The ability of purified serospecific agglutinogens from Bordetella pertussis to protect mice against intranasal infection has been examined. Immunization with agglutinogen 2 protected mice against infection with 1.2.0 or 1.2.3 serotypes of B. pertussis, whereas immunization with agglutinogen 3 protected mice against infection with all serotypes. More importantly immunization with serospecific agglutinogen resulted in immune selection so that organisms recovered following infection did not express the immunizing antigen. The results are consistent with the suggestions that protection of children with whole cell pertussis vaccine is to some extent serospecific and that agglutinogens should be considered as constituents of acellular pertussis vaccines. PMID:2573215

  14. [Potential for the clinical use of intranasal rifathyroin for diagnosis and treatment].

    PubMed

    Starkova, N T; Butrova, S A; Surkov, S I; Kotova, G A; Nazarov, A N; Bobrovskaia, T A

    1991-01-01

    It has been shown that stimulated TSH and prolactin levels in intranasal administration of rifathyroin are comparable with the results of i.v. administration of the drug. Intranasal administration can be used for both therapeutic and diagnostic purposes. PMID:1788208

  15. Effects of nanoparticle doping on the phase transitional behaviour of ferroelectric liquid crystal Langmuir-Blodgett composite films

    NASA Astrophysics Data System (ADS)

    Kaur, Ramneek; Raina, K. K.

    2015-12-01

    Langmuir-Blodgett films of ferroelectric liquid crystals (FLCs) doped with a low concentration of functionalized Al: ZnO (AZO) nanoparticles were prepared and characterized. Pressure-area isotherms show that the nanoparticles as well as FLC composite systems have the capability to form stable monolayers at the air-water interface. The molecular interaction between nanoparticles and FLC molecules increased during barrier compression, which resulted in increased surface pressure. We observed various phases in isotherms with increasing concentration of nanoparticles in the FLC matrix. An X-ray diffraction profile at a low angle confirmed that FLCs retain their layer structure at a low concentration doping of AZO nanoparticles in the FLC matrix. Atomic force microscopy images indicate that low wt% composites are uniformly deposited without disturbing the translation behaviour of SmC* liquid crystals.

  16. Data on energy-band-gap characteristics of composite nanoparticles obtained by modification of the amorphous potassium polytitanate in aqueous solutions of transition metal salts

    PubMed Central

    Zimnyakov, D.A.; Sevrugin, A.V.; Yuvchenko, S.A.; Fedorov, F.S.; Tretyachenko, E.V.; Vikulova, M.A.; Kovaleva, D.S.; Krugova, E.Y.; Gorokhovsky, A.V.

    2016-01-01

    Here we present the data on the energy-band-gap characteristics of composite nanoparticles produced by modification of the amorphous potassium polytitanate in aqueous solutions of different transition metal salts. Band gap characteristics are investigated using diffuse reflection spectra of the obtained powders. Calculated logarithmic derivative quantity of the Kubelka–Munk function reveals a presence of local maxima in the regions 0.5–1.5 eV and 1.6–3.0 eV which correspond to band gap values of the investigated materials. The values might be related to the constituents of the composite nanoparticles and intermediate products of their chemical interaction. PMID:27158654

  17. Field dependent transition to the non-linear regime in magnetic hyperthermia experiments: Comparison between maghemite, copper, zinc, nickel and cobalt ferrite nanoparticles of similar sizes

    NASA Astrophysics Data System (ADS)

    Verde, E. L.; Landi, G. T.; Carrião, M. S.; Drummond, A. L.; Gomes, J. A.; Vieira, E. D.; Sousa, M. H.; Bakuzis, A. F.

    2012-09-01

    Further advances in magnetic hyperthermia might be limited by biological constraints, such as using sufficiently low frequencies and low field amplitudes to inhibit harmful eddy currents inside the patient's body. These incite the need to optimize the heating efficiency of the nanoparticles, referred to as the specific absorption rate (SAR). Among the several properties currently under research, one of particular importance is the transition from the linear to the non-linear regime that takes place as the field amplitude is increased, an aspect where the magnetic anisotropy is expected to play a fundamental role. In this paper we investigate the heating properties of cobalt ferrite and maghemite nanoparticles under the influence of a 500 kHz sinusoidal magnetic field with varying amplitude, up to 134 Oe. The particles were characterized by TEM, XRD, FMR and VSM, from which most relevant morphological, structural and magnetic properties were inferred. Both materials have similar size distributions and saturation magnetization, but strikingly different magnetic anisotropies. From magnetic hyperthermia experiments we found that, while at low fields maghemite is the best nanomaterial for hyperthermia applications, above a critical field, close to the transition from the linear to the non-linear regime, cobalt ferrite becomes more efficient. The results were also analyzed with respect to the energy conversion efficiency and compared with dynamic hysteresis simulations. Additional analysis with nickel, zinc and copper-ferrite nanoparticles of similar sizes confirmed the importance of the magnetic anisotropy and the damping factor. Further, the analysis of the characterization parameters suggested core-shell nanostructures, probably due to a surface passivation process during the nanoparticle synthesis. Finally, we discussed the effect of particle-particle interactions and its consequences, in particular regarding discrepancies between estimated parameters and expected

  18. Intranasally Administered Adjunctive Dexmedetomidine Reduces Perioperative Anesthetic Requirements in General Anesthesia

    PubMed Central

    Wu, Xiang; Hang, Li-Hua; Wang, Hong; Shao, Dong-Hua; Xu, Yi-Guo; Cui, Wei

    2016-01-01

    Purpose Intranasal dexmedetomidine is an effective sedative for premedication and is regularly used to reduce preoperative tension and anxiety in children. This study aimed to assess the effect of intranasally adjunctive dexmedetomidine on perioperative sedative and analgesic requirements in adults. Materials and Methods Patients were randomly divided into four groups to receive preoperative administration of saline, intranasal dexmedetomidine 1 µg/kg and 2 µg/kg, and intravenous dexmedetomidine 1 µg/kg, respectively. Propofol and remifentanil were target-controlled infused to maintain intraoperative bispectral index at 45–55 and blood pressure at baseline value±20%. Sufentanil was administered to maintain postoperative visual analogue scale ≤3. Perioperative anesthetics requirements were compared using nonparametric tests. Results Intranasal dexmedetomidine significantly attenuated propofol requirements for anesthesia induction and maintenance in a dose-dependent manner. Patients given intranasal dexmedetomidine 2 µg/kg required less remifentanil for anesthesia maintenance. The first postoperative request for sufentanil analgesia was delayed in patients given intranasal dexmedetomidine 2 µg/kg. The anesthetics-sparing effect of intranasal dexmedetomidine was significantly weaker than intravenous dexmedetomidine at the same dose of 1 µg/kg. The incidences of adverse events, including hemodynamic instability and delayed recovery, were comparable with and without intranasal dexmedetomidine. Conclusion Intranasal administration of dexmedetomidine can reduce perioperative anesthetic requirements, and a dose of dexmedetomidine 2 µg/kg produces a better effect in adults. The anesthetics-sparing effect of intranasal dexmedetomidine 1 µg/kg is less than that with the same intravenous dose of dexmedetomidine. PMID:27189297

  19. Intranasal treatment of central nervous system dysfunction in humans.

    PubMed

    Chapman, Colin D; Frey, William H; Craft, Suzanne; Danielyan, Lusine; Hallschmid, Manfred; Schiöth, Helgi B; Benedict, Christian

    2013-10-01

    One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke. PMID:23135822

  20. Bioavailability of intranasal promethazine dosage forms in dogs

    NASA Technical Reports Server (NTRS)

    Ramanathan, R.; Geary, R. S.; Bourne, D. W.; Putcha, L.

    1998-01-01

    Intramuscular promethazine (PMZ) is used aboard the US Space Shuttle to ameliorate symptoms of space motion sickness. Bioavailability after an oral dose of PMZ during space flight is thought to be impaired because of gastrointestinal disturbances associated with weightlessness and space motion sickness. In an attempt to find an alternative dosage form for use in space, we evaluated two intranasal (i.n.) dosage forms of PMZ in dogs for absorption and bioavailability relative to that of an equivalent intramuscular dose. Promethazine (5 mg kg-1) was administered as two intranasal dosage forms and as an intramuscular (i.m.) dose to three dogs in a randomised cross-over design. Serial blood samples were taken and analysed for PMZ concentrations and the absorption and bioavailability of PMZ were calculated for the three dosage forms. PMZ absorption from the carboxymethyl cellulose microsphere i.n. dosage form was more rapid and complete than from the myverol cubic gel formulation or from an i.m. injection. Bioavailability of the microsphere formulation was also greater than that of the gel formulation (AUC 3009 vs 1727 ng h ml-1). The bioavailability of the two i.n. dosage forms (relative to that of the i.m. injection) were 94% (microsphere) and 54% (gel). The i.n. microsphere formulation of PMZ offers great promise as an effective non-invasive alternative for treating space motion sickness due to its rapid absorption and bioavailability equivalent to the i.m. dose.

  1. Host resistance to intranasal Acinetobacter baumannii reinfection in mice.

    PubMed

    Qiu, Hongyu; Li, Zack; KuoLee, Rhonda; Harris, Greg; Gao, Xiaoling; Yan, Hongbin; Xu, H Howard; Chen, Wangxue

    2016-07-01

    Acinetobacter baumannii is a major causative agent of healthcare-associated infection and develops multidrug resistance rapidly. However, little is known in the host defense mechanisms against this infection. In this study, we examined if mice recovered from a previous intranasal A. baumannii infection (recovered mice) are fully protected against a subsequent reinfection. We found that, despite the presence of specific serum IgG and mucosal IgA responses prior to the reinfection, the recovered mice were only marginally better protected against intranasal challenge with low doses of homologous or heterologous A. baumannii strains than the naïve mice. Post-challenge immune and inflammatory (cells and cytokines) responses were generally comparable between recovered and naïve mice although the recovered mice produced significantly higher amounts of IFN-γ and IL-17 and had higher percentages and numbers of resident lung CD44(hi)CD62L(-)CD4(+) and CD19(+) B lymphocytes. Taken together, our results suggest that mice recovered from a previous A. baumannii infection remain susceptible to reinfection, indicating the complexity of immune protection mechanism for this Gram-negative, multidrug-resistant emerging pathogen. PMID:27194730

  2. Clinical implications for breath-powered powder sumatriptan intranasal treatment.

    PubMed

    Tepper, Stewart J

    2013-09-01

    The acute treatment of migraine requires matching patient need to drug and formulation. In particular, nausea and vomiting, quick time to peak intensity, and the common gastroparesis of migraineurs, all call for a variety of non-oral formulations for treatment of attacks. A novel breath-powered powder sumatriptan intranasal treatment offers an improvement, at least in pharmacokinetics, over conventional liquid nasal sumatriptan spray. The device for delivery in this breath-powered nasal sumatriptan uses natural nose anatomy to close the soft palate and propel the sumatriptan high up in the nasal cavity on one side with bidirectional airflow coming out the other side. This approach has the potential to reduce adverse events and improve efficacy. Phase 3 data on this system are in press at the time of this writing and results appear promising. The clinical role for a fast acting non-oral nasal formulation will be in those for whom tablets are bound to fail, that is, in the setting of nausea and vomiting or when the time to central sensitization, allodynia, and disabling migraine is too short for the patient to respond to a tablet. This review provides a clinical perspective on the breath-powered powder sumatriptan intranasal treatment. PMID:23809006

  3. Intranasal IGF-1 Reduced Rat Pup Germinal Matrix Hemorrhage.

    PubMed

    Lekic, Tim; Flores, Jerry; Klebe, Damon; Doycheva, Desislava; Rolland, William B; Tang, Jiping; Zhang, John H

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most devastating neurological problem of premature infants. Current treatment strategies are ineffective and brain injury is unpreventable. Insulin-like growth factor 1 (IGF-1) is an endogenous protein shown to have multiple neuroprotective properties. We therefore hypothesized that IGF-1 would reduce brain injury after GMH. Neonatal rats (P7 age) received stereotactic collagenase into the right ganglionic eminence. The following groups were studied: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal IGF-1. Three days later, the animals were evaluated using the righting-reflex (early neurobehavior), Evans blue dye leakage (blood-brain barrier (BBB) permeability), brain water content (edema), and hemoglobin assay (extent of bleeding). Three weeks later, juvenile rats were tested using a water maze (delayed neurobehavior), and then were sacrificed on day 28 for assessment of hydrocephalus (ventricular size). Intranasal IGF-1 treated animals had improved neurological function, and amelioration of BBB permeability, edema, and re-bleeding. IGF-1 may play a part in protective brain signaling following GMH, and our observed protective effect may offer new promise for treatment targeting this vulnerable patient population. PMID:26463950

  4. Intranasal scopolamine affects the semicircular canals centrally and peripherally.

    PubMed

    Weerts, Aurélie P; Putcha, Lakshmi; Hoag, Stephen W; Hallgren, Emma; Van Ombergen, Angelique; Van de Heyning, Paul H; Wuyts, Floris L

    2015-08-01

    Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS. PMID:25953832

  5. Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.

    PubMed

    2003-01-01

    submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigerator-stable liquid formulation of FluMist and as much as $US50 million for licensing of FluMist internationally. In July 2003 MedImmune announced that it had received approximately $US28 million in milestone payments during Q2 of 2003 for the approval of FluMist. CSL Ltd of Australia will collaborate on the development, sale and distribution of MedImmune Vaccine's vaccine in Australia, New Zealand and certain countries in the South Pacific. MedImmune is to acquire vaccine research programmes in respiratory syncytial virus and cytomegalovirus from MedImmune Vaccines. The company's primary interest is in FluMist. In May 2002, MedImmune licensed exclusive rights to Crucell's proprietary human cell line PER.C6 for use in its influenza vaccine programmes. On 11 March 2002, American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth-Lederle to Wyeth. Wyeth's vaccines division is called Wyeth Vaccines. On 29 September 2000, Aviron announced that it had been awarded a $US2.7 million Challenge Grant from NIAID for development of vaccines against pandemic strains of influenza based on FluMist intranasal technology. The cold-adapted live influenza vaccine has been widely evaluated in the US and Japan since 1975 in clinical trials involving several thousand people. Aviron completed phase II clinical trials in adults in the US and phase III trials in US children aged 15-71 months. Additional phase III trials in adults and the elderly are ongoing. Aviron also commenced phase III trials to test the safety of its intranasal live vaccine in children with moderate to severe asthma. The vaccine is delivered using the AccuSpray nasal delivery system by Becton Dickinson, which will supply the system for FluMist through the 2001-2002 influenza season under an agreement with Aviron made in August 1998. On 7 March 2000, Aviron announced that Wyeth-Lederle Vaccines

  6. AN in vitro evaluation of a carmustine-loaded Nano-co-Plex for potential magnetic-targeted intranasal delivery to the brain.

    PubMed

    Akilo, Olufemi D; Choonara, Yahya E; Strydom, André M; du Toit, Lisa C; Kumar, Pradeep; Modi, Girish; Pillay, Viness

    2016-03-16

    Targeted delivery of carmustine (BCNU), an efficient brain tumor therapeutic, has been challenged with bioavailability issues due to the Blood Brain Barrier (BBB). The currently effective delivery approach is by implants at the site of the tumor, but this is highly invasive. The intranasal route, which is non-invasive and bypasses the BBB, may be alternative route for delivering BCNU to the brain. In this work, polyvinyl alcohol/polyethyleneimine/fIuorecein isothiocyanate complex (Polyplex) coated iron-oxide nanoparticles (Magnetite) were synthesized employing co-precipitation, epoxidation and EDC/NHS coupling reactions. The Polyplex coated magnetite (Nano-co-Plex) was loaded with BCNU for potential magnetically targeted delivery to the brain following intranasal administration. The Nano-co-Plex was characterized employing Thermogravimetric analysis (TGA), Superconducting Quantum Interference Device (SQUID) magnetometry, Fourier Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), X-ray Diffractometry (XRD), Transmission Electron Microscopy (TEM) and Zetasize analysis. Results revealed superparamagnetic hexagonally shaped "core-shell" nanoparticles with cell labeling attributes, of size ranging between 30-50 nm, and a zeta potential value of + 32 ± 2 mV. The Nano-co-Plex synthesized was found to possess high degree of crystallinity with 32% Polyplex coating. The loading and release studies indicated a time-dependent loading with maximum loading capacity of 176.82 μg BCNU/mg of the carrier and maximum release of 75.8% of the loaded BCNU. Cytotoxicity of the BCNU-loaded Nano-co-Plex displayed superiority over the conventional BCNU towards human glioblastoma (HG) cells. Cell studies revealed enhanced uptake and internalization of BCNU-loaded Nano-co-plex in HG cells in the presence of an external magnetic field. These Nano-co-Plexes may be ideal as an intranasal magnetic drug targeting device for BCNU delivery. PMID:26806465

  7. Synthesis and phase transition under ultra-high pressure of ZnS nanoparticles modified by sodium bis(2-ethylhexyl) sulfosuccinate

    NASA Astrophysics Data System (ADS)

    Ji, Yunliang; Guo, Lin; Xu, Huibin; Liu, Jing; Li, Xiaodong; Li, Yanchun; Wu, Ziyu; Simon, Paul

    2003-07-01

    ZnS nanoparticles modified by AOT with different particle sizes (5 nm and 13 nm) were prepared in reverse micelles. The products show the zinc-blende (B3) structure at atmospheric pressure, and the B3 structure was proved to exist at smaller size dimensions than the B4 structure. The pressure-induced phase transition to the rock salt (B1) phase was studied by in situ high-pressure energy-dispersive X-ray diffraction experiments. The transition began at a pressure of around 15.4 GPa for the 5 nm sample and at 16 GPa for the 13 nm sample. It is indicated that the transition pressure is not obviously dependent on the grain size of the nano-crystals in our experiments. From the small transition pressure gap between the two different sizes it can be deduced that the transition pressure goes to the same value below a certain particle size. This feature could be caused by the crystal lattice contraction due to the strong surface pressure. Our results imply, that the new high-pressure phase is metastable and cannot exist in ordinary circumstances.

  8. Transition Metal Phosphide Nanoparticles Supported on SBA-15 as Highly Selective Hydrodeoxygenation Catalysts for the Production of Advanced Biofuels.

    PubMed

    Yang, Yongxing; Ochoa-Hernández, Cristina; de la Peña O'Shea, Víctor A; Pizarro, Patricia; Coronado, Juan M; Serrano, David P

    2015-09-01

    A series of catalysts constituted by nanoparticles of transition metal (M = Fe, Co, Ni and Mo) phosphides (TMP) dispersed on SBA-15 were synthesized by reduction of the corresponding metal phosphate precursors previously impregnated on the mesostructured support. All the samples contained a metal-loading of 20 wt% and with an initial M/P mole ratio of 1, and they were characterized by X-ray diffraction (XRD), N2 sorption, H2-TPR and transmission electron microscopy (TEM). Metal phosphide nanocatalysts were tested in a high pressure continuous flow reactor for the hydrodeoxygenation (HDO) of a methyl ester blend containing methyl oleate (C17H33-COO-CH3) as main component (70%). This mixture constitutes a convenient surrogate of triglycerides present in vegetable oils, and following catalytic hydrotreating yields mainly n-alkanes. The results of the catalytic assays indicate that Ni2P/SBA-15 catalyst presents the highest ester conversion, whereas the transformation rate is about 20% lower for MoP/SBA-15. In contrast, catalysts based on Fe and Co phosphides show a rather limited activity. Hydrocarbon distribution in the liquid product suggests that both hydrodeoxygenation and decarboxylation/decarbonylation reactions occur simultaneously over the different catalysts, although MoP/SBA-15 possess a selectivity towards hydrodeoxygenation exceeding 90%. Accordingly, the catalyst based on MoP affords the highest yield of n-octadecane, which is the preferred product in terms of carbon atom economy. Subsequently, in order to conjugate the advantages of both Ni and Mo phosphides, a series of catalysts containing variable proportions of both metals were prepared. The obtained results reveal that the mixed phosphides catalysts present a catalytic behavior intermediate between those of the monometallic phosphides. Accordingly, only marginal enhancement of the yield of n-octadecane is obtained for the catalysts with a Mo/Ni ratio of 3. Nevertheless, owing to this high selectivity

  9. Intranasal oxytocin increases social grooming and food sharing in the common vampire bat Desmodus rotundus.

    PubMed

    Carter, Gerald G; Wilkinson, Gerald S

    2015-09-01

    Intranasal oxytocin (OT) delivery has been used to non-invasively manipulate mammalian cooperative behavior. Such manipulations can potentially provide insight into both shared and species-specific mechanisms underlying cooperation. Vampire bats are remarkable for their high rates of allogrooming and the presence of regurgitated food sharing among adults. We administered intranasal OT to highly familiar captive vampire bats of varying relatedness to test for an effect on allogrooming and food sharing. We found that intranasal OT did not have a detectable effect on food-sharing occurrence, but it did increase the size of regurgitated food donations when controlling for dyad and amount of allogrooming. Intranasal OT in females increased the amount of allogrooming per partner and across all partners per trial, but not the number of partners. We also found that the peak effect of OT treatments occurred 30-50min after administration, which is consistent with the reported latency for intranasal OT to affect relevant brain areas in rats and mice. Our results suggest that intranasal OT is a potential tool for influencing dyadic cooperative investments, but measuring prior social relationships may be necessary to interpret the results of hormonal manipulations of cooperative behavior and it may be difficult to alter partner choice in vampire bats using intranasal OT alone. PMID:26475061

  10. Comparative efficacy of intranasal and oral vaccines against Bordetella bronchiseptica in dogs.

    PubMed

    Ellis, J A; Gow, S P; Waldner, C L; Shields, S; Wappel, S; Bowers, A; Lacoste, S; Xu, Z; Ball, E

    2016-06-01

    In order to determine the comparative efficacy of vaccines administered intranasally or orally to protect puppies from disease subsequent to experimental infection with Bordetella bronchiseptica (Bb), a randomized controlled trial was performed using 48 approximately 8-week-old specific pathogen free, Bb naive Beagle puppies. Puppies were randomized into three groups and administered vaccines containing Bb intranasally or orally, or a placebo intranasally. Twenty-one days later, all dogs were challenge exposed via aerosol administration of Bb. Clinical signs, nasal bacterial shedding and immune responses were monitored for 28 days after challenge. Intranasally vaccinated puppies had significantly lower rates of coughing, nasal discharge, retching and sneezing (i.e. were less sick clinically) than control puppies. The distinction between the orally vaccinated puppies and the control puppies was less consistent. The orally vaccinated puppies had less coughing and less retching than the control puppies, but nasal discharge and sneezing did not differ from control animals. Orally vaccinated puppies had higher rates of coughing, nasal discharge, retching and sneezing than the intranasally vaccinated puppies. Although both intranasal and oral Bb vaccines stimulated immune responses associated with disease sparing following Bb infection, the intranasal route of delivery conferred superior clinical outcomes. The observed difference in clinical efficacy suggests the need to question the rationale for the use of currently available orally administered Bb vaccines. PMID:27256028

  11. Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice.

    PubMed

    Zhang, Huinan; Meng, Jingru; Zhou, Shimeng; Liu, Yunhan; Qu, Di; Wang, Ling; Li, Xubo; Wang, Ning; Luo, Xiaoxing; Ma, Xue

    2016-03-01

    Exendin-4 is now considered as a promising drug for the treatment of cerebral ischemia. To determine the neuroprotective effects of intranasal exendin-4, C57BL/6J mice were intranasally administered with exendin-4 daily for 7 days before middle cerebral artery occlusion (MCAO) surgery. Intranasally administered exendin-4 produced higher brain concentrations and lower plasma concentrations when compared to identical doses administered interperitoneally. Neurological deficits and volume of infarcted lesions were analyzed 24 h after ischemia. Intranasal administration of exendin-4 exhibited significant neuroprotection in C57BL/6 mice subjected to MCAO by reducing neurological deficit scores and infarct volume. The neuroprotective effects of exendin-4 were blocked by the knockdown of GLP-1R with shRNA. However, exendin-4 has no impact on glucose and insulin levels which indicated that the neuroprotective effect was mediated by the activation of GLP-1R in the brain. Exendin-4 intranasal administration restored the balance between pro- and anti-apoptotic proteins and decreased the expression of Caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. These findings provided evidence that exendin-4 intranasal administration exerted a neuroprotective effect mediated by an anti-apoptotic mechanism in MCAO mice and protected neurons against ischemic injury through the GLP-1R pathway in the brain. Intranasal delivery of exendin-4 might be a promising strategy for the treatment of ischemic stroke. PMID:26689204

  12. Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases.

    PubMed

    Meredith, M Elizabeth; Salameh, Therese S; Banks, William A

    2015-07-01

    The blood-brain barrier (BBB) is a major impediment to the therapeutic delivery of peptides and proteins to the brain. Intranasal delivery often provides a non-invasive means to bypass the BBB. Advantages of using intranasal delivery include minimizing exposure to peripheral organs and tissues, thus reducing systemic side effects. It also allows substances that typically have rapid degradation in the blood time to exert their effect. Intranasal delivery provides the ability to target proteins and peptides to specific regions of the brain when administered with substrates like cyclodextrins. In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP. We have described their rationale for use, distribution in the brain after intranasal injection, how intranasal administration differed from other modes of delivery, and their use in clinical trials, if applicable. Intranasal delivery of drugs, peptides, and other proteins could be very useful in the future for the prevention or treatment of brain related diseases. PMID:25801717

  13. Vanadium Dioxide Nanoparticle-based Thermochromic Smart Coating: High Luminous Transmittance, Excellent Solar Regulation Efficiency, and Near Room Temperature Phase Transition.

    PubMed

    Zhu, Jingting; Zhou, Yijie; Wang, Bingbing; Zheng, Jianyun; Ji, Shidong; Yao, Heliang; Luo, Hongjie; Jin, Ping

    2015-12-23

    An annealing-assisted preparation method of well-crystallized VxW1-xO2(M)@SiO2 core-shell nanoparticles for VO2-based thermochromic smart coatings (VTSC) is presented. The additional annealing process reduces the defect density of the initial hydrothermally prepared VxW1-xO2(M) nanoparticles and enhances their crystallinity so that the thermochromic film based on VxW1-xO2(M)@SiO2 nanoparticles can exhibit outstanding thermochromic performance with balanced solar regulation efficiency (ΔTsol) of 17.3%, luminous transmittance (Tlum) up to 52.2%, and critical phase transition temperature (Tc) around 40.4 °C, which is very promising for practical application. Furthermore, it makes great progress in reducing Tc of VTSC to near room temperature (25.2 °C) and simutaneously maintaining excellent optical properties (ΔTsol = 14.7% and Tlum = 50.6%). Such thermochromic performance is good enough to make VTSC applicable to practical architecture. PMID:26618391

  14. Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.

    PubMed

    Krishnan, Jishnu K S; Arun, Peethambaran; Appu, Abhilash P; Vijayakumar, Nivetha; Figueiredo, Taíza H; Braga, Maria F M; Baskota, Sudikshya; Olsen, Cara H; Farkas, Natalia; Dagata, John; Frey, William H; Moffett, John R; Namboodiri, Aryan M A

    2016-03-01

    Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality. PMID:26751814

  15. Topical and Intranasal Analgesic Therapy in a Woman with Refractory Postherpetic Neuralgia

    PubMed Central

    Hohmeier, Kenneth C.; Almon, Lyndsey M.

    2015-01-01

    A patient-specific, stepped approach to topical and intranasal analgesic pharmacotherapy was effective in reducing refractory postherpetic neuralgia (PHN) not responding to the current standard of care for PHN. The use of topical analgesic therapy allowed for higher concentrations of medication locally while reducing the likelihood of systemic side effects common to the drugs used. No adverse effects were noted for either topical or intranasal drug therapy. The patient-specific, stepped approach resulted in clinically significant decreases in pain on visual analog scale (VAS), with the use of intranasal ketamine 10% solution and topical gabapentin 6%, ketoprofen 10%, lidocaine 5%, and ketamine 10% cream. PMID:25949241

  16. Field-induced transitions from negative to positive exchange bias in nanoparticles with inverted ferromagnetic-antiferromagnetic core-shell morphology

    NASA Astrophysics Data System (ADS)

    Hu, Yong; Wu, Guo-Zhen; Liu, Yan; Du, An

    2012-03-01

    In an antiferromagnetic (core)/ferromagnetic (shell) nanoparticle, the transition behaviors from negative (NEB) to positive exchange bias (PEB) at low temperature after field cooling are studied in detail. The NEB field may exhibit an oscillatory behavior due to the competition between interfacial coupling and cooling field. The critical cooling fields, at which the transitions occur, exhibit a logarithmic decrement with the decrease of interfacial coupling, but indicate a linear decrease with the decrease of antiferromagnetic coupling or with the further dilution in the antiferromagnetic core. With the further increase of cooling field, the PEB field increases linearly and finally levels off. Moreover, the weaker antiferromagnetic coupling may enhance the NEB field value, whereas the suppression of PEB may be observed by diluting the antiferromagnetic core. The magnetization reversal by coherent rotation strongly depends on the variation of the magnetic parameters, because its occurrence just needs to consume a lower additional energy, which is the main reason for these unique phenomena. We have shed new light on the microscopic origin of the peculiar magnetic properties in the nanoparticles with such an inverted magnetic structure.

  17. Intranasal glucagon: a promising approach for treatment of severe hypoglycemia.

    PubMed

    Pontiroli, Antonio E

    2015-01-01

    Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia. PMID:25385946

  18. Anaphylaxis following intranasal challenge of mice sensitized with ovalbumin.

    PubMed Central

    McCaskill, A C; Hosking, C S; Hill, D J

    1984-01-01

    Mice sensitized with two intraperitoneal injections of ovalbumin and challenged intranasally with the same antigen developed a non-fatal anaphylactic shock peaking in severity 30 min after challenge. Increases in haematocrit were noted which corresponded to the severity of signs of shock displayed by mice. Severity of shock also correlated with IgE and IgG levels. Sensitization by the nasal route, and use of B. pertussis vaccine as adjuvant had no qualitative effect upon the response. Cobra venom factor depletion of C3 in vivo did not alter the response of mice, which suggests anaphylaxis did not involve complement activation. Sensitivity was not transferrable to non-immune mice with serum. Passive sensitization with polyclonal and monoclonal antibodies produced inconsistent results. Possible mechanisms of anaphylaxis are discussed. PMID:6706376

  19. Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide.

    PubMed

    Shelke, Santosh; Shahi, Sadhana; Jadhav, Kiran; Dhamecha, Dinesh; Tiwari, Roshan; Patil, Hemlata

    2016-06-01

    The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3(2) factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM). TEM confirms spherical morphology of ethosomes, whereas Malvern zeta sizer confirms that the vesicle size was in the range of 191 ± 6.55-381.3 ± 61.0 nm. Ethosomes were incorporated in gel using poloxamer 407 and carbopol 934 as thermoreversible and mucoadhesive polymers, respectively. Ethosomal gels were evaluated for their pH, viscosity, mucoadhesive strength, in vitro drug release and ex vivo drug permeation through the sheep nasal mucosa. Mucoadhesive strength and pH was found to be 4400 ± 45 to 5500 ± 78.10 dynes/cm(2) and 6.0 ± 0.3 to 6.2 ± 0.1, respectively. In-vitro drug release from the optimized ethosomal gel formulation (G4) was found to be almost 100 % and ex vivo permeation of 4980 µg/ml with a permeability coefficient of 11.94 ± 0.04 × 10(-5) cm/s after 24 h. Histopathological study of the nasal mucosa confirmed non-toxic nature of ethosomal gels. Formulated EH loaded ethosomal thermoreversible gel could serve as the better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its bioavailability. PMID:27091045

  20. Guinea Pig Lung Lavage Cells After Intranasal BCG Sensitization

    PubMed Central

    Terai, T.; Ganguly, Rama; Waldman, Robert H.

    1979-01-01

    Recent studies have suggested that intranasal administration of antigen can induce local cell-mediated immunity in lung lavage cells. The present study was designed to examine the changes in composition of lung lavage cells and their capacity to produce the lymphokine migration inhibitory factor after intranasal immunization with BCG in guinea pigs. Results indicate that guinea pigs responded to respiratory tract BCG infection with an increase in immunocompetent cells in the bronchoalveolar tract and with production of migration inhibitory factor. After local pulmonary BCG administration, the total number of cells increased as compared with that of the uninfected animals, the increase being statistically significant within 2 weeks. This marked increase in the total cell population is due to a more than doubling of the number of macrophages in the lavage fluid. Animals also developed at this time positive delayed hypersensitivity to intradermally administered purified protein derivative. A significant increase in the total lymphoid cells and macrophage population was observed again at 6 weeks after sensitization, suggesting that the response is biphasic in nature. At 6 weeks, however, there was also a significant rise in total lymphocytes and T cell population in addition to macrophage numbers. This increase in T cells correlated with an increase in production of migration inhibitory factor in the presence of purified protein derivative. These data suggest that the immune response of the respiratory tract after BCG challenge involves increased recruitment of immunocompetent cells locally at the site of infection and that these cells are capable of producing effector molecules in terms of the elaboration of migration inhibitory factor. PMID:387595

  1. Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans

    PubMed Central

    Kirkpatrick, Matthew G.; Francis, Sunday M.; Lee, Royce; de Wit, Harriet; Jacob, Suma

    2014-01-01

    MDMA (±3,4-methylenedioxymethamphetamine, ‘ecstasy’) is reportedly used recreationally because it increases feelings of sociability and interpersonal closeness. Prior work suggests that the pro-social effects of MDMA may be mediated by release of oxytocin. A direct examination of plasma levels of oxytocin after acute doses of oxytocin and MDMA, in the same individuals, would provide further evidence for the idea that MDMA produces its prosocial effects by increasing oxytocin. Fourteen healthy MDMA users participated in a 4-session, double-blind study in which they received oral MDMA (0.75 and 1.5 mg/kg), intranasal oxytocin (20 IU or 40 IU), and placebo. Plasma oxytocin concentrations, as well as cardiovascular and subjective effects were assessed before and at several time points after drug administration. MDMA (1.5 mg/kg only) increased plasma oxytocin levels to a mean peak of 83.7 pg/ml at approximately 90–120 minutes, compared to 18.6 pg/ml after placebo. Intranasal oxytocin (40 IU, but not 20 IU) increased plasma oxytocin levels to 48.0 pg/ml, 30–60 min after nasal spray administration. MDMA dose-dependently increased heart rate, blood pressure, feelings of euphoria (e.g., ‘High’ and ‘Like Drug’), and feelings of sociability, whereas oxytocin had no cardiovascular or subjective effects. The subjective and cardiovascular responses to MDMA were not related to plasma oxytocin levels, although the N was small for this analysis. Future studies examining the effects of oxytocin antagonists on responses to MDMA will help to determine the mechanism by which MDMA produces pro-social effects. PMID:24882155

  2. Development and Evaluation of a Novel Intranasal Spray for the Delivery of Amantadine.

    PubMed

    Lungare, Shital; Bowen, James; Badhan, Raj

    2016-03-01

    The aim of this study was to develop and characterize an intranasal delivery system for amantadine hydrochloride (AMT). Optimal formulations consisted of a thermosensitive polymer Pluronic® 127 and either carboxymethyl cellulose or chitosan which demonstrated gel transition at nasal cavity temperatures (34 ± 1°C). Rheologically, the loss tangent (Tan δ) confirmed a 3-stage gelation phenomena at 34 ± 1°C and non-Newtonian behavior. Storage of optimized formulation carboxymethyl cellulose and optimal formulation chitosan at 4°C for 8 weeks resulted in repeatable release profiles at 34°C when sampled, with a Fickian mechanism earlier on but moving toward anomalous transport by week 8. Polymers (Pluronic® 127, carboxymethyl cellulose, and chitosan) demonstrated no significant cellular toxicity to human nasal epithelial cells up to 4 mg/mL and up to 1 mM for AMT (IC50: 4.5 ± 0.05 mM). Optimized formulation carboxymethyl cellulose and optimal formulation chitosan demonstrated slower release across an in vitro human nasal airway model (43%-44% vs 79 ± 4.58% for AMT). Using a human nasal cast model, deposition into the olfactory regions (potential nose-to-brain) was demonstrated on nozzle insertion (5 mm), whereas tilting of the head forward (15°) resulted in greater deposition in the bulk of the nasal cavity. PMID:26886345

  3. Increased superconducting transition temperature of a niobium thin film proximity coupled to gold nanoparticles using linking organic molecules.

    PubMed

    Katzir, Eran; Yochelis, Shira; Zeides, Felix; Katz, Nadav; Kalcheim, Yaov; Millo, Oded; Leitus, Gregory; Myasodeyov, Yuri; Shapiro, Boris Ya; Naaman, Ron; Paltiel, Yossi

    2012-03-01

    The superconducting critical temperature, T(C), of thin Nb films is significantly modified when gold nanoparticles (NPs) are chemically linked to the Nb film, with a consistent enhancement when using 3 nm long disilane linker molecules. The T(C) increases by up to 10% for certain linker length and NP size. No change is observed when the nanoparticles are physisorbed with nonlinking molecules. Electron tunneling spectra acquired on the linked NPs below T(C) typically exhibit zero-bias peaks. We attribute these results to a pairing mechanism coupling electrons in the Nb and the NPs, mediated by the organic linkers. PMID:22463444

  4. Increased Superconducting Transition Temperature of a Niobium Thin Film Proximity Coupled to Gold Nanoparticles Using Linking Organic Molecules

    NASA Astrophysics Data System (ADS)

    Katzir, Eran; Yochelis, Shira; Zeides, Felix; Katz, Nadav; Kalcheim, Yaov; Millo, Oded; Leitus, Gregory; Myasodeyov, Yuri; Shapiro, Boris Ya.; Naaman, Ron; Paltiel, Yossi

    2012-03-01

    The superconducting critical temperature, TC, of thin Nb films is significantly modified when gold nanoparticles (NPs) are chemically linked to the Nb film, with a consistent enhancement when using 3 nm long disilane linker molecules. The TC increases by up to 10% for certain linker length and NP size. No change is observed when the nanoparticles are physisorbed with nonlinking molecules. Electron tunneling spectra acquired on the linked NPs below TC typically exhibit zero-bias peaks. We attribute these results to a pairing mechanism coupling electrons in the Nb and the NPs, mediated by the organic linkers.

  5. Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice.

    PubMed

    Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

    2016-01-01

    Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of (125)I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug. PMID:27323911

  6. The effect of long-term use of intranasal steroids on intraocular pressure

    PubMed Central

    Şimşek, Ali; Bayraktar, Cem; Doğan, Sedat; Karataş, Mehmet; Sarıkaya, Yasin

    2016-01-01

    Long-term use of topical nasal steroids (especially older generation steroids) has been shown to elevate intraocular pressure (IOP), but newer intranasal steroids are thought to have a minimal effect on IOP because of their low bioavailability. This study aimed to investigate alterations in IOP with two commonly used intranasal steroids for a 6-month period of time. One-hundred allergic rhinitis patients, divided equally into two groups, used mometasone furoate and fluticasone furoate intranasal steroids for 6 months. IOPs were measured before treatment and repeated at the 3rd, 6th, 12th, and 24th weeks of treatment. The IOPs of the groups were then compared. No statistically significant alteration was observed between the groups during the treatment time period. It was found that new generation intranasal steroids can be used safely, and there may not be an increased risk of IOP elevation in prolonged use in normal healthy people. PMID:27354761

  7. Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice

    PubMed Central

    Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

    2016-01-01

    Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of 125I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug. PMID:27323911

  8. Intranasal epidermoid cyst causing upper airway obstruction in three brachycephalic dogs.

    PubMed

    Murgia, D; Pivetta, M; Bowlt, K; Volmer, C; Holloway, A; Dennis, R

    2014-08-01

    This case report describes three brachycephalic dogs with intranasal epidermoid cysts that were causing additional upper airway obstruction. Although epidermoid cysts have been described in several locations in dogs, to the authors' knowledge intranasal epidermoid cysts have not been previously reported. All dogs had mucopurulent to haemorrhagic nasal discharge. Magnetic resonance imaging of the head revealed the presence of unilateral or bilateral intranasal cystic lesions obstructing the nasal cavities partially or completely, with atrophy of the ipsilateral nasal turbinates. The cystic lesions were surgically excised in all dogs using a modified lateral alveolar mucosal approach to the affected nasal cavity. Aerobic, anaerobic and fungal culture of the cystic contents were negative and histology of the excised tissue was consistent with a benign intranasal epidermoid cyst in each dog. Upper airway obstruction was clinically improved in two dogs. PMID:24697627

  9. [Intranasal administration of immunoglobulins--perspectives for use in medical practice].

    PubMed

    Novikova, L I; Aleshkin, V A; Borisova, I V; Zueva, M M

    2008-01-01

    Effectiveness of topical use of immunoglobulines in respiratory infections along with preparations for parenteral use is discussed. Immunoglobuline preparations for intranasal use (drops, spays, aerosols) should take place among preparations intended for prevention and treatment of influenza, parainfluenza, respiratory syncitial virus infection and others. Potential to intranasal use of complex immunoglobulin preparation containing polymeric and monomeric antibodies of different isotypes is also discussed. PMID:19004281

  10. Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route.

    PubMed

    Mittal, Deepti; Md, Shadab; Hasan, Quamrul; Fazil, Mohammad; Ali, Asgar; Baboota, Sanjula; Ali, Javed

    2016-01-01

    The aim of the present study was to prepare and evaluate a rasagiline-loaded chitosan glutamate nanoparticles (RAS-CG-NPs) by ionic gelation of CG with tripolyphosphate anions (TPP). RAS-loaded CG-NPs were characterized for particle size, size distribution, encapsulation efficiency and in vitro drug release. The mean particles size, polydispersity index (PDI) and encapsulation efficiency was found to be 151.1 ± 10.31, 0.380 ± 0.01 and 96.43 ± 4.23, respectively. Biodistribution of RAS formulations in the brain and blood of mice following intranasal (i.n.) and intravenous (i.v.) administration was performed using HPLC analytical method. The drug concentrations in brain following the i.n. of CG-NPs were found to be significantly higher at all the time points compared to both drug (i.n.) and drug CG-NPs (i.v.). The Cmax (999.25 ng/ml) and AUC (2086.60 ng h/ml) of formulation CG-NPs (i.n) were found to be significantly higher than CG-NPs (i.v.) and RAS solution (i.n.). The direct transport percentage (DTP%) values of RAS-loaded CG-NPs (i.n.) as compared to drug solution (i.n.) increased from 66.27 ± 1.8 to 69.27 ± 2.1%. The results showed significant enhancement of bioavailability in brain, after administration of the RAS-loaded CG-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinson's disease therapy. PMID:24786489

  11. The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study

    PubMed Central

    Riediger, Christine; Haschke, Manuel; Bitter, Christoph; Fabbro, Thomas; Schaeren, Stefan; Urwyler, Albert; Ruppen, Wilhelm

    2015-01-01

    Objectives Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. Materials and methods In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. Results Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. Discussion In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting. PMID:25709497

  12. Role of intranasal fentanyl in breakthrough pain management in cancer patients

    PubMed Central

    Leppert, Wojciech

    2010-01-01

    Fentanyl is a strong opioid analgesic, which is commonly used in the form of a transdermal patch for the treatment of chronic cancer pain. An intranasal route of fentanyl administration is a novel treatment for breakthrough cancer pain (BTCP). The prevalence, assessment, and management of BTCP is outlined in this paper, and basic pharmacodynamic and pharmacokinetic properties, dosing guidelines, and clinical experience with the use of intranasal fentanyl in this indication are discussed. Intranasal fentanyl is an attractive and convenient mode of BTCP treatment in opioid-tolerant patients due to its quick onset and short duration of action, noninvasive administration route, high bioavailability, and avoidance of a hepatic first-pass effect. Until now, few clinical trials have been conducted with intranasal fentanyl, but all have confirmed its usefulness and acceptability in BTCP treatment. Intranasal fentanyl may be used in opioid-tolerant patients without nasal pathologies. The dose should be titrated in each patient regardless of the regular opioid dose administered. Future studies should compare intranasal fentanyl with other fentanyl formulations used for BTCP management, and with analgesia, adverse effects, and quality of life taken into consideration. PMID:21188114

  13. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163

    PubMed Central

    Hashizume, Rintaro; Ozawa, Tomoko; Gryaznov, Sergei M.; Bollen, Andrew W.; Lamborn, Kathleen R.; Frey, William H.; Deen, Dennis F.

    2008-01-01

    The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xeno-grafts intranasally with GRN163, an oligonucleotide N3′→P5′thio-phosphoramidate telomerase inhibitor. 3′-Fuorescein isothiocyanate (FITC)–labeled GRN163 was administered intranasally every 2 min as 6 μl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients. PMID:18287341

  14. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163.

    PubMed

    Hashizume, Rintaro; Ozawa, Tomoko; Gryaznov, Sergei M; Bollen, Andrew W; Lamborn, Kathleen R; Frey, William H; Deen, Dennis F

    2008-04-01

    The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts intranasally with GRN163, an oligonucleotide N3'-->P5'thio-phosphoramidate telomerase inhibitor. 3'-Fuorescein isothiocyanate (FITC)-labeled GRN163 was administered intranasally every 2 min as 6 microl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients. PMID:18287341

  15. Intranasal delivery of nanomicelle curcumin promotes corneal epithelial wound healing in streptozotocin-induced diabetic mice.

    PubMed

    Guo, Chuanlong; Li, Mengshuang; Qi, Xia; Lin, Guiming; Cui, Fenghua; Li, Fengjie; Wu, Xianggen

    2016-01-01

    Corneal nerves are mainly derived from the ophthalmic branch of the trigeminal ganglion (TG). Corneal neuropathy contributes to epithelial degenerative changes in diabetic keratopathy. Efficient drug delivery to TG may be beneficial for the treatment of diabetic keratopathy. This article described intranasal delivery of nanomicelle curcumin to correct pathophysiological conditions in TG to promote corneal epithelial/nerve wound healing in streptozotocin-induced diabetic mice. A diabetic mice model with corneal epithelium abrasion was established. Ocular topical and/or intranasal nanomicelle curcumin treatments were performed, and treatment efficacy and mechanisms of action were explored. Results showed that intranasal nanomicelle curcumin treatment promoted corneal epithelial wound healing and recovery of corneal sensation. Enhanced accumulation of reactive oxygen species, reduced free radical scavengers, increased mRNA expressions of inflammatory cytokines, and decreased mRNA expressions of neurotrophic factors in the cornea and TG neuron were observed in diabetic mice with corneal epithelium abrasions. Intranasal nanomicelle curcumin treatment effectively recovered these pathophysiological conditions, especially that of the TG neuron, and a strengthened recovery was observed with ocular topical combined with intranasal treatment. These findings indicated that intranasal curcumin treatment effectively helped promote diabetic corneal epithelial/nerve wound healing. This novel treatment might be a promising strengthened therapy for diabetic keratopathy. PMID:27405815

  16. Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration

    PubMed Central

    Lochhead, Jeffrey J; Wolak, Daniel J; Pizzo, Michelle E; Thorne, Robert G

    2015-01-01

    The intranasal administration route is increasingly being used as a noninvasive method to bypass the blood–brain barrier because evidence suggests small fractions of nasally applied macromolecules may reach the brain directly via olfactory and trigeminal nerve components present in the nasal mucosa. Upon reaching the olfactory bulb (olfactory pathway) or brainstem (trigeminal pathway), intranasally delivered macromolecules appear to rapidly distribute within the brains of rodents and primates. The mechanisms responsible for this distribution have yet to be fully characterized. Here, we have used ex vivo fluorescence imaging to show that bulk flow within the perivascular space (PVS) of cerebral blood vessels contributes to the rapid central distribution of fluorescently labeled 3 and 10 kDa dextran tracers after intranasal administration in anesthetized adult rats. Comparison of tracer plasma levels and fluorescent signal distribution associated with the PVS of surface arteries and internal cerebral vessels showed that the intranasal route results in unique central access to the PVS not observed after matched intravascular dosing in separate animals. Intranasal targeting to the PVS was tracer size dependent and could be regulated by modifying nasal epithelial permeability. These results suggest cerebral perivascular convection likely has a key role in intranasal drug delivery to the brain. PMID:25492117

  17. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans.

    PubMed

    Gancheva, Sofiya; Koliaki, Chrysi; Bierwagen, Alessandra; Nowotny, Peter; Heni, Martin; Fritsche, Andreas; Häring, Hans-Ulrich; Szendroedi, Julia; Roden, Michael

    2015-06-01

    Studies in rodents suggest that insulin controls hepatic glucose metabolism through brain-liver crosstalk, but human studies using intranasal insulin to mimic central insulin delivery have provided conflicting results. In this randomized controlled crossover trial, we investigated the effects of intranasal insulin on hepatic insulin sensitivity (HIS) and energy metabolism in 10 patients with type 2 diabetes and 10 lean healthy participants (CON). Endogenous glucose production was monitored with [6,6-(2)H2]glucose, hepatocellular lipids (HCLs), ATP, and inorganic phosphate concentrations with (1)H/(31)P magnetic resonance spectroscopy. Intranasal insulin transiently increased serum insulin levels followed by a gradual lowering of blood glucose in CON only. Fasting HIS index was not affected by intranasal insulin in CON and patients. HCLs decreased by 35% in CON only, whereas absolute hepatic ATP concentration increased by 18% after 3 h. A subgroup of CON received intravenous insulin to mimic the changes in serum insulin and blood glucose levels observed after intranasal insulin. This resulted in a 34% increase in HCLs without altering hepatic ATP concentrations. In conclusion, intranasal insulin does not affect HIS but rapidly improves hepatic energy metabolism in healthy humans, which is independent of peripheral insulinemia. These effects are blunted in patients with type 2 diabetes. PMID:25576060

  18. Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration.

    PubMed

    Lochhead, Jeffrey J; Wolak, Daniel J; Pizzo, Michelle E; Thorne, Robert G

    2015-03-01

    The intranasal administration route is increasingly being used as a noninvasive method to bypass the blood-brain barrier because evidence suggests small fractions of nasally applied macromolecules may reach the brain directly via olfactory and trigeminal nerve components present in the nasal mucosa. Upon reaching the olfactory bulb (olfactory pathway) or brainstem (trigeminal pathway), intranasally delivered macromolecules appear to rapidly distribute within the brains of rodents and primates. The mechanisms responsible for this distribution have yet to be fully characterized. Here, we have used ex vivo fluorescence imaging to show that bulk flow within the perivascular space (PVS) of cerebral blood vessels contributes to the rapid central distribution of fluorescently labeled 3 and 10 kDa dextran tracers after intranasal administration in anesthetized adult rats. Comparison of tracer plasma levels and fluorescent signal distribution associated with the PVS of surface arteries and internal cerebral vessels showed that the intranasal route results in unique central access to the PVS not observed after matched intravascular dosing in separate animals. Intranasal targeting to the PVS was tracer size dependent and could be regulated by modifying nasal epithelial permeability. These results suggest cerebral perivascular convection likely has a key role in intranasal drug delivery to the brain. PMID:25492117

  19. pH-induced vesicle-to-micelle transition in amphiphilic diblock copolymer: investigation by energy transfer between in situ formed polymer embedded gold nanoparticles and fluorescent dye.

    PubMed

    Maiti, Chiranjit; Banerjee, Rakesh; Maiti, Saikat; Dhara, Dibakar

    2015-01-01

    The ability to regulate the formation of nanostructures through self-assembly of amphiphilic block copolymers is of immense significance in the field of biology and medicine. In this work, a new block copolymer synthesized by using reversible addition-fragmentation chain transfer (RAFT) polymerization technique from poly(ethylene glycol) monomethyl ether acrylate (PEGMA) and Boc-l-tryptophan acryloyloxyethyl ester (Boc-l-trp-HEA) was found to spontaneously form pH-responsive water-soluble nanostructures after removal of the Boc group. While polymer vesicles or polymerosomes were formed at physiological pH, the micelles were formed at acidic pH (< 5.2), and this facilitated a pH-induced reversible vesicle-to-micelle transition. Formation of these nanostructures was confirmed by different characterization techniques, viz. transmission electron microscopy, dynamic light scattering, and steady-state fluorescence measurements. Further, these vesicles were successfully utilized to reduce HAuCl4 and stabilize the resulting gold nanoparticles (AuNPs). These AuNPs, confined within the hydrophobic shell of the vesicles, could participate in energy transfer process with fluorescent dye molecules encapsulated in the core of the vesicles, thus forming a nanometal surface energy transfer (NSET) pair. Subsequently, following the efficiency of energy transfer between this pair, it was possible to monitor the process of transition from vesicles to micelles. Thus, in this work, we have successfully demonstrated that NSET can be used to follow the transition between nanostructures formed by amphiphilic block copolymers. PMID:25494810

  20. Precipitation of coherent FeRh nanoparticles with highly suppressed magnetostructural transition temperatures in rapidly solidified (FeRh)5Cu95 alloys

    NASA Astrophysics Data System (ADS)

    Barua, Radhika; Jiang, Xiujuan; Shield, Jeff; Heiman, Don; Lewis, Laura

    2012-02-01

    Magnetostructural phase transitions have the capability of delivering large functional effects in response to small excursions in magnetic field, temperature and strain; this potential might be amplified in nanostructured systems by virtue of large surface:volume ratios. Nanoprecipitates (˜10nm) of FeRh, a well-known magnetostructural material, were studied with structural and magnetic probes in a rapidly solidified phase-separated system of (FeRh)5Cu95. Magnetization studies indicate a dramatic reduction in the magnetostructural phase transition temperature (Tt) of the nanoscaled FeRh phase relative to the bulk value (δT=Tt,Bulk - Tt,Nano = 220 K). Transmission electron microscopy (TEM) and selected area electron diffraction (SAED) reveals a coherent orientational relationship between the FeRh (aFeRh = 3.09 å)and Cu (aCu = 3.78 å) phases. At the matrix/precipitate interface a constrained misfit strain of ɛ = 0.18 is observed. The reduction of the magnetostructural phase transition temperature and evolution of the magnetic properties with system annealing is analyzed in the context of the strain between the FeRh nanoparticles and the Cu matrix.

  1. Sulfidation of rock-salt-type transition metal oxide nanoparticles as an example of a solid state reaction in colloidal nanoparticles.

    PubMed

    Chen, Chih-Jung; Chiang, Ray-Kuang

    2011-01-28

    The sulfidation of colloidal rock-salt-type MO (M = Fe, Mn and Co) nanocrystals was performed in organic solvents using dissolved elemental sulfur at moderate temperatures. The vacancy defects in these rock-salt-type structures clearly promote complete oxide-sulfide conversion. The conversion products were hollow metal sulfide (pyrrhotite (Fe(1-x)S), Co(1-x)S and α-MnS) nanoparticles. These conversions by sulfidation proceed rapidly, making difficult the isolation of intermediates. The sulfidation intermediates, when the supply of sulfur was insufficient, had interesting structures, in which the metal oxide cores were surrounded by metal sulfide shells or had surfaces that were decorated with metal sulfide islands. Based on the above results, a mechanism of surface nucleation, shell formation, and void formation by diffusion processes is proposed. PMID:21140007

  2. Le sumatriptan intranasal pour la migraine chez les enfants

    PubMed Central

    Goldman, Ran D.; Meckler, Garth D.

    2015-01-01

    Résumé Question Je vois de plus en plus d’enfants et d’adolescents qui souffrent de céphalées pouvant se classer dans la catégorie des migraines. J’ai fait des lectures sur le sumatriptan par voie intranasale comme thérapie abortive. Est-ce un traitement efficace? Réponse La migraine aiguë chez les enfants et les adolescents est fréquente et difficile à traiter. Le sumatriptan intranasal est une option sûre et généralement efficace pour les enfants et les adolescents. La dose actuellement recommandée est de 20 mg pour les enfants qui pèsent plus de 40 kg et de 10 mg pour ceux dont le poids se situe entre 20 et 39 kg. Il faudrait faire des études de plus grande envergure pour contrecarrer les limitations des échantillons de petite taille et mieux comprendre la faible concentration plasmique et les effets placebo observés dans les études jusqu’à présent.

  3. Stimulus Selection for Intranasal Sensory Isolation: Eugenol Is an Irritant

    PubMed Central

    Wise, Paul M.; Lundström, Johan N.

    2012-01-01

    Both the olfactory and the trigeminal systems are able to respond to intranasal presentations of chemical vapor. Accordingly, when the nose detects a volatile chemical, it is often unclear whether we smell it, feel it, or both. The distinction may often be unimportant in our everyday perception of fragrances or aromas, but it can matter in experiments that purport to isolate olfactory processes or study the interaction between olfaction and chemesthesis. Researchers turn to a small pool of compounds that are believed to be “pure olfactory” stimuli with little or no trigeminal impact. The current report reexamines one such commonly used compound, namely eugenol, a flavor and fragrance ingredient that has anesthetic properties under some conditions. Using a standard method involving many trials during an experimental session (Experiment 1), subjects were unable to reliably lateralize eugenol, consistent with claims that this compound is detected primarily through olfaction. However, with more limited exposure (Experiments 2 and 3), subjects were able to lateralize eugenol. We speculate that anesthetic properties of eugenol could blunt its trigeminal impact in some paradigms. Regardless, the current experiments suggest that eugenol can in fact stimulate the trigeminal nerve but in a complex concentration–dependent manner. Implications and strategies for selection of model odorants are discussed. PMID:22293937

  4. Pupillary responses to intranasal trigeminal and olfactory stimulation.

    PubMed

    Schneider, Christine B; Ziemssen, Tjalf; Schuster, Benno; Seo, Han-Seok; Haehner, Antje; Hummel, Thomas

    2009-07-01

    The aim of the present study was to investigate whether pupillary responses to odorous stimuli reflect their intensity or hedonic tone. A total of 21 healthy subjects participated in the study. Using a computer-controlled olfactometer, subjects received intranasal stimuli including odors of rose (PEA; 2 concentrations), lemon and rotten eggs, plus the trigeminal irritant CO2 (also at two concentrations). Changes in the pupil diameter were obtained ipsilaterally to the side of stimulus presentation. Both trigeminal and olfactory stimulation produced an increase in pupillary diameter. Latencies for pupillary reaction were fastest for the higher concentration of CO2 and slowest after the presentation of PEA at the low concentration. Response amplitudes were largest in response to stimulation with CO2 at the high concentration, while they were smallest in response to odorous stimulation with PEA. Response latencies decreased with increasing stimulus intensity. No such correlation was found for hedonic ratings and pupillary reactions. Thus, the change in the pupillary diameter indicates differences between stimulus modalities and stimulus strength, but not pleasantness or unpleasantness of the odors. PMID:19484181

  5. Intranasal epidermal growth factor treatment rescues neonatal brain injury

    NASA Astrophysics Data System (ADS)

    Scafidi, Joseph; Hammond, Timothy R.; Scafidi, Susanna; Ritter, Jonathan; Jablonska, Beata; Roncal, Maria; Szigeti-Buck, Klara; Coman, Daniel; Huang, Yuegao; McCarter, Robert J.; Hyder, Fahmeed; Horvath, Tamas L.; Gallo, Vittorio

    2014-02-01

    There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

  6. Intranasal epidermal growth factor treatment rescues neonatal brain injury

    PubMed Central

    Scafidi, Joseph; Hammond, Timothy R.; Scafidi, Susanna; Ritter, Jonathan; Jablonska, Beata; Roncal, Maria; Szigeti-Buck, Klara; Coman, Daniel; Huang, Yuegao; McCarter, Robert J.; Hyder, Fahmeed; Horvath, Tamas L.; Gallo, Vittorio

    2014-01-01

    There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (<32 weeks gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments1,2. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI3. In a previous study, we demonstrated that epidermal growth factor receptor (EGFR) plays an important role in oligodendrocyte development4. Here, we examine whether enhanced epidermal growth factor receptor (EGFR) signaling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioral recovery in the developing brain. Using an established model of very preterm brain injury, we demonstrate that selective overexpression of human (h)EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells (OPCs) and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioral deficits on white matter-specific paradigms. Inhibition of EGFR signaling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in OPCs at a specific time after injury is clinically feasible and applicable for the treatment of premature children with white matter injury. PMID:24390343

  7. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Tam, V. H.; Chow, D. S. L.; Putcha, L.

    2015-01-01

    An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS). The bioavailability and pharmacokinetics (PK) were evaluated under IND (Investigational New Drug) guidelines. The aim of the project was to develop a PK model that can predict the relationships among plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial protocol with INSCOP. Twelve healthy human subjects were administered at three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. PK compartmental models, using actual dosing and sampling time, were established using Phoenix (version 1.2). Model selection was based on a likelihood ratio test on the difference of criteria (-2LL (i.e. log-likelihood ratio test)) and comparison of the quality of fit plots. The results: Predictable correlations among scopolamine concentrations in compartments of plasma, saliva and urine were established, and for the first time the model satisfactorily predicted the population and individual PK of INSCOP in plasma, saliva and urine. The model can be utilized to predict the INSCOP plasma concentration by saliva and urine data, and it will be useful for monitoring the PK of scopolamine in space and other remote environments using non-invasive sampling of saliva and/or urine.

  8. Intranasal Midazolam Sedation in a Pediatric Emergency Dental Clinic.

    PubMed

    Peerbhay, Fathima; Elsheikhomer, Ahmed Mahgoub

    2016-01-01

    The purpose of this study was to compare the effectiveness and recovery times of 0.3 and 0.5 mg/kg intranasal midazolam (INM) administered with a mucosal atomizer device (MAD) in a pediatric emergency dental hospital clinic. One hundred eighteen children aged from 4 to 6 years were randomly administered either 0.3 or 0.5 mg/kg INM via an MAD in a triple-blinded randomized controlled trial. Sedation was achieved to some degree in 100% of the sample. The pulse rate and oxygen saturation were within the normal range in 99% of the patients. A burning sensation was reported in 9% of children. The recovery time of the 0.5 mg/kg group was statistically longer than that of the 0.3 mg/kg group (16.5 vs 18.8 minutes) but the difference was not clinically significant. The findings of this study show that 0.3 or 0.5 mg/kg doses of INM resulted in safe and effective sedation. The 0.5 mg/kg dose was more effective than the 0.3 mg/kg dose in reducing anxiety. PMID:27585415

  9. Brain Uptake of Neurotherapeutics after Intranasal versus Intraperitoneal Delivery in Mice

    PubMed Central

    Chauhan, Mihir B.; Chauhan, Neelima B.

    2015-01-01

    There is a growing global prevalence of neurodegenerative diseases such as Alzheimer’s disease and dementia. Current treatment for neurodegenerative diseases is limited due to the blood brain barrier’s ability to restrict the entry of therapeutics to the brain. In that context, direct delivery of drugs from nose to brain has gained emerging interest as an important alternative to oral and parenteral routes of administration. Although there are considerable reports showing promising results after intranasal drug delivery in various disease-models and investigatory human clinical trials, there are very few studies showing a detailed pharmacokinetics with regard to the uptake and retention of intranasally delivered material(s) within specific brain regions, which are critical determining factors for dosing conditions and optimal treatment regimen. This investigation compared a time-dependent brain uptake and resident time of various radiolabeled candidate neurotherapeutics after a single bolus intranasal or intraperitoneal administration in mice. Results indicate that the brain uptake of intranasally delivered therapeutic(s) is > 5 times greater than that after intraperitoneal delivery. The peak uptake and resident time of all intranasally delivered test therapeutics for all brain regions is observed to be between 30min-12h, depending upon the distance of brain region from the site of administration, followed by gradual fading of radioactive counts by 24h post intranasal administration. Current study confirms the usefulness of intranasal administration as a non- invasive and efficient means of delivering therapeutics to the brain to treat neurodegenerative diseases including Alzheimer’s disease. PMID:26366437

  10. Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.

    PubMed

    Manda, Prashanth; Kushwaha, Avadhesh Singh; Kundu, Santanu; Shivakumar, H N; Jo, Seong Bong; Murthy, S Narasimha

    2016-02-28

    The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain. PMID:26732557

  11. The magnetic transition in ε-Fe{sub 2}O{sub 3} nanoparticles: Magnetic properties and hyperfine interactions from Mössbauer spectroscopy

    SciTech Connect

    Kohout, J. Závěta, K.; Kubániová, D.; Kmječ, T.; Kubíčková, L.; Brázda, P.; Klementová, M.; Šantavá, E.; Lančok, A.

    2015-05-07

    The nanoparticles of ε-Fe{sub 2}O{sub 3} enriched with {sup 57}Fe isotope in amorphous silica matrix were prepared by sol-gel technique starting from a single molecular precursor for both Fe{sub 2}O{sub 3} and silica. From the X-ray powder diffraction pattern ε-Fe{sub 2}O{sub 3} was identified as the major phase and α-Fe{sub 2}O{sub 3} and β-Fe{sub 2}O{sub 3} were observed as minor iron oxide phases. Using the log-normal distribution for fitting the experimental data from the TEM micrographs, the characteristic size of particles d{sub 0} ∼ 25 nm was derived. The rather high coercivity of ∼2.1 T at room temperature was confirmed for our nanoparticle system. From the dependences of magnetization on temperature a two-step magnetic transition spread between 100 K and 153 K was indicated. From the {sup 57}Fe Mössbauer spectra measured in the temperature range of 4.2–300 K, the hyperfine parameters for one tetrahedral and three octahedral sites of ε-Fe{sub 2}O{sub 3} structure were identified. The in-field spectra in the external magnetic fields up to 6 T were taken both above and below the indicated two-step magnetic transition. Their dependence on temperature and external magnetic field suggests that the first step in the temperature range of 153 K–130 K is related to the spin reorientation of the local magnetic moments in the magnetic sublattices and the second step in temperatures 130 K–100 K may be associated with the intermediate spin–high spin state transition of Fe{sup 3+} cation in the tetrahedral sublattice expressed in the change of the hyperfine magnetic field.

  12. Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke.

    PubMed

    Lioutas, Vasileios-Arsenios; Alfaro-Martinez, Freddy; Bedoya, Francisco; Chung, Chen-Chih; Pimentel, Daniela A; Novak, Vera

    2015-08-01

    Treatment options for stroke remain limited. Neuroprotective therapies, in particular, have invariably failed to yield the expected benefit in stroke patients, despite robust theoretical and mechanistic background and promising animal data. Insulin and insulin-like growth factor 1 (IGF-1) play a pivotal role in critical brain functions, such as energy homeostasis, neuronal growth, and differentiation. They may exhibit neuroprotective properties in acute ischemic stroke based upon their vasodilatory, anti-inflammatory and antithrombotic effects, as well as improvements of functional connectivity, neuronal metabolism, neurotransmitter regulation, and remyelination. Intranasally administered insulin has demonstrated a benefit for prevention of cognitive decline in older people, and IGF-1 has shown potential benefit to improve functional outcomes in animal models of acute ischemic stroke. The intranasal route presents a feasible, tolerable, safe, and particularly effective administration route, bypassing the blood-brain barrier and maximizing distribution to the central nervous system (CNS), without the disadvantages of systemic side effects and first-pass metabolism. This review summarizes the neuroprotective potential of intranasally administered insulin and IGF-1 in stroke patients. We present the theoretical background and pathophysiologic mechanisms, animal and human studies of intranasal insulin and IGF-1, and the safety and feasibility of intranasal route for medication administration to the CNS. PMID:26040423

  13. Induction of systemic immune responses to measles virus synthetic peptides administered intranasally.

    PubMed

    Hathaway, L J; Partidos, C D; Vohra, P; Steward, M W

    1995-11-01

    A systemic antibody response was induced when a chimeric peptide containing two copies of a promiscuous T-cell epitope and one copy of a B-cell epitope (TTB) from the fusion protein of measles virus (MV) was administered to mice intranasally without adjuvant. A higher antibody titre was produced when the peptide was administered intranasally with cholera toxin B subunit (CTB) as an adjuvant and these antibodies crossreacted with the MV. Furthermore, splenocytes from intranasally immunized mice proliferated in vitro in the presence of the TTB peptide. The immune response following intranasal immunization with the peptide was influenced by the MHC haplotype of the strain of mice used. Thus CBA and BALB/c mice were high responders whereas C57BL/6 mice were low responders. Although peptide administered intranasally with CTB to CBA mice induced an immune response, no significant protection was observed against intra-cranial challenge with canine distemper virus which is antigenically related to MV. PMID:8578832

  14. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines

    NASA Astrophysics Data System (ADS)

    Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-Ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

    2010-07-01

    Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel (`nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

  15. Intranasal mite allergen induces allergic asthma-like responses in NC/Nga mice.

    PubMed

    Shibamori, Masafumi; Ogino, Keiki; Kambayashi, Yasuhiro; Ishiyama, Hironobu

    2006-01-25

    Airway responses induced by intranasal administration of mite allergen without adjuvant were studied in NC/Nga mice. A crude extract of Dermatophagoides farinae (Df) was administered for 5 consecutive days and a single intranasal challenge booster dose was given 1 week after the last sensitization. 24 h after the single challenge, the airway hyperresponsiveness (AHR) was measured and the bronchoalveolar lavage fluid (BALF) was analyzed for numbers of eosinophils and neutrophils, and both cytokine and chemokine levels. There were marked increases in number of eosinophils in the BALF, AHR, Th2 cytokines (IL-5 and IL-13), and chemokine (eotaxin-1 and eotaxin-2) levels in the BALF following Df exposure. C57BL/6N, A/J, BALB/c, and CBA/JN mouse strains were also exposed to Df crude extract, but all of the measured responses were strongest in NC/Nga mice. Furthermore, Df-exposed NC/Nga mice showed the goblet cell hyperplasia, pulmonary eosinophilic inflammation, and increases in both total serum IgE and Df-specific IgG1. After intranasal exposure of NC/Nga mice to crude extract of Dermatophagoides pteronyssinus, the BALF eosinophilia and AHR were similar to responses induced by Df. None of the study parameters were increased in response to intranasal exposure to ovalbumin. These data demonstrated that NC/Nga mice developed allergic asthma-like responses after intranasal exposure to mite allergens. PMID:16229861

  16. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines.

    PubMed

    Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

    2010-07-01

    Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel ('nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination. PMID:20562880

  17. Preparation of lorazepam-loaded microemulsions for intranasal delivery and its pharmacokinetics.

    PubMed

    Yao, J; Hou, L; Zhou, J P; Zhang, Z Q; Sun, L

    2009-10-01

    The purpose of this study was to develop a microemulsion system for intranasal delivery of lorazepam. The phase behavior and properties of microemulsions were characterized in a pseudo-ternary system composed of Cremophor EL 35/Transcutol P/Lauroglycol FCC or Labrafil M 1944CS/water, and intranasal absorption of lorazepam from microemulsions was investigated in rabbit. The microemulsions, comprising of FCC, Cremophor EL 35/Transcutol P (1.5:1) and water, were optimal for intranasal delivery of lorazepam. These systems had a higher solubilization capacity with the particle size of <150 nm, and were stable at ambient conditions for at least six months. In vivo absorption studies showed that intranasal absorption of lorazepam from microemulsions at 0.38 mg/kg had the larger AUC(0-t), the longer half-life and the prolonged circulation time with the mean bioavailability of 80.84% for ME2 and 63.48% for ME8 as compared to the intramuscular injection at 0.16 mg/kg. These results indicate that microemulsions may bea promising approach for the intranasal delivery of lorazepam. PMID:19947165

  18. Evaluation of intranasal Midazolam spray as a sedative in pediatric patients for radiological imaging procedures

    PubMed Central

    Chokshi, Anisha A.; Patel, Vipul R.; Chauhan, Parthiv R.; Patel, Deep J.; Chadha, Indu A.; Ramani, Monal N.

    2013-01-01

    Context: Preoperative anxiety and uncooperativeness experienced by pediatric patients are commonly associated with postoperative behavioral problems. Aims: We aimed to evaluate the efficacy and safety of intranasal Midazolam as a sedative in a pediatric age group for radiological imaging procedures and to note onset of sedation, level of sedation, condition of patient during separation from parents and effect on the cardio-respiratory system. Settings and Design: Randomized double-blinded study. Subjects and Methods: Fifty patients of the pediatric age group of American Society of Anesthesiologist grade 2 and 3 who came for any radiological imaging procedures were studied. Patients were randomly allocated to receive, intranasally, either Midazolam 0.5 mg/kg (group A N = 25) or normal saline (group B N = 25) in both nostrils (0.25 mg/kg in each) 15 min before the procedure. Time for onset of sedation and satisfactory sedation, sedation score, separation score, hemodynamic changes and side-effects were recorded. Statistical Analysis Used: Student's t-test. Results: Intranasal Midazolam group had a significantly shorter time for onset of sedation and satisfactory sedation. Mean sedation score and mean separation score at 10 min and 15 min intervals were significant in intranasal Midazolam as compared with normal saline (P < 0.001). Conclusions: Intranasal Midazolam 0.5 mg/kg is safe and effective and provides adequate sedation for easy separation from the parents and reduced requirement of intravenous supplementation during radiological imaging procedures without any untoward side-effects. PMID:25885831

  19. Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

    PubMed Central

    Krakauer, Teresa; Buckley, Marilyn

    2012-01-01

    Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window. PMID:23105977

  20. Blockade of STAT3 in T Cells Inhibits Germinal Center Reactions against Intranasal Allergens

    PubMed Central

    Choi, Garam; Chung, Yeonseok

    2016-01-01

    Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of TGF-β. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Co-transfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung. PMID:27133258

  1. Position on zinc delivery to olfactory nerves in intranasal insulin phase I-III clinical trials.

    PubMed

    Hamidovic, A

    2015-11-01

    Zinc in pancreatic insulin is essential for processing and action of the peptide, while in commercial preparations zinc promotes hexameric structure and prevents aggregate formation. In 2002, for the first time, insulin was delivered to humans intranasally with resulting cerebrospinal fluid insulin increases, but steady peripheral insulin levels. The novel method of increasing brain insulin levels without changes in the periphery resulted in an expansion of brain insulin research in clinical trials. As pre-clinical research has shown that brain insulin modulates a number functions, including food cravings and eating behavior, learning and memory functions, stress and mood regulation; realization of beneficial effects of insulin in modulating these functions in clinical populations became a possibility with the new direct-to-brain insulin delivery methodology. However, zinc, being integral to insulin structure and function, is neurotoxic, and has resulted in adverse effects to human health. In the last century, intranasal zinc was given preventively during the time of polio outbreak, and in the 21st century intranasal zinc was widely used over the counter to prevent common cold. In both cases, patients experienced partial or complete loss of smell. This paper is the first one to analyze zinc salts and concentrations of those two epidemiological adversities and directly compare formulations distributed to the public with animal toxicity data. The information gained from animal and epidemiological data provides a foundation for the formation of opinion given in this paper regarding safety of intranasal zinc in emerging clinical trials with intranasal insulin. PMID:26386292

  2. Chronic Intranasal Oxytocin Causes Long-term Impairments in Partner Preference Formation in Male Prairie Voles

    PubMed Central

    Bales, Karen L.; Perkeybile, Allison M.; Conley, Olivia G.; Lee, Meredith H.; Guoynes, Caleigh D.; Downing, Griffin M.; Yun, Catherine R.; Solomon, Marjorie; Jacob, Suma; Mendoza, Sally P.

    2012-01-01

    Background Oxytocin (OT) is a hormone shown to be involved in social bonding in animal models. Intranasal OT is currently in clinical trials for use in disorders such as autism and schizophrenia. We examined long-term effects of intranasal OT given developmentally in the prairie vole (Microtus ochrogaster), a socially monogamous rodent, often used as an animal model to screen drugs that have therapeutic potential for social disorders. Methods We treated voles with one of three dosages of intranasal OT, or saline, from day 21 (weaning) through day 42 (sexual maturity). We examined both social behavior immediately following administration, as well as long-term changes in social and anxiety behavior after treatment ceased. Group sizes varied from 8 to 15 voles (n = 89 voles total). Results Treatment with OT resulted in acute increases in social behavior in males with familiar partners, as seen in humans. However, long-term developmental treatment with low doses of intranasal OT resulted in a deficit in partner preference behavior (a reduction of contact with a familiar opposite-sex partner, used to index pair-bond formation) by males. Conclusions Long-term developmental treatment with OT may show results different to those predicted by short-term studies, as well as significant sex differences and dosage effects. Further animal study is crucial to determining safe and effective strategies for use of chronic intranasal OT, especially during development. PMID:23079235

  3. Intranasal hydroxypropyl-β-cyclodextrin-adjuvanted influenza vaccine protects against sub-heterologous virus infection.

    PubMed

    Kusakabe, Takato; Ozasa, Koji; Kobari, Shingo; Momota, Masatoshi; Kishishita, Natsuko; Kobiyama, Kouji; Kuroda, Etsushi; Ishii, Ken J

    2016-06-01

    Intranasal vaccination with inactivated influenza viral antigens is an attractive and valid alternative to currently available influenza (flu) vaccines; many of which seem to need efficient and safe adjuvant, however. In this study, we examined whether hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used pharmaceutical excipient to improve solubility and drug delivery, can act as a mucosal adjuvant for intranasal flu vaccines. We found that intranasal immunization of mice with hemagglutinin split- as well as inactivated whole-virion influenza vaccine with HP-β-CD resulted in secretion of antigen-specific IgA and IgGs in the airway mucosa and the serum as well. As a result, both HP-β-CD adjuvanted-flu intranasal vaccine protected mice against lethal challenge with influenza virus, equivalent to those induced by experimental cholera toxin-adjuvanted ones. Of note, intranasal use of HP-β-CD as an adjuvant induced significantly lower antigen-specific IgE responses than that induced by aluminum salt adjuvant. These results suggest that HP-β-CD may be a potent mucosal adjuvant for seasonal and pandemic influenza vaccine. PMID:27160037

  4. Intranasal Delivery of Umbilical Cord-Derived Mesenchymal Stem Cells Preserves Myelination in Perinatal Brain Damage.

    PubMed

    Oppliger, Byron; Joerger-Messerli, Marianne; Mueller, Martin; Reinhart, Ursula; Schneider, Philipp; Surbek, Daniel V; Schoeberlein, Andreina

    2016-08-15

    Preterm white matter injury (WMI) is an important cause for long-term disability. Stem cell transplantation has been proposed as a novel therapeutic approach. However, intracerebral transplantation is not feasible for clinical purpose in newborns. Intranasal delivery of cells to the brain might be a promising, noninvasive therapeutic approach to restore the damaged brain. Therefore, our goal is to study the remyelinating potential of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) after intranasal delivery. Wistar rat pups, previously brain-damaged by a combined hypoxic-ischemic and inflammatory insult, received hWJ-MSC (150,000 cells in 3 μL) that were intranasally delivered twice to each nostril (600,000 cells total). WMI was assessed by immunohistochemistry and western blot for myelination, astrogliosis, and microgliosis. The expression of preoligodendrocyte markers, and neurotrophic factors, was analyzed by real-time polymerase chain reaction. Animals treated with intranasally delivered hWJ-MSC showed increased myelination and decreased gliosis compared to untreated animals. hWJ-MSC may, therefore, modulate the activation of microglia and astrocytes, resulting in a change of the brain microenvironment, which facilitates the maturation of oligodendrocyte lineage cells. This is the first study to show that intranasal delivery of hWJ-MSC in rats prevented hypomyelination and microgliosis in a model of WMI in the premature rat brain. Further studies should address the dose and frequency of administration. PMID:27392671

  5. Intranasal T-LysYal® as adjunctive therapy for patients after functional endoscopic sinus surgery.

    PubMed

    Gelardi, M; Taliente, S; Fiorella, M L; Quaranta, N; De Candia, N; Russo, C; Mola, P; Ciofalo, A; Zambetti, G; Cantone, E; Arnone, F; Macchi, A; Rosso, P; Ciprandi, G

    2016-01-01

    Functional Endoscopic Sinus Surgery (FESS) is a common day surgery technique for upper airway disorders. Hyaluronic acid (HA) is a fundamental component of the human connective tissue. HA may exert reparative, anti-inflammatory and immune-modulating activities. Recently, a new intranasal HA formulation has been proposed: a supramolecular system containing lysine hyaluronate, thymine and sodium chloride (T-LysYal®). This randomized study investigated whether intranasal T-LysYal® (RinoLysYal®, Farmigea, Italy) was able to reduce symptom severity, endoscopic features, and nasal cytology in 83 patients (49 males and 34 females mean age 45.4±6.2 years) treated with FESS. All patients were treated with isotonic saline solution for 4 weeks, and a sub-group (active group) was also treated with intranasal T-LysYal®. Patients were visited at baseline, after treatment, and after 4-week follow-up. Intranasal T-LysYal® treatment significantly reduced the quote of patients with symptoms, endoscopic features, and inflammatory cells in comparison to isotonic solution. In conclusion, the present study demonstrates that intranasal T-LysYal® is able to significantly improve patients after FESS and its effect is long lasting. PMID:27049103

  6. Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

    PubMed

    Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

    2015-10-01

    Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. PMID:26278659

  7. Postprandial Administration of Intranasal Insulin Intensifies Satiety and Reduces Intake of Palatable Snacks in Women

    PubMed Central

    Hallschmid, Manfred; Higgs, Suzanne; Thienel, Matthias; Ott, Volker; Lehnert, Hendrik

    2012-01-01

    The role of brain insulin signaling in the control of food intake in humans has not been thoroughly defined. We hypothesized that the hormone contributes to the postprandial regulation of appetite for palatable food, and assessed the effects on appetite and snack intake of postprandial versus fasted intranasal insulin administration to the brain in healthy women. Two groups of subjects were intranasally administered 160 IU insulin or vehicle after lunch. Two hours later, consumption of cookies of varying palatability was measured under the pretext of a taste test. In a control study, the effects of intranasal insulin administered to fasted female subjects were assessed. Compared with placebo, insulin administration in the postprandial but not in the fasted state decreased appetite as well as intake and rated palatability of chocolate chip cookies (the most palatable snack offered). In both experiments, intranasal insulin induced a slight decrease in plasma glucose but did not affect serum insulin concentrations. Data indicate that brain insulin acts as a relevant satiety signal during the postprandial period, in particular reducing the intake of highly palatable food, and impacts peripheral glucose homeostasis. Postprandial intranasal insulin administration might be useful in curtailing overconsumption of snacks with accentuated rewarding value. PMID:22344561

  8. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women.

    PubMed

    Hallschmid, Manfred; Higgs, Suzanne; Thienel, Matthias; Ott, Volker; Lehnert, Hendrik

    2012-04-01

    The role of brain insulin signaling in the control of food intake in humans has not been thoroughly defined. We hypothesized that the hormone contributes to the postprandial regulation of appetite for palatable food, and assessed the effects on appetite and snack intake of postprandial versus fasted intranasal insulin administration to the brain in healthy women. Two groups of subjects were intranasally administered 160 IU insulin or vehicle after lunch. Two hours later, consumption of cookies of varying palatability was measured under the pretext of a taste test. In a control study, the effects of intranasal insulin administered to fasted female subjects were assessed. Compared with placebo, insulin administration in the postprandial but not in the fasted state decreased appetite as well as intake and rated palatability of chocolate chip cookies (the most palatable snack offered). In both experiments, intranasal insulin induced a slight decrease in plasma glucose but did not affect serum insulin concentrations. Data indicate that brain insulin acts as a relevant satiety signal during the postprandial period, in particular reducing the intake of highly palatable food, and impacts peripheral glucose homeostasis. Postprandial intranasal insulin administration might be useful in curtailing overconsumption of snacks with accentuated rewarding value. PMID:22344561

  9. Brain delivery of insulin boosted by intranasal coadministration with cell-penetrating peptides.

    PubMed

    Kamei, Noriyasu; Takeda-Morishita, Mariko

    2015-01-10

    Intranasal administration is considered as an alternative route to enable effective drug delivery to the central nervous system (CNS) by bypassing the blood-brain barrier. Several reports have proved that macromolecules can be transferred directly from the nasal cavity to the brain. However, strategies to enhance the delivery of macromolecules from the nasal cavity to CNS are needed because of their low delivery efficiencies via this route in general. We hypothesized that the delivery of biopharmaceuticals to the brain parenchyma can be facilitated by increasing the uptake of drugs by the nasal epithelium including supporting and neuronal cells to maximize the potentiality of the intranasal pathway. To test this hypothesis, the CNS-related model peptide insulin was intranasally coadministered with the cell-penetrating peptide (CPP) penetratin to mice. As a result, insulin coadministered with l- or d-penetratin reached the distal regions of the brain from the nasal cavity, including the cerebral cortex, cerebellum, and brain stem. In particular, d-penetratin could intranasally deliver insulin to the brain with a reduced risk of systemic insulin exposure. Thus, the results obtained in this study suggested that CPPs are potential tools for the brain delivery of peptide- and protein-based pharmaceuticals via intranasal administration. PMID:25445695

  10. Promnestic effects of intranasally applied pregnenolone in rats.

    PubMed

    Abdel-Hafiz, Laila; Chao, Owen Y; Huston, Joseph P; Nikolaus, Susanne; Spieler, Richard E; de Souza Silva, Maria A; Mattern, Claudia

    2016-09-01

    The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration. PMID:27423520

  11. Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder.

    PubMed

    Koch, Saskia B J; van Zuiden, Mirjam; Nawijn, Laura; Frijling, Jessie L; Veltman, Dick J; Olff, Miranda

    2016-07-01

    The neuropeptide oxytocin (OT) has been suggested as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder (PTSD) because of its anxiolytic and prosocial properties. We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration (40 IU) in PTSD patients. We conducted a randomized, placebo-controlled, cross-over resting-state fMRI study in male and female police officers with (n=37, 21 males) and without PTSD (n=40, 20 males). We investigated OT administration effects on subjective anxiety and functional connectivity of basolateral (BLA) and centromedial (CeM) amygdala subregions with prefrontal and salience processing areas. In PTSD patients, OT administration resulted in decreased subjective anxiety and nervousness. Under placebo, male PTSD patients showed diminished right CeM to left ventromedial prefrontal cortex (vmPFC) connectivity compared with male trauma-exposed controls, which was reinstated after OT administration. Additionally, female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex (dACC) connectivity compared with female trauma-exposed controls, which was dampened after OT administration. Although caution is warranted, our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD, either via increased control of the vmPFC over the CeM (males) or via decreased salience processing of the dACC and BLA (females). Our findings add to accumulating evidence that OT administration could potentially enhance treatment response in PTSD. PMID:26741286

  12. Intranasal inhalation of oxytocin improves face processing in developmental prosopagnosia.

    PubMed

    Bate, Sarah; Cook, Sarah J; Duchaine, Bradley; Tree, Jeremy J; Burns, Edwin J; Hodgson, Timothy L

    2014-01-01

    Developmental prosopagnosia (DP) is characterised by a severe lifelong impairment in face recognition. In recent years it has become clear that DP affects a substantial number of people, yet little work has attempted to improve face processing in these individuals. Intriguingly, recent evidence suggests that intranasal inhalation of the hormone oxytocin can improve face processing in unimpaired participants, and we investigated whether similar findings might be noted in DP. Ten adults with DP and 10 matched controls were tested using a randomized placebo-controlled double-blind within-subject experimental design (AB-BA). Each participant took part in two testing sessions separated by a 14-25 day interval. In each session, participants inhaled 24 IU of oxytocin or placebo spray, followed by a 45 min resting period to allow central oxytocin levels to plateau. Participants then completed two face processing tests: one assessing memory for a set of newly encoded faces, and one measuring the ability to match simultaneously presented faces according to identity. Participants completed the Multidimensional Mood Questionnaire (MMQ) at three points in each testing session to assess the possible mood-altering effects of oxytocin and to control for attention and wakefulness. Statistical comparisons revealed an improvement for DP but not control participants on both tests in the oxytocin condition, and analysis of scores on the MMQ indicated that the effect cannot be attributed to changes in mood, attention or wakefulness. This investigation provides the first evidence that oxytocin can improve face processing in DP, and the potential neural underpinnings of the findings are discussed alongside their implications for the treatment of face processing disorders. PMID:24074457

  13. Intranasal midazolam administration enhances amnesic effect in rats.

    PubMed

    Kadono, Takao; Kawano, Takashi; Yamanaka, Daiki; Tateiwa, Hiroki; Urakawa, Manami; Locatelli, Fabricio M; Yokoyama, Masataka

    2016-06-01

    Intranasal (i.n.) administration of midazolam has been shown to be effective and safe for its sedative, anxiolytic, and anticonvulsant effects. However, there has been no investigation on the influence of i.n. administration on midazolam-induced anterograde amnesia. In addition, although the potential of direct drug delivery from the nose to the central nervous system (CNS) has recently become a topic of great interest, it remains unclear whether this pathway is also involved after i.n. midazolam. In this study, we examined the efficacy and the underlying mechanism of i.n. administration compared with intramuscular (i.m.) administration on midazolam-induced amnesia in rats. Equivalent doses of 0.6 mg/kg midazolam were administered via either the i.m or the i.n. route. Anterograde amnesia was assessed by a contextual/cued fear conditioning test. Each animal was conditioned 20 min after drug administration and then tested for a freezing response 24 h later. Midazolam administration by either route produced a similar level of light sedation (minimum spontaneous activity). However, i.n. administration of midazolam induced significantly less freezing behavior compared with i.m. midazolam. Furthermore, in rats with disrupted electrical input from the olfactory epithelium after an olfactotoxicant 3-methylindole administration, the i.n.-mediated enhanced amnesic effect of midazolam was not observed. Our findings indicate that i.n midazolam could probably generate olfactory signals to the brain via benzodiazepine receptors and, compared with i.m. administration, can produce a more significant amnesic effect without alteration in sedative levels. Further clinical studies are warranted. PMID:26943484

  14. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Tam, V.; Putcha, L.

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials for an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP. METHODS: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model discrimination was performed, by minimizing the Akaike Information Criteria (AIC), maximizing the coefficient of determination (r²) and by comparison of the quality of fit plots. RESULTS: The best structural model to describe scopolamine disposition after INSCOP administration (minimal AIC =907.2) consisted of one compartment for plasma, saliva and urine respectively that were inter-connected with different rate constants. The estimated values of PK parameters were compiled in Table 1. The model fitting exercises revealed a nonlinear PK for scopolamine between plasma and saliva compartments for K21, Vmax and Km. CONCLUSION: PK model for INSCOP was developed and for the first time it satisfactorily predicted the PK of scopolamine in plasma, saliva and urine after INSCOP administration. Using non-linear PK yielded the best structural model to describe scopolamine disposition between plasma and saliva compartments, and inclusion of non-linear PK resulted in a significant improved model fitting. The model can be utilized to predict scopolamine plasma concentration using saliva and/or urine data that

  15. Anatomical and Histological Factors Affecting Intranasal Drug and Vaccine Delivery

    PubMed Central

    Gizurarson, Sveinbjörn

    2012-01-01

    The aim of this review is to provide an understanding of the anatomical and histological structure of the nasal cavity, which is important for nasal drug and vaccine delivery as well as the development of new devices. The surface area of the nasal cavity is about 160 cm2, or 96 m2 if the microvilli are included. The olfactory region, however, is only about 5 cm2 (0.3 m2 including the microvilli). There are 6 arterial branches that serve the nasal cavity, making this region a very attractive route for drug administration. The blood flow into the nasal region is slightly more than reabsorbed back into the nasal veins, but the excess will drain into the lymph vessels, making this region a very attractive route for vaccine delivery. Many of the side effects seen following intranasal administration are caused by some of the 6 nerves that serve the nasal cavity. The 5th cranial nerve (trigeminus nerve) is responsible for sensing pain and irritation following nasal administration but the 7th cranial nerve (facial nerve) will respond to such irritation by stimulating glands and cause facial expressions in the subject. The first cranial nerve (olfactory nerve), however, is the target when direct absorption into the brain is the goal, since this is the only site in our body where the central nervous system is directly expressed on the mucosal surface. The nasal mucosa contains 7 cell types and 4 types of glands. Four types of cells and 2 types of glands are located in the respiratory region but 6 cell types and 2 types of glands are found in the olfactory region. PMID:22788696

  16. Anatomical and histological factors affecting intranasal drug and vaccine delivery.

    PubMed

    Gizurarson, Sveinbjörn

    2012-11-01

    The aim of this review is to provide an understanding of the anatomical and histological structure of the nasal cavity, which is important for nasal drug and vaccine delivery as well as the development of new devices. The surface area of the nasal cavity is about 160 cm2, or 96 m2 if the microvilli are included. The olfactory region, however, is only about 5 cm2 (0.3 m2 including the microvilli). There are 6 arterial branches that serve the nasal cavity, making this region a very attractive route for drug administration. The blood flow into the nasal region is slightly more than reabsorbed back into the nasal veins, but the excess will drain into the lymph vessels, making this region a very attractive route for vaccine delivery. Many of the side effects seen following intranasal administration are caused by some of the 6 nerves that serve the nasal cavity. The 5th cranial nerve (trigeminus nerve) is responsible for sensing pain and irritation following nasal administration but the 7th cranial nerve (facial nerve) will respond to such irritation by stimulating glands and cause facial expressions in the subject. The first cranial nerve (olfactory nerve), however, is the target when direct absorption into the brain is the goal, since this is the only site in our body where the central nervous system is directly expressed on the mucosal surface. The nasal mucosa contains 7 cell types and 4 types of glands. Four types of cells and 2 types of glands are located in the respiratory region but 6 cell types and 2 types of glands are found in the olfactory region. PMID:22788696

  17. Pharmacokinetics of Scopolamine Intranasal Gel Formulation (INSCOP) During Antiorthostatic Bedrest

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Du, B.; Daniels, V.

    2010-01-01

    Space Motion Sickness (SMS) is experienced during early flight days of space missions and on reduced gravity simulation flights which require treatment with medications. Oral administration of scopolamine tablets is still a common practice to prevent SMS symptoms. Bioavailability of medications taken by mouth for SMS is often low and variable. Intranasal (IN) administration of medications has been reported to achieve higher and more reliable bioavailability than from an equivalent oral dose. In this FDA reviewed phase II clinical trial, we evaluated pharmacokinetics of an investigative new drug formulation, INSCOP during ambulatory (AMB) and antiorthostatic bedrest (HBR), a ground-based microgravity analog. Twelve subjects including 6 males and 6 females received 0.2 and 0.4 mg doses of INSCOP on separate days during AMB and ABR in a randomized, double blind cross over experimental design. Blood samples were collected at regular time intervals for 24 h post dose and analyzed for free scopolamine concentrations by an LC-MS-MS method. Pharmacokinetic parameters were calculated using concentration versus time data and compared between AMB and ABR conditions. Results indicated that maximum concentration and relative bioavailability increased marginally during ABR compared to AMB; differences in PK parameters between AMB and ABR were greater with 0.2 mg than with 0.4 mg dose. Gender specific differences in PK parameters was observed both during AMB and ABR with differences higher in females between the two conditions than in males. A significant observation is that while gender differences in PK appear to exist, the differences in primary PK parameters between AMB and ABR after IN administration, unlike oral administration, are minimal and may not be clinically significant for both genders.

  18. Intranasal and oral vaccination with protein-based antigens: advantages, challenges and formulation strategies.

    PubMed

    Wang, Shujing; Liu, Huiqin; Zhang, Xinyi; Qian, Feng

    2015-07-01

    Most pathogens initiate their infections at the human mucosal surface. Therefore, mucosal vaccination, especially through oral or intranasal administration routes, is highly desired for infectious diseases. Meanwhile, protein-based antigens provide a safer alternative to the whole pathogen or DNA based ones in vaccine development. However, the unique biopharmaceutical hurdles that intranasally or orally delivered protein vaccines need to overcome before they reach the sites of targeting, the relatively low immunogenicity, as well as the low stability of the protein antigens, require thoughtful and fine-tuned mucosal vaccine formulations, including the selection of immunostimulants, the identification of the suitable vaccine delivery system, and the determination of the exact composition and manufacturing conditions. This review aims to provide an up-to-date survey of the protein antigen-based vaccine formulation development, including the usage of immunostimulants and the optimization of vaccine delivery systems for intranasal and oral administrations. PMID:25944045

  19. Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury.

    PubMed

    Donega, Vanessa; Nijboer, Cora H; van Tilborg, Geralda; Dijkhuizen, Rick M; Kavelaars, Annemieke; Heijnen, Cobi J

    2014-11-01

    Previous work from our group has shown that intranasal MSC-treatment decreases lesion volume and improves motor and cognitive behavior after hypoxic-ischemic (HI) brain damage in neonatal mice. Our aim was to determine the kinetics of MSC migration after intranasal administration, and the early effects of MSCs on neurogenic processes and gliosis at the lesion site. HI brain injury was induced in 9-day-old mice and MSCs were administered intranasally at 10days post-HI. The kinetics of MSC migration were investigated by immunofluorescence and MRI analysis. BDNF and NGF gene expression was determined by qPCR analysis following MSC co-culture with HI brain extract. Nestin, Doublecortin, NeuN, GFAP, Iba-1 and M1/M2 phenotypic expression was assessed over time. MRI and immunohistochemistry analyses showed that MSCs reach the lesion site already within 2h after intranasal administration. At 12h after administration the number of MSCs at the lesion site peaks and decreases significantly at 72h. The number of DCX(+) cells increased 1 to 3days after MSC administration in the SVZ. At the lesion, GFAP(+)/nestin(+) and DCX(+) expression increased 3 to 5days after MSC-treatment. The number of NeuN(+) cells increased within 5days, leading to a dramatic regeneration of the somatosensory cortex and hippocampus at 18days after intranasal MSC administration. Interestingly, MSCs expressed significantly more BDNF gene when exposed to HI brain extract in vitro. Furthermore, MSC-treatment resulted in the resolution of the glial scar surrounding the lesion, represented by a decrease in reactive astrocytes and microglia and polarization of microglia towards the M2 phenotype. In view of the current lack of therapeutic strategies, we propose that intranasal MSC administration is a powerful therapeutic option through its functional repair of the lesion represented by regeneration of the cortical and hippocampal structure and decrease of gliosis. PMID:24945601

  20. Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection.

    PubMed

    Fréchou, Magalie; Zhang, Shaodong; Liere, Philippe; Delespierre, Brigitte; Soyed, Nouha; Pianos, Antoine; Schumacher, Michael; Mattern, Claudia; Guennoun, Rachida

    2015-10-01

    Progesterone is a potential neuroprotective agent for cerebral stroke. One of the STAIR's recommendations is to test different routes of delivery of therapeutic agents. Here, we investigated the neuroprotective efficacy of intranasal delivery of progesterone in oleogel. Male mice were subjected to transient middle cerebral occlusion (MCAO) for 1 h. Mice received intranasal or intraperitoneal administrations of progesterone (8 mg/kg) at 1, 6, and 24 h post-MCAO. Plasma and brain levels of steroids were measured by gas chromatography-mass spectrometry 2 and 24 h after the last administration of progesterone. Behavioral and histopathological analyzes were performed at 48 h post-MCAO. For blood-brain barrier (BBB) permeability analysis, mice received one intranasal administration of progesterone or placebo at reperfusion and Evans Blue and sodium fluorescein extravasations were assessed at 4 h post-MCAO. Two hours after its nasal administration, progesterone reached elevated levels in brain and plasma and was bioconverted to its 5α-reduced metabolites and to 20α-dihydroprogesterone. However, brain levels of progesterone and its metabolites were about half those measured after intraperitoneal injections, whereas levels of 11-deoxycorticosterone and corticosterone were 5-times lower. In contrast, after 24 h, higher levels of progesterone were measured in brain and plasma after intranasal than after intraperitoneal delivery. Intranasal progesterone decreased the mortality rate, improved motor functions, reduced infarct, attenuated neuronal loss, and decreased the early BBB disruption. This study demonstrates a good bioavailability, a prolonged absorption and a good neuroprotective efficacy of intranasal delivery of progesterone, thus potentially offering an efficient, safe, non-stressful and very easy mode of administration in stroke patients. PMID:26079443

  1. Phase Transition of ZnxMn1-xS Dilute Magnetic Semiconductor Nanoparticles under Ultra-high Pressure

    SciTech Connect

    Z Zong; Y Ma; T Hu; Q Cui; M Zhang; G Zou

    2011-12-31

    The high-pressure behavior of different doping content of ZnS nanocrystals has been investigated using angle-dispersive synchrotron X-ray powder diffraction up to 45.1 GPa. A phase transformation from the zinc-blende(ZB) to the rock-salt (RS) structure is observed at pressures of about 17.7 and 18.3 GPa at room temperature, corresponding to the Mn{sup 2+} ion mole percent content solutions 0.85% and 1.26%, respectively. The obtained results indicate that the Mn{sup 2+} doping could obviously enhance the phase transition pressure of ZnS nanocrystal. The elevation of phase transition pressure could origin from the higher surface energy induced by ion doping.

  2. Protection of cattle against rinderpest by intranasal immunisation with a dry powder tissue culture vaccine.

    PubMed

    Anderson, J; Fishbourne, E; Corteyn, A; Donaldson, A I

    2000-11-22

    Dry powder tissue culture rinderpest vaccine containing 10(2.5) TCID(50) of virus per dose administered intranasally to cattle induced high titre circulating antibody responses and protection against challenge with a virulent strain of rinderpest virus. A reduction in the dose of virus to 10(1.1) TCID(50) resulted in a failure to elicit detectable antibody responses and a lack of protection. Intranasal powder vaccine offers several advantages over conventional needle-administered aqueous rinderpest vaccine, including greater stability in the absence of a cold chain, reduced risk of 'needle transfer' of other microbial agents present in the vaccinated herd and lower cost. PMID:11115707

  3. Impact of Gender on Pharmocokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Lei, Wu.; S-L Chow, Diana

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS), which is commonly experienced by astronauts during space missions. The bioavailability and pharmacokinetics (PK) were evaluated under IND guidelines. Since information is lacking on the effect of gender on the PK of Scopolamine, we examined gender differences in PK parameters of INSCOP at three dose levels of 0.1, 0.2 and 0.4 mg. Methods: Plasma scopolamine concentrations as a function of time data were collected from twelve normal healthy human subjects (6 male/6 female) who participated in a fully randomized double blind crossover study. The PK parameters were derived using WinNonlin. Covariate analysis of PK profiles was performed using NONMEN and statistically compared using a likelihood ratio test on the difference of objective function value (OFV). Statistical significance for covariate analysis was set at P<0.05(?OFV=3.84). Results: No significant difference in PK parameters between male and female subjects was observed with 0.1 and 0.2 mg doses. However, CL and Vd were significantly different between male and female subjects at the 0.4 mg dose. Results from population covariate modeling analysis indicate that a onecompartment PK model with first-order elimination rate offers best fit for describing INSCOP concentration-time profiles. The inclusion of sex as a covariate enhanced the model fitting (?OFV=-4.1) owing to the genderdependent CL and Vd differences after the 0.4 mg dose. Conclusion: Statistical modeling of scopolamine concentration-time data suggests gender-dependent pharmacokinetics of scopolamine at the high dose level of 0.4 mg. Clearance of the parent compound was significantly faster and the volume of distribution was significantly higher in males than in females, As a result, including gender as a covariate to the pharmacokinetic model of scopolamine offers the best fit for PK modeling of the drug at dose

  4. Laser-driven phase transitions in aqueous colloidal gold nanoparticles under high pressure: picosecond pump-probe study.

    PubMed

    Hashimoto, Shuichi; Katayama, Tetsuro; Setoura, Kenji; Strasser, Michael; Uwada, Takayuki; Miyasaka, Hiroshi

    2016-02-14

    Pump-probe transient extinction spectroscopy was used to analyze 355 nm picosecond laser heating-induced phenomena in 60 nm-diameter aqueous gold nanoparticles (AuNPs) under a high pressure of 60 MPa. Kinetic spectroscopy revealed that a supercritical layer surrounding the AuNP nucleated with a lifetime of approximately 1 ns during its dynamic expansion and decay for a fluence of 19.6 mJ cm(-2). Moreover, in the post-mortem transmission electron micrographs we observed a number of fragments, a small percentage of size-reduced cores, and erupted particles among the intact particles after 60 shots, suggesting that evaporation occurred under laser illumination. The particle temperature calculation indicated that evaporation begins with a liquid droplet AuNP surrounded by a supercritical layer at temperatures below the boiling point of gold. By applying high pressure, we obtained a clear picture of the evaporation event, which was not possible at ambient pressure because bubble formation caused particle temperatures to rise uncontrollably. In this study, we shed light on the critical role of the supercritical layer formed around the AuNP under high pressure during laser-induced evaporation. PMID:26812175

  5. Irreversible phase transitions due to laser-based T-jump heating of precursor Eu:ZrO{sub 2}/Tb:Y{sub 2}O{sub 3} core/shell nanoparticles

    SciTech Connect

    Gunawidjaja, Ray; Diez-y-Riega, Helena; Eilers, Hergen

    2015-09-15

    Amorphous precursors of Eu-doped-ZrO{sub 2}/Tb-doped-Y{sub 2}O{sub 3} (p-Eu:ZrO{sub 2}/p-Tb:Y{sub 2}O{sub 3}) core/shell nanoparticles are rapidly heated to temperatures between 200 °C and 950 °C for periods between 2 s and 60 s using a CO{sub 2} laser. During this heating process the nanoparticles undergo irreversible phase changes. The fluorescence spectra due to Eu{sup 3+} dopants in the core and Tb{sup 3+} dopants in the shell are used to identify distinct phases within the material and to generate time/temperature phase diagrams. Such phase diagrams can potentially help to determine unknown time/temperature histories in thermosensor applications. - Graphical abstract: A CO{sub 2} laser is used for rapid heating of p-Eu:ZrO{sub 2}/p-Tb:Y{sub 2}O{sub 3} core/shell nanoparticles. Optical spectra are used to identify distinct phases and to determine its thermal history. - Highlights: • Synthesized oxide precursors of lanthanide doped core/shell nanoparticles. • Heated core/shell nanoparticles via laser-based T-jump technique. • Observed time- and temperature-dependent irreversible phase transition.

  6. Intranasal immunization of mice with a bovine respiratory syncytial virus vaccine induces superior immunity and protection compared to those by subcutaneous delivery or combinations of intranasal and subcutaneous prime-boost strategies.

    PubMed

    Mapletoft, John W; Latimer, Laura; Babiuk, Lorne A; van Drunen Littel-van den Hurk, Sylvia

    2010-01-01

    Bovine respiratory syncytial virus (BRSV) infects cells of the respiratory mucosa, so it is desirable to develop a vaccination strategy that induces mucosal immunity. To achieve this, various delivery routes were compared for formalin-inactivated (FI) BRSV formulated with CpG oligodeoxynucleotide (ODN) and polyphosphazene (PP). Intranasal delivery of the FI-BRSV formulation was superior to subcutaneous delivery in terms of antibody, cell-mediated, and mucosal immune responses, as well as reduction in virus replication after BRSV challenge. Although intranasal delivery of FI-BRSV also induced higher serum and lung antibody titers and gamma interferon (IFN-gamma) production in the lungs than intranasal-subcutaneous and/or subcutaneous-intranasal prime-boost strategies, no significant differences were observed in cell-mediated immune responses or virus replication in the lungs of challenged mice. Interleukin 5 (IL-5), eotaxin, and eosinophilia were enhanced after BRSV challenge in the lungs of subcutaneously immunized mice compared to unvaccinated mice, but not in the lungs of mice immunized intranasally or through combinations of the intranasal and subcutaneous routes. These results suggest that two intranasal immunizations with FI-BRSV formulated with CpG ODN and PP are effective and safe as an approach to induce systemic and mucosal responses, as well to reduce virus replication after BRSV challenge. Furthermore, intranasal-subcutaneous and subcutaneous-intranasal prime-boost strategies were also safe and almost as efficacious. In addition to the implications for the development of a protective BRSV vaccine for cattle, formulation with CpG ODN and PP could also prove important in the development of a mucosal vaccine that induces protective immunity against human RSV. PMID:19864487

  7. Intranasal Dexmedetomidine on Stress Hormones, Inflammatory Markers, and Postoperative Analgesia after Functional Endoscopic Sinus Surgery

    PubMed Central

    Tang, Chaoliang; Huang, Xiang; Kang, Fang; Chai, Xiaoqing; Wang, Song; Yin, Guobing; Wang, Hongtao; Li, Juan

    2015-01-01

    Background. A strong ongoing intraoperative stress response can cause serious adverse reactions and affect the postoperative outcome. This study evaluated the effect of intranasally administered dexmedetomidine (DEX) in combination with local anesthesia (LA) on the relief of stress and the inflammatory response during functional endoscopic sinus surgery (FESS). Methods. Sixty patients undergoing FESS were randomly allocated to receive either intranasal DEX (DEX group) or intranasal saline (Placebo group) 1 h before surgery. Stress hormones, inflammatory markers, postoperative pain relief, hemodynamic variables, blood loss, surgical field quality, body movements, and satisfaction were assessed. Results. Plasma epinephrine, norepinephrine, and blood glucose levels were significantly lower in DEX group as were the plasma IL-6 and TNF-α levels (P < 0.05). The weighted areas under the curve (AUCw) of the VAS scores were also significantly lower in DEX group at 2–12 h after surgery (P < 0.001). Furthermore, hemodynamic variables, blood loss, body movements, discomfort with hemostatic stuffing, surgical field quality, and satisfaction scores of patients and surgeons were significantly better (P < 0.05) in DEX group. Conclusions. Patients receiving intranasal DEX with LA for FESS exhibited less perioperative stress and inflammatory response as well as better postoperative comfort with hemostatic stuffing and analgesia. PMID:26199465

  8. Brain microdialysate, CSF and plasma pharmacokinetics of ligustrazine hydrochloride in rats after intranasal and intravenous administration.

    PubMed

    Wang, Qiao; Tang, Zhan; Zhang, Wanggang

    2013-10-01

    The aim of this work was to investigate the pharmacokinetics of ligustrazine hydrochloride (LZH) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal (10 mg/kg) or intravenous administration (10 mg/kg) in male Sprague-Dawley rats. Plasma, CSF and cerebral cortex microdialysates were collected at timed intervals for the measurement of LZH by a quick and sensitive HPLC-UV method. LZH entered the brain quickly following both routes of administration. No significant difference was observed between the AUCCSF or cortex /AUCplasma ratio of LZH after intranasal administration (38.4%, 17.4%) and that after intravenous injection (45.9%, 19.9%). The drug targeting index (DTI) was 0.85 and 0.91 in the CSF and cortex, respectively. In conclusion, LZH is rapidly absorbed into the systemic circulation following intranasal administration. There is no direct pathway for LZH transport from the nasal cavity to the brain. The rapidity and magnitude of LZH penetration into the brain indicate that intranasal administration of this agent is a promising alternative to intravenous administration. PMID:23868712

  9. Abuse Potential of Intranasal Buprenorphine versus Buprenorphine/Naloxone in Buprenorphine-Maintained Heroin Users

    PubMed Central

    Jones, Jermaine D.; Sullivan, Maria A.; Vosburg, Suzanne K.; Manubay, Jeanne M.; Mogali, Shanthi; Metz, Verena; Comer, Sandra D.

    2014-01-01

    In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose-dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse. PMID:25060839

  10. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

    PubMed

    Reger, M A; Watson, G S; Frey, W H; Baker, L D; Cholerton, B; Keeling, M L; Belongia, D A; Fishel, M A; Plymate, S R; Schellenberg, G D; Cherrier, M M; Craft, S

    2006-03-01

    Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer's disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism. PMID:15964100

  11. Intranasal temperature and humidity profile in patients with nasal septal perforation before and after surgical closure.

    PubMed

    Lindemann, J; Leiacker, R; Stehmer, V; Rettinger, G; Keck, T

    2001-10-01

    Common complaints of patients with a nasal septal perforation are crusting, dryness and bleeding. As shown previously, intranasal humidity values are significantly lower in patients with a septal perforation compared with healthy volunteers. The aim of this study was to determine the influence of surgical closure of septal perforations on intranasal temperature and humidity, and to evaluate changes in clinical symptoms after surgery. Ten patients with septal perforations were included in the study. Intranasal temperature and humidity were measured at the nasal valve and anterior turbinate areas before and after surgical closure. Clinical symptoms were assessed using a nasal symptom score. The end-inspiratory humidity values were significantly (P < or = 0.05) higher postoperatively than preoperatively. The increase in temperature at the anterior turbinate area was significantly higher postoperatively. The temperature values at the nasal valve area were not significantly different. Recurrent epistaxis and nasal dryness were reduced after surgery. Nasal septal perforations disturb the intranasal temperature and humidity profile. After surgical closure, heating and humidification is improved. This may be responsible for the reduction of frequent complaints such as bleeding and dryness. PMID:11678954

  12. Development of an intranasal vaccine to prevent urinary tract infection by Proteus mirabilis.

    PubMed

    Li, Xin; Lockatell, C Virginia; Johnson, David E; Lane, M Chelsea; Warren, John W; Mobley, Harry L T

    2004-01-01

    Proteus mirabilis commonly infects the complicated urinary tract and is associated with urolithiasis. Stone formation is caused by bacterial urease, which hydrolyzes urea to ammonia, causing local pH to rise, and leads to the subsequent precipitation of magnesium ammonium phosphate (struvite) and calcium phosphate (apatite) crystals. To prevent these infections, we vaccinated CBA mice with formalin-killed bacteria or purified mannose-resistant, Proteus-like (MR/P) fimbriae, a surface antigen expressed by P. mirabilis during experimental urinary tract infection, via four routes of immunization: subcutaneous, intranasal, transurethral, and oral. We assessed the efficacy of vaccination using the CBA mouse model of ascending urinary tract infection. Subcutaneous or intranasal immunization with formalin-killed bacteria and intranasal or transurethral immunization with purified MR/P fimbriae significantly protected CBA mice from ascending urinary tract infection by P. mirabilis (P < 0.05). To investigate the potential of MrpH, the MR/P fimbrial tip adhesin, as a vaccine, the mature MrpH peptide (residues 23 to 275, excluding the signal peptide), and the N-terminal receptor-binding domain of MrpH (residues 23 to 157) were overexpressed as C-terminal fusions to maltose-binding protein (MBP) and purified on amylose resins. Intranasal immunization of CBA mice with MBP-MrpH (residues 23 to 157) conferred effective protection against urinary tract infection by P. mirabilis (P < 0.002). PMID:14688082

  13. Direct nose-to-brain delivery of lamotrigine following intranasal administration to mice.

    PubMed

    Serralheiro, Ana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2015-07-25

    Pharmacoresistance is considered one of the major causes underlying the failure of the anticonvulsant therapy, demanding the development of alternative and more effective therapeutic approaches. Due to the particular anatomical features of the nasal cavity, intranasal administration has been explored as a means of preferential drug delivery to the brain. The purpose of the present study was to assess the pharmacokinetics of lamotrigine administered by the intranasal route to mice, and to investigate whether a direct transport of the drug from nose to brain could be involved. The high bioavailability achieved for intranasally administered lamotrigine (116.5%) underscored the fact that a substantial fraction of the drug has been absorbed to the systemic circulation. Nonetheless, the heterogeneous biodistribution of lamotrigine in different brain regions, with higher concentration levels attained in the olfactory bulb comparatively to the frontal cortex and the remaining portion of the brain, strongly suggest that lamotrigine was directly transferred to the brain via the olfactory neuronal pathway, circumventing the blood-brain barrier. Therefore, it seems that intranasal route can be assumed as a suitable and valuable drug delivery strategy for the chronic treatment of epilepsy, also providing a promising alternative approach for a prospective management of pharmacoresistance. PMID:25979854

  14. Intranasal Insulin Suppresses Food Intake via Enhancement of Brain Energy Levels in Humans

    PubMed Central

    Jauch-Chara, Kamila; Friedrich, Alexia; Rezmer, Magdalena; Melchert, Uwe H.; G. Scholand-Engler, Harald; Hallschmid, Manfred; Oltmanns, Kerstin M.

    2012-01-01

    Cerebral insulin exerts anorexic effects in humans and animals. The underlying mechanisms, however, are not clear. Because insulin physiologically facilitates glucose uptake by most tissues of the body and thereby fosters intracellular energy supply, we hypothesized that intranasal insulin reduces food consumption via enhancement of the neuroenergetic level. In a double-blind, placebo–controlled, within-subject comparison, 15 healthy men (BMI 22.2 ± 0.37 kg/m2) aged 22–28 years were intranasally administered insulin (40 IU) or placebo after an overnight fast. Cerebral energy metabolism was assessed by 31P magnetic resonance spectroscopy. At 100 min after spray administration, participants consumed ad libitum from a test buffet. Our data show that intranasal insulin increases brain energy (i.e., adenosine triphosphate and phosphocreatine levels). Cerebral energy content correlates inversely with subsequent calorie intake in the control condition. Moreover, the neuroenergetic rise upon insulin administration correlates with the consecutive reduction in free-choice calorie consumption. Brain energy levels may therefore constitute a predictive value for food intake. Given that the brain synchronizes food intake behavior in dependence of its current energetic status, a future challenge in obesity treatment may be to therapeutically influence cerebral energy homeostasis. Intranasal insulin, after optimizing its application schema, seems a promising option in this regard. PMID:22586589

  15. Intranasal Insulin Therapy for Cognitive Impairment and Neurodegeneration: Current State of the Art

    PubMed Central

    de la Monte, Suzanne M.

    2015-01-01

    Introduction Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also minimize potentially hazardous off-target effects. Areas covered This review covers the role of intra-nasal insulin therapy for cognitive impairment and neurodegeneration, particularly Alzheimer's disease. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The author provides evidence that brain insulin resistance is an important and early abnormality in Alzheimer's disease, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy. Expert Opinion Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival, and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy, and specificity of intranasal insulin therapy. PMID:24215447

  16. Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users.

    PubMed

    Jones, Jermaine D; Sullivan, Maria A; Vosburg, Suzanne K; Manubay, Jeanne M; Mogali, Shanthi; Metz, Verena; Comer, Sandra D

    2015-07-01

    In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse. PMID:25060839

  17. Intranasal delivery to the central nervous system: mechanisms and experimental considerations.

    PubMed

    Dhuria, Shyeilla V; Hanson, Leah R; Frey, William H

    2010-04-01

    The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review. PMID:19877171

  18. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers

    PubMed Central

    Middleton, L.S.; Nuzzo, P.A.; Lofwall, M.R.; Moody, D.E.; Walsh, S.L.

    2011-01-01

    Aims Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. Design A randomized, double-blind, placebo-controlled, crossover study. Setting An in-patient research unit at the University of Kentucky. Participants Healthy adults (n=10) abusing, but not physically dependent on, intranasal opioids. Measurements Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject- and observer-rated measures were collected before and for up to 72 hours after drug administration. Findings Both formulations produced time- and dose-dependent increases on subjective and physiological mu-opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time-course were observed. Buprenorphine bioavailability was 38–44% and Tmax was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. Conclusions It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non-dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine

  19. Effects of intranasal and peripheral oxytocin or gastrin-releasing peptide administration on social interaction and corticosterone levels in rats.

    PubMed

    Kent, Pamela; Awadia, Alisha; Zhao, Leah; Ensan, Donna; Silva, Dinuka; Cayer, Christian; James, Jonathan S; Anisman, Hymie; Merali, Zul

    2016-02-01

    The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin's ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5 μg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5 μg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20 μg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20 μg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels. PMID:26658172

  20. Evaluation of brain targeting efficiency of intranasal microemulsion containing olanzapine: pharmacodynamic and pharmacokinetic consideration.

    PubMed

    Patel, Rashmin B; Patel, Mrunali R; Bhatt, Kashyap K; Patel, Bharat G; Gaikwad, Rajiv V

    2016-01-01

    The objective of this study was to develop and evaluate olanzapine (OZP) -loaded microemulsions (OZPME) for intranasal delivery in the treatment of schizophrenia. The OZPME was formulated by the spontaneous microemulsification method and characterized for physicochemical parameters. Pharmacodynamic assessments (apomorphine - induced compulsive behavior and spontaneous locomotor activity) were performed using mice. All formulations were radiolabeled with technetium-99 ((99m)Tc), and biodistribution of drug in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rabbits was performed to determine the uptake of the OZP into the brain. OZPME were found clear and stable with average globule size of 23.87 ± 1.07 nm. In pharmacodynamic assessments, significant (p < 0.05) difference in parameters estimated were found between the treated and control groups. (99m)Tc-labeled OZP solution (OZPS)/OZPME/OZP mucoadhesive microemulsion (OZPMME) were found to be stable and suitable for in vivo studies. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of OZPMME compared to intravenous OZPME was found to be five to six times higher signifying larger extent of distribution of the OZP in brain. Drug targeting efficiency and direct drug transport were found to be highest for intranasal OZPMME, compared to intravenous OZPME. Furthermore, rabbit brain scintigraphy also demonstrated higher intranasal uptake of the OZP into the brain. This investigation demonstrates a prompt and larger extent of transport of OZP into the brain through intranasal OZPMME, which may prove beneficial for treatment of schizophrenia. PMID:24845478

  1. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xTg-AD mice

    PubMed Central

    Chen, Yanxing; Run, Xiaoqin; Liang, Zhihou; Zhao, Yang; Dai, Chun-ling; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2014-01-01

    Background: It is well documented that elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer’s disease (AD). Recent studies suggest that anesthesia may increase the risk for cognitive decline and AD through promoting abnormal hyperphosphorylation of tau, which is crucial to neurodegeneration seen in AD. Methods: We treated 3xTg-AD mice, a commonly used transgenic mouse model of AD, with daily intranasal administration of insulin (1.75 U/day) for one week. The insulin- and control-treated mice were then anesthetized with single intraperitoneal injection of propofol (250 mg/kg body weight). Tau phosphorylation and tau protein kinases and phosphatases in the brains of mice 30 min and 2 h after propofol injection were then investigated by using Western blots and immunohistochemistry. Results: Propofol strongly promoted hyperphosphorylation of tau at several AD-related phosphorylation sites. Intranasal administration of insulin attenuated propofol-induced hyperphosphorylation of tau, promoted brain insulin signaling, and led to up-regulation of protein phosphatase 2A, a major tau phosphatase in the brain. Intranasal insulin also resulted in down-regulation of several tau protein kinases, including cyclin-dependent protein kinase 5, calcium/calmodulin-dependent protein kinase II, and c-Jun N-terminal kinase. Conclusion: Our results demonstrate that pretreatment with intranasal insulin prevents AD-like tau hyperphosphorylation. These findings provide the first evidence supporting that intranasal insulin administration might be used for the prevention of anesthesia-induced cognitive decline and increased risk for AD and dementia. PMID:24910612

  2. Protection of mice from rabies by intranasal immunization with inactivated rabies virus.

    PubMed

    Yoneda, Atsushi; Tuchiya, Kotaro; Takashima, Yasuhiro; Arakawa, Takeshi; Tsuji, Naotoshi; Hayashi, Yoshihiro; Matsumoto, Yasunobu

    2008-01-01

    The mucosal immunization method is a needle-free alternative way of vaccination. This study evaluated the efficacy of mucosal immunization for rabies. Mice were intranasally administered five times with inactivated and concentrated rabies virus antigen (CRV) supplemented with or without cholera toxin (CT). The anti-rabies virus antibody titer of mice intranasally immunized with CRV plus CT (CRV/CT) was comparable to that of mice intraperitoneally immunized twice with the same amount of CRV. Virus neutralizing (VNA) titers of mice immunized intranasally with CRV/CT were slightly lower than those of intraperitoneally immunized mice. Both anti-rabies virus ELISA antibody and VNA titers of mice immunized with CRV without CT were significantly lower than those of mice immunized with CRV/CT. In mice intranasally immunized with CRV/CT, and intraperitoneally immunized mice, high levels of IgG(2a) antibody were detected, suggesting the activation of Th1-driven cellular immunity by the two ways of immunization. All immunized mice were challenged intracerebrally with a lethal dose of virulent rabies virus CVS strain. The survival rates of mice immunized with CRV/CT and CRV without CT were 67% and 17%, respectively, while the rate of intraperitoneally immunized mice was 100%. Antigen-specific whole IgG and IgG(2a), and VNA titers of survived mice were significantly higher than those of dead mice at the challenge day. These data suggest the possibility of intranasal immunization with inactivated antigen as a rabies vaccination strategy and the importance of a mucosal adjuvant such as CT. PMID:18256513

  3. Intranasal steroids: managing allergic rhinitis and tailoring treatment to patient preference.

    PubMed

    Meltzer, Eli O

    2005-01-01

    Allergic rhinitis (AR) can have a significant impact on patient quality of life (QoL), affecting learning ability and work productivity. Both the consequences of the impairment and the costs of treatment are associated with a large economic burden. The management of AR includes allergen avoidance, pharmacotherapy, and immunotherapy. Current pharmacotherapy options are oral and intranasal antihistamines, intranasal corticosteroids (INS), intranasal chromones, oral and intranasal decongestants, oral and intranasal anticholinergic agents, and antileukotrienes. A number of guidelines recommend INS as first-line treatment for persistent and moderate-to-severe AR. Although both patient and physician concern over the long-term safety of oral systemic steroids has previously prevented widespread use of INS, it is important to note that they have a superior risk/benefit ratio compared with other monotherapies. Indeed, the limited systemic bioavailability of INS agents, when used at recommended doses, has resulted in very low rates of systemic adverse effects, as shown by a lack of either hypothalamic-pituitary-adrenal axis or growth suppression. Large, controlled clinical studies have shown comparable efficacy and safety among the newer INS; therefore, clinicians may need to consider other factors, such as good patient compliance, when selecting an appropriate INS agent for a patient. In addition, patients often prefer one agent over another, and compliance may be improved by selecting the preferred agent. The development of two new questionnaires, the Clinical Practice Patient Preference Questionnaire and the Clinical Trial Patient Preference Questionnaire, may prove useful in selecting the optimal treatment regimen for patients. PMID:16541967

  4. Intranasal vaccination with adjuvant-free S. aureus antigens effectively protects mice against experimental sepsis.

    PubMed

    Stegmiller, Nataly Pescinalli; Barcelos, Estevão Carlos; Leal, Janine Miranda; Covre, Luciana Polaco; Donatele, Dirlei Molinari; de Matos Guedes, Herbet Leonel; Cunegundes, Marco Cesar; Rodrigues, Rodrigo Ribeiro; Gomes, Daniel Cláudio Oliviera

    2016-06-24

    Staphylococcus aureus (S. aureus) is a Gram-positive coccal bacterium comprising part of the human skin, nares and gastrointestinal tract normal microbiota. It is also an important cause of nosocomial/community-acquired infections in humans and animals, which can cause a diverse array of infections, including sepsis, which is a progressive systemic inflammation response syndrome that is frequently fatal. The emergence of drug-resistant strains and the high toxicity of the treatments used for these infections point out the need to develop an effective, inexpensive and safe vaccine that can be used prophylactically. In this work, we used an experimental sepsis model to evaluate the effectiveness of whole antigens from S. aureus (SaAg) given by the intranasal route to induce protective immunity against S. aureus infection in mice. BALB/c mice were vaccinated via intranasal or intramuscular route with two doses of SaAg, followed by biocompatibility and immunogenicity evaluations. Vaccinated animals did not show any adverse effects associated with the vaccine, as determined by transaminase and creatinine measurements. Intranasal, but not intramuscular vaccination with SaAg led to a significant reduction in IL-10 production and was associated with increased level of IFN-γ and NO. SaAg intranasal vaccination was able to prime cellular and humoral immune responses and inducing a higher proliferation index and increased production of specific IgG1/IgG2, which contributed to decrease the bacterial load in both liver and the spleen and improve survival during sepsis. These findings present the first evidence of the effectiveness of whole Ag intranasal-based vaccine administration, which expands the vaccination possibilities against S. aureus infection. PMID:27091687

  5. Intranasal Corticosteroids in Management of Acute Sinusitis: A Systematic Review and Meta-Analysis

    PubMed Central

    Hayward, Gail; Heneghan, Carl; Perera, Rafael; Thompson, Matthew

    2012-01-01

    PURPOSE Acute sinusitis is a common condition in ambulatory care, where it is frequently treated with antibiotics, despite little evidence of their benefit. Intranasal corticosteroids might relieve symptoms; however, evidence for this benefit is currently unclear. We performed a systematic review and meta-analysis of the effects of intranasal corticosteroids on the symptoms of acute sinusitis. METHODS We searched MEDLINE, EMBASE, the Cochrane Central register of Controlled Trials (CENTRAL), and Centre for Reviews and Dissemination databases until February 2011 for studies comparing intranasal corticosteroids with placebo in children or adults having clinical symptoms and signs of acute sinusitis or rhinosinusitis in ambulatory settings. We excluded chronic/allergic sinusitis. Two authors independently extracted data and assessed the studies’ methodologic quality. RESULTS We included 6 studies having a total of 2,495 patients. In 5 studies, antibiotics were prescribed in addition to corticosteroids or placebo. Intranasal corticosteroids resulted in a significant, small increase in resolution of or improvement in symptoms at days 14 to 21 (risk difference [RD] = 0.08; 95% CI, 0.03–0.13). Analysis of individual symptom scores revealed most consistently significant benefits for facial pain and congestion. Subgroup analysis by time of reported outcomes showed a significant beneficial effect at 21 days (RD = 0.11; 95% CI, 0.06–0.17), but not at 14 to 15 days (RD = 0.05; 95% CI, −0.01 to 0.11). Meta-regression analysis of trials using different doses of mometasone furoate showed a significant dose-response relationship (P=.02). CONCLUSIONS Intranasal corticosteroids offer a small therapeutic benefit in acute sinusitis, which may be greater with high doses and with courses of 21 days’ duration. Further trials are needed in antibiotic-naïve patients. PMID:22585889

  6. OUTCOME OF DOGS WITH INTRANASAL LYMPHOMA TREATED WITH VARIOUS RADIATION AND CHEMOTHERAPY PROTOCOLS: 24 CASES.

    PubMed

    George, Rebecca; Smith, Annette; Schleis, Stephanie; Brawner, William; Almond, Gregory; Kent, Michael; Wypij, Jackie; Borrego, Juan; Moore, Antony; Keyerleber, Michele; Kraiza, Sarah

    2016-05-01

    Tumors of the nasal cavity comprise approximately 1% of all neoplasms in dogs. Canine intranasal lymphoma is rare and reports evaluating the outcome of treatment are lacking. The goal of this observational, descriptive, multi-institutional study was to evaluate the overall median survival times (MSTs) in a group of dogs with intranasal lymphoma that were treated with irradiation and/or chemotherapy. Dogs meeting these inclusion criteria were retrospectively recruited from medical archives at multiple institutions. Eighteen cases of intermediate to high grade intranasal lymphoma and six cases of low-grade intranasal lymphoma were identified. The date of diagnosis, method of diagnosis, treatment received (radiation and/or chemotherapy protocols), and date of death were recorded. Kaplan-Meier survival analysis was performed on the intermediate to high grade group to calculate overall MST. Log-rank tests were performed to compare effects of treatment with radiation therapy ± chemotherapy and chemotherapy alone. Kaplan-Meier survival analysis was performed separately on the low-grade group. The overall MST was 375 days for the intermediate to high grade group. Cases treated with radiation ± chemotherapy had an MST of 455 days (n = 12) and those treated with chemotherapy alone (n = 6) had an MST of 157 days in the intermediate to high grade group. The MST was 823 days for the low-grade group. Results support the use of radiation therapy for treatment of canine intranasal lymphoma, however a randomized, controlled, clinical trial would be needed for more definitive recommendations. The role of adjunctive chemotherapy also may require further investigation. PMID:26763938

  7. Effect of intranasal rosiglitazone on airway inflammation and remodeling in a murine model of chronic asthma

    PubMed Central

    Lee, Hwa Young; Rhee, Chin Kook; Kang, Ji Young; Park, Chan Kwon; Lee, Sook Young; Kwon, Soon Suk; Kim, Young Kyoon; Yoon, Hyoung Kyu

    2016-01-01

    Background/Aims: Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. Methods: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. Results: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and NF-κB. Conclusions: These results suggest that intranasal administration of rosiglitazone can prevent not only air way inf lammation but also air way remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and NF-κB pathways. PMID:26767862

  8. Long-term exposure to intranasal oxytocin in a mouse autism model.

    PubMed

    Bales, K L; Solomon, M; Jacob, S; Crawley, J N; Silverman, J L; Larke, R H; Sahagun, E; Puhger, K R; Pride, M C; Mendoza, S P

    2014-01-01

    Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT. PMID:25386957

  9. Exacerbation of Influenza Virus Infections in Mice by Intranasal Treatments and Implications for Evaluation of Antiviral Drugs

    PubMed Central

    von Itzstein, Mark; Bhatt, Beenu; Tarbet, E. Bart

    2012-01-01

    Compounds lacking oral activity may be delivered intranasally to treat influenza virus infections in mice. However, intranasal treatments greatly enhance the virulence of such virus infections. This can be partially compensated for by giving reduced virus challenge doses. These can be 100- to 1,000-fold lower than infections without such treatment and still cause equivalent mortality. We found that intranasal liquid treatments facilitate virus production (probably through enhanced virus spread) and that lung pneumonia was delayed by only 2 days relative to a 1,000-fold higher virus challenge dose not accompanied by intranasal treatments. In one study, zanamivir was 90 to 100% effective at 10 mg/kg/day by oral, intraperitoneal, and intramuscular routes against influenza A/California/04/2009 (H1N1) virus in mice. However, the same compound administered intranasally at 20 mg/kg/day for 5 days gave no protection from death although the time to death was significantly delayed. A related compound, Neu5Ac2en (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid), was ineffective at 100 mg/kg/day. Intranasal zanamivir and Neu5Ac2en were 70 to 100% protective against influenza A/NWS/33 (H1N1) virus infections at 0.1 to 10 and 30 to 100 mg/kg/day, respectively. Somewhat more difficult to treat was A/Victoria/3/75 virus that required 10 mg/kg/day of zanamivir to achieve full protection. These results illustrate that treatment of influenza virus infections by the intranasal route requires consideration of both virus challenge dose and virus strain in order to avoid compromising the effectiveness of a potentially useful antiviral agent. In addition, the intranasal treatments were shown to facilitate virus replication and promote lung pathology. PMID:23027194

  10. Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind, Cross-Over Study

    PubMed Central

    Daughters, Katie; Manstead, Antony S. R.; Hubble, Kelly; Rees, Aled; Thapar, Anita; van Goozen, Stephanie H. M.

    2015-01-01

    The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration ‘wait-time’ prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups. PMID:26669935

  11. Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind, Cross-Over Study.

    PubMed

    Daughters, Katie; Manstead, Antony S R; Hubble, Kelly; Rees, Aled; Thapar, Anita; van Goozen, Stephanie H M

    2015-01-01

    The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration 'wait-time' prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups. PMID:26669935

  12. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic. PMID:25432887

  13. Characterization and treatment of postsurgical dental implant pain employing intranasal ketorolac.

    PubMed

    Bockow, Rebecca; Korostoff, Jonathan; Pinto, Andres; Hutcheson, Matthew; Secreto, Stacey A; Bodner, Laura; Hersh, Elliot V

    2013-09-01

    The intensity and duration of pain following surgical placement of dental implants has not been well studied. Thus, the aim of this open-label study was to characterize the nature of postsurgical pain following the placement of one to three implants. The secondary goal was to explore the analgesic efficacy and tolerability of intranasal ketorolac in this patient population. Following implant surgery, postoperative pain was rated moderate or severe in 25/28 patients (89 percent), requiring prn analgesic dosing for up to 3 days in 14/25 individuals (56 percent). Intranasal ketorolac displayed an analgesic onset within 20 minutes, a duration of at least 6 hours, and was well tolerated by the cohort with brief stinging of the nasal mucosa reported by 9/25 individuals (36 percent). PMID:24564610

  14. Surgical and Localized Radiation Therapy for an Intranasal Adenocarcinoma in a Rabbit

    PubMed Central

    NAKATA, Makoto; MIWA, Yasutsugu; TSUBOI, Masaya; UCHIDA, Kazuyuki

    2014-01-01

    An 8-year-old spayed female Netherland Dwarf rabbit presented with a two-month history of dyspnea and snoring. A computed tomography (CT) scan of the head revealed mass lesions in the right nasal cavity. Surgical exenteration of the lesions was performed, and the histopathological diagnosis was an intranasal adenocarcinoma. On the basis of this diagnosis, radiotherapy was planned and consisted of eight fractions of 6 Gy administered once a week. After the completion of radiation therapy, the soft tissue density in the right nasal cavity, as detected by CT, significantly decreased. The prognosis has remained good for over 3 years after treatment. This paper is the first to describe the clinical and pathological features of an intranasal tumor in a rabbit. PMID:25649953

  15. Chitosan and cyclodextrin in intranasal microemulsion for improved brain buspirone hydrochloride pharmacokinetics in rats.

    PubMed

    Bshara, Hamza; Osman, Rihab; Mansour, Samar; El-Shamy, Abd El-Hameed A

    2014-01-01

    The aim of this study was to develop buspirone hydrochloride microemulsion formulations for intranasal administration to improve the drug bioavailability and provide high drug brain levels. For the purpose, chitosan aspartate, and hydroxypropyl-β-cyclodextrin were incorporated in the microemulsions. The prepared formulations were characterized. Biological investigations including pharmacokinetic studies, brain drug targeting efficiency determinations and histopathological examinations were performed on rats. The results showed that safe and stable mucoadhesive microemulsion suitable for nasal administration were successfully prepared. Ex vivo drug permeation revealed high drug permeation from microemulsions. Absolute bioavailability after intranasal administration of buspirone mucoadhesive microemulsion increased significantly and plasma concentration peaked at 15 min. The AUC0-360(brain) was 3 times that obtained after intravenous administration. A high brain targeting efficiency (86.6%) and a direct nose to brain transport (88%) confirmed the direct nose to brain transport of buspirone following nasal administration of the microemulsions. PMID:24274510

  16. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice

    PubMed Central

    Zhang, Yongli; Dai, Chun-ling; Chen, Yanxing; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2016-01-01

    Elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer’s disease (AD). At present, there is no treatment that can prevent anesthesia-induced postoperative cognitive dysfunction. Here, we treated mice with daily intranasal administration of insulin (1.75 U/day) for one week before anesthesia induced by intraperitoneal injection of propofol and maintained by inhalation of sevoflurane for 1 hr. We found that the insulin treatment prevented anesthesia-induced deficit in spatial learning and memory, as measured by Morris water maze task during 1–5 days after exposure to anesthesia. The insulin treatment also attenuated anesthesia-induced hyperphosphorylation of tau and promoted the expression of synaptic proteins and insulin signaling in the brain. These findings show a therapeutic potential of intranasal administration of insulin before surgery to reduce the risk of anesthesia-induced cognitive decline and AD. PMID:26879001

  17. Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

    PubMed

    Katare, Yogesh K; Daya, Ritesh P; Sookram Gray, Christal; Luckham, Roger E; Bhandari, Jayant; Chauhan, Abhay S; Mishra, Ram K

    2015-09-01

    Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain. PMID:26226403

  18. A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

    PubMed Central

    Lapidus, Kyle A.B.; Levitch, Cara F.; Perez, Andrew M.; Brallier, Jess W.; Parides, Michael K.; Soleimani, Laili; Feder, Adriana; Iosifescu, Dan V.; Charney, Dennis S.; Murrough, James W.

    2014-01-01

    Background The N-methyl-d-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods Twenty patients with major depression were randomized and 18 completed two treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution in a randomized, double-blind, crossover study. The primary efficacy outcome measure was change in depression severity 24 hours following ketamine or placebo, measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours following ketamine compared to placebo [t=4.39, p<0.001; estimated mean MADRS score difference of 7.6 ± 3.7 (95% CI: 3.9 – 11.3)]. Eight of 18 patients (44%) met response criteria 24 hours following ketamine administration, compared to 1 of 18 (6%) following placebo (p=0.033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression. Trial Registration clinicaltrials.gov identifier NCT01304147 PMID:24821196

  19. The reinforcing and subjective effects of intravenous and intranasal buprenorphine in heroin users.

    PubMed

    Jones, Jermaine D; Madera, Gabriela; Comer, Sandra D

    2014-07-01

    Abuse of buprenorphine (BUP) by the intravenous (IV) route has been documented in several studies, and reports of intranasal (IN) abuse are increasing. However, no studies have directly compared the effects of BUP when it is administered intranasally and intravenously. The present secondary analysis used data from two separate studies to compare the reinforcing and subjective effects of IV and IN buprenorphine. One study evaluated IV buprenorphine (N=13) and the other evaluated IN buprenorphine (N=12). Participants were maintained on 2 mg sublingual (SL) BUP and tested with each intranasal or intravenous buprenorphine test dose (0 mg, 2 mg, 4 mg, 8 mg, and 16 mg). During morning laboratory sessions, participants received money (US $20) and sample doses of IN or IV BUP, and then completed subjective effects questionnaires. Later that day, they completed a self-administration task to receive 10% portions of the drug and/or money they previously sampled. In general, positive subjective ratings for both IV and IN BUP were significantly greater than placebo, with IV BUP having a greater effect than IN BUP. All active BUP doses (IV and IN) maintained significantly higher progressive ratio breakpoint values than placebo, but breakpoint values for IV BUP were greater than for IN BUP. Buprenorphine is an effective maintenance treatment for opioid dependence, valued for its ability to reduce the positive subjective effects of other opioids. Nevertheless, the present data demonstrate that in participants maintained on a low dose of SL BUP, the medication itself has abuse liability when used intravenously or intranasally. PMID:24793093

  20. Prehospital intranasal evaporative cooling for out-of-hospital cardiac arrest: a pilot, feasibility study.

    PubMed

    Lyon, Richard M; Van Antwerp, Jerry; Henderson, Charles; Weaver, Anne; Davies, Gareth; Lockey, David

    2014-10-01

    Intranasal evaporative cooling presents a novel means of initiating therapeutic hypothermia after an out-of-hospital cardiac arrest (OHCA). Few studies have evaluated the use of intranasal therapeutic hypothermia using the Rhinochill device in the prehospital setting. We sought to evaluate the use of Rhinochill in the Physician Response Unit of London's Air Ambulance, aiming to describe the feasibility of employing it during prehospital resuscitation for OHCA. We prospectively evaluated the Rhinochill device over a 7-month period. Inclusion criteria for deployment included: age above 18 years, Physician Response Unit on-scene within maximum of 10 min after return-of-spontaneous circulation (ROSC), witnessed OHCA or unwitnessed downtime of less than 10 min, pregnancy not suspected, normal nasal anatomy, and likely ICU candidate if ROSC were to be achieved. Thirteen patients were included in the evaluation. The average time from the 999 call to initiation of cooling was 39.5 min (range 22-61 min). The average prehospital temperature change in patients who achieved ROSC was -1.9°C. Patients were cooled for an average of 38 min prehospital. In all cases, the doctor and paramedic involved with the resuscitation reported that the Rhinochill was easy to set up and use during resuscitation and that it did not interfere with standard resuscitation practice. Intranasal evaporative cooling using the Rhinochill system is feasible in an urban, prehospital, doctor/paramedic response unit. Cooling with Rhinochill was not found to interfere with prehospital resuscitation and resulted in significant core body temperature reduction. Further research on the potential benefit of intra-arrest and early initiation of intranasal evaporative cooling is warranted. PMID:24300245

  1. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine

    PubMed Central

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID:26954254

  2. Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance

    PubMed Central

    Lile, Joshua A.; Stoops, William W.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

    2015-01-01

    Background Medications development for methamphetamine dependence is ongoing, but no widely accepted, effective pharmacotherapy has been identified. Previous studies have demonstrated neurobiological perturbations to central GABAA activity following chronic stimulant use, and that positive modulation of GABAA receptors attenuates the neurochemical and behavioral response to stimulant drugs such as methamphetamine. Therefore, GABAA modulators could be useful as pharmacotherapies for stimulant-use disorders. Methods This study tested the hypothesis that intranasal methamphetamine would be safe and well tolerated during maintenance on extended-release alprazolam (XR), and that the effects of methamphetamine would be attenuated. Eight non-treatment-seeking, stimulant-dependent individuals completed an inpatient experiment in which ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) were administered after four days of alprazolam XR maintenance (0 and 1 mg/day). Results Intranasal methamphetamine produced prototypical effects (e.g., increased positive subjective ratings and elevated cardiovascular signs). The combination of intranasal methamphetamine and alprazolam XR was safe and well tolerated. Alprazolam XR produced small, but orderly, reductions in some of the subjective effects of methamphetamine, and performance impairment. Conclusions The present results demonstrate that methamphetamine use during alprazolam XR treatment would not pose a significant safety risk. Given the potential of GABAA positive modulators to manage certain aspects of stimulant abuse and dependence (i.e., drug-induced seizures, anxiety and stress), but the relatively small impact on the acute abuse-related effects of methamphetamine observed here, additional research with GABAA positive modulators is warranted, but should consider their use as an adjunct component of combination behavioral and/or drug treatment. PMID:21737214

  3. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine.

    PubMed

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID:26954254

  4. Chemoprevention of lung tumorigenesis by intranasally administered diindolylmethane in A/J mice

    PubMed Central

    Kassie, Fekadu

    2013-01-01

    The main reasons for the failure of most chemopreventive agents during clinical trials are poor in vivo bioavailability and dose-limiting side effects. One potential approach to surmount these problems in lung cancer chemoprevention trials could be direct delivery of agents into the pulmonary tissue. In this study, we assessed the efficacy of intranasally delivered bio-response diindolylmethane (BRD) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in mice. Mice treated with NNK (two doses of 50mg/kg at an interval of a week, intraperitoneal) developed 16.3±2.9 lung tumors per mouse. Post-carcinogen administration of BRD, via intranasal instillation, for 24 weeks, twice a week, at a dose of 2mg per mouse (0.6mg pure diindolylmethane per mouse) reduced the lung tumor multiplicity to 4.6±2.2 tumors per mouse (72% reduction). Likewise, large tumors (>1mm) were almost completely abolished and multiplicities of tumors with a size of 0.5–1mm were reduced by 74%. Tumor volume was also reduced by 82%. Further studies using an in vitro model of lung tumorigenesis showed that BRD exhibited pronounced antiproliferative and apoptotic effects in premalignant and malignant bronchial cells but only minimal effects in parental immortalized cells through, at least in part, suppression of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. These results showed the potent lung tumor inhibitory activities of low doses of BRD given via intranasal instillation and, therefore, intranasal delivery of BRD holds a great promise for lung cancer chemoprevention in subjects at high risk to develop lung cancer. PMID:23239747

  5. Awareness and Attitudes Toward Intranasal Naloxone Rescue for Opioid Overdose Prevention.

    PubMed

    Kirane, Harshal; Ketteringham, Michael; Bereket, Sewit; Dima, Richie; Basta, Ann; Mendoza, Sonia; Hansen, Helena

    2016-10-01

    Opioid overdose prevention is a pressing public health concern and intranasal naloxone rescue kits are a useful tool in preventing fatal overdose. We evaluated the attitudes, knowledge, and experiences of patients and providers related to overdose and naloxone rescue. Over a six month period, patients and providers within a large community hospital in Staten Island were recruited to complete tailored questionnaires for their respective groupings. 100 patients and 101 providers completed questionnaires between August, 2014 and January, 2015. Patient participants were primarily Caucasian males with a mean age of 37.7 years, of which 65% accurately identified naloxone for opioid overdose, but only 21% knew more specific clinical features. 68% of patients had previously witnessed a drug overdose. Notably, 58% of patients anticipated their behavior would change if provided access to an intranasal naloxone rescue kit, of which 83% predicted an increase in opioid use. Prior overdose was significantly correlated with anticipating no change in subsequent opioid use pattern (p=0.02). 99% of patients reported that their rapport with their health-care provider would be enhanced if offered an intranasal naloxone rescue kit. As for providers, 24% had completed naloxone rescue kit training, and 96% were able to properly identify its clinical application. 50% of providers felt naloxone access would decrease the likelihood of an overdose occurring, and 58% felt it would not contribute to high-risk behavior. Among providers, completion of naloxone training was correlated with increased awareness of where to access kits for patients (p<0.001). This study suggests that patients and providers have distinct beliefs and attitudes toward overdose prevention. Patient-Provider discussion of overdose prevention enhances patients' rapport with providers. However, access to an intranasal naloxone rescue kit may make some patients more vulnerable to high-risk behavior. Future research efforts

  6. Intranasal oxytocin administration is associated with enhanced endogenous pain inhibition and reduced negative mood states

    PubMed Central

    Goodin, Burel R.; Anderson, Austen J. B.; Freeman, Emily L.; Bulls, Hailey W.; Robbins, Meredith T.; Ness, Timothy J.

    2014-01-01

    Objectives This study examined whether the administration of intranasal oxytocin was associated with pain sensitivity, endogenous pain inhibitory capacity, and negative mood states. Methods A total of 30 pain-free, young adults each completed three laboratory sessions on consecutive days. The first session (baseline) assessed ischemic pain sensitivity, endogenous pain inhibition via conditioned pain modulation (CPM), and negative mood using the Profile of Mood States (POMS). CPM was tested on the dominant forearm and ipsilateral masseter muscle using algometry (test stimulus) and the cold pressor task (conditioning stimulus; non-dominant hand). For the second and third sessions, participants initially completed the State-Trait Anxiety Inventory (STAI) and then self-administered a single (40IU/1mL) dose of intranasal oxytocin or placebo in a randomized counter-balanced order. Thirty minutes post-administration, participants again completed the STAI and repeated assessments of ischemic pain sensitivity and CPM followed by the POMS. Results Findings demonstrated that ischemic pain sensitivity did not significantly differ across the three study sessions. CPM at the masseter, but not the forearm, was significantly greater following administration of oxytocin compared to placebo. Negative mood was also significantly lower following administration of oxytocin compared to placebo. Similarly, anxiety significantly decreased following administration of oxytocin but not placebo. Discussion This study incorporated a placebo-controlled, double-blind, within-subjects crossover design with randomized administration of intranasal oxytocin and placebo. The data suggest that the administration of intranasal oxytocin may augment endogenous pain inhibitory capacity and reduce negative mood states including anxiety. PMID:25370147

  7. Treatment of renal colic by desmopressin intranasal spray and diclofenac sodium.

    PubMed

    el-Sherif, A E; Salem, M; Yahia, H; al-Sharkawy, W A; al-Sayrafi, M

    1995-05-01

    The vasopressin analogue, 1-desamino-8-arginine vasopressin (desmopressin), is a potent antidiuretic without the pressor effects of vasopressin. A total of 18 patients with acute renal colic due to stone disease received 40 microgramsf1p4mopressin intranasal spray with encouraging results. There was a significant decrease in the colic pain intensity from an initial mean visual analogue score of 67 +/- 17 mm. to 39 +/- 36 mm. within 30 minutes (p < 0.001). Eight patients (44.4%) had complete pain relief within 30 minutes of administering intranasal desmopressin spray. Nine of 10 patients who required intramuscular diclofenac sodium achieved complete pain relief within another 30 minutes. In other words, when intranasal desmopressin spray was administered before diclofenac sodium, 94.4% of the patients achieved complete pain relief and were discharged home. The mechanism of analgesic action of desmopressin in renal colic is uncertain. At the peripheral level, desmopressin may alleviate the acute renal colic through its potent antidiuretic effect or by relaxing the renal pelvic and ureteral smooth muscles. The central analgesic effect of desmopressin by stimulating the release of the hypothalamic beta-endorphin is proposed. We conclude that intranasal desmopressin spray can be used successfully in the treatment of renal colic. It may also replace prostaglandin synthetase inhibitors in treating renal colic with the advantage of avoiding the potential side effects. Further studies are needed to investigate whether the combination of desmopressin with analgesics or spasmolytic drugs offers competitive results compared with those achieved by prostaglandin synthetase inhibitors in the treatment of renal colic. PMID:7714949

  8. Chitosan coated nanostructured lipid carriers for brain delivery of proteins by intranasal administration.

    PubMed

    Gartziandia, Oihane; Herran, Enara; Pedraz, Jose Luis; Carro, Eva; Igartua, Manoli; Hernandez, Rosa Maria

    2015-10-01

    The remarkable increase in the prevalence of neurodegenerative diseases has become a serious public health problem. Considering the lack of effective treatments to address these diseases and the difficulties in accessing the brain due to the blood-brain barrier (BBB), to attain a successful strategy to improve drug delivery to the brain, the administration route becomes a point of interest. The intranasal route provides a non-invasive method to bypass the BBB. Moreover, the development of new technologies for the protection and delivery of peptides is an interesting approach to consider. Thus, in this work, a suitable chitosan coated nanostructured lipid carrier (CS-NLC) formulation with the capacity to reach the brain after being intranasally administered was successfully developed and optimized. The optimal formulation displayed a particle size of 114 nm with a positive surface charge of +28 mV. The in vitro assays demonstrated the biocompatibility of the nanocarrier and its cellular uptake by 16HBE14o- cells. Furthermore, no haemagglutination or haemolysis processes were observed when the particles were incubated with erythrocytes, and no toxicity signals appeared in the nasal mucosa of mice after the administration of CS-NLCs. Finally, the biodistribution study of CS-NLC-DiR demonstrated an efficient brain delivery of the particles after intranasal administration. In conclusion, CS-NLC can be considered to be a safe and effective nanocarrier for nose-to-brain drug delivery; however, to obtain a higher concentration of the drug in the brain following intranasal administration, further modifications are warranted in the CS-NLC formulation. PMID:26209963

  9. Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging.

    PubMed

    Maimaiti, Shaniya; Anderson, Katie L; DeMoll, Chris; Brewer, Lawrence D; Rauh, Benjamin A; Gant, John C; Blalock, Eric M; Porter, Nada M; Thibault, Olivier

    2016-01-01

    Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca(2+)-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP. PMID:25659889

  10. Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route

    PubMed Central

    Pathak, Rudree; Prasad Dash, Ranjeet; Misra, Manju; Nivsarkar, Manish

    2014-01-01

    Intranasal drug administration is receiving increased attention as a delivery method for bypassing the blood–brain barrier and rapidly targeting therapeutics to the CNS. However, rapid mucociliary clearance in the nasal cavity is a major hurdle. The purpose of this study was to evaluate the effect of mucoadhesive polymers in enhancing the delivery of nimodipine microemulsion to the brain via the intranasal route. The optimized mucoadhesive microemulsion was characterized, and the in vitro drug release and in vivo nasal absorption of drug from the new formulation were evaluated in rats. The optimized formulation consisted of Capmul MCM as oil, Labrasol as surfactant, and Transcutol P as co-surfactant, with a particle size of 250 nm and zeta potential value of −15 mV. In vitro and ex vivo permeation studies showed an initial burst of drug release at 30 min and sustained release up to 6 h, attributable to the presence of free drug entrapped in the mucoadhesive layer. In vivo pharmacokinetic studies in rats showed that the use of the mucoadhesive microemulsion enhanced brain and plasma concentrations of nimodipine. These results suggest that incorporation of a mucoadhesive agent in a microemulsion intranasal delivery system can increase the retention time of the formulation and enhance brain delivery of drugs. PMID:26579378

  11. Attenuation of histamine-induced airway effects by intranasal application of levocetirizine in mice.

    PubMed

    Kitayama-Sugiyama, Chie; Mochizuki, Naoko; Murata, Hitomi; Katsura, Masashi; Kamei, Chiaki

    2013-10-01

    The present study was performed to investigate the histamine-induced airway effect of levocetirizine, an active enantiomer of cetirizine, by intranasal application using ddY mice. Nasal rubbing and sneezing after histamine application into the nasal cavity were used as an index of histamine-induced airway effect in mice. Intranasal application of levocetirizine inhibited both nasal rubbing and sneezing concentration-dependently, and the ED50 values were 0.62 (0.51-0.77) and 0.70 (0.51-1.02) %/site for nasal rubbing and sneezing, respectively. ED50 values of cetirizine were 1.24 (1.02-1.59) and 1.35 (1.02-2.08) %/site for nasal rubbing and sneezing, respectively. Levocetirizine also inhibited nasal rubbing and sneezing when administered orally. These results clearly indicate that levocetirizine was about two times more potent than cetirizine by intranasal application, similar to the findings of the former's affinity for human histamine H1 receptors. In addition, the present findings raise the expectation of the development of levocetirizine nasal drops. PMID:23855419

  12. Preparation, characterization, and in vivo evaluation of intranasally administered liposomal formulation of donepezil.

    PubMed

    Al Asmari, Abdulrahman K; Ullah, Zabih; Tariq, Mohammad; Fatani, Amal

    2016-01-01

    The adequate amount of drug delivery to the brain in neurological patients is a major problem faced by the physicians. Recent studies suggested that intranasal administration of liposomal formulation may improve the drug delivery to the brain. In the present study, an attempt was made to study the brain bioavailability of commonly used anti-Alzheimer drug donepezil (DNP) liposomal formulation by intranasal route in rats. We adopted the thin layer hydration technique for the preparation of liposomes by using cholesterol, polyethylene glycol, and 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). The prepared liposomes were characterized by determining particle size, shape, surface morphology, zeta potential, encapsulation efficiency, and in vitro release of DNP. The pharmacokinetic parameters of liposomal DNP in plasma and brain of rats were determined following oral and nasal administration. The results of this study showed that the DNP liposomal formulation was stable with a consistent size (102 ± 3.3 nm) and shape. The prepared liposomes showed high encapsulation efficiency (84.91% ±3 .31%) and sustained-release behavior. The bioavailability of DNP in plasma and brain increased significantly (P<0.05) after administration of liposomal formulation by the intranasal route. Histopathological examination showed that the formulation was safe and free from toxicity. It can be concluded that the nasal administration of liposomal preparation may provide an efficient and reliable mode of drug delivery to the central nervous system. PMID:26834457

  13. Intranasal Flu Vaccine Protective against Seasonal and H5N1 Avian Influenza Infections

    PubMed Central

    Alsharifi, Mohammed; Lobigs, Mario; Koskinen, Aulikki; Regner, Matthias; Trinidad, Lee; Boyle, David B.; Müllbacher, Arno

    2009-01-01

    Background Influenza A (flu) virus causes significant morbidity and mortality worldwide, and current vaccines require annual updating to protect against the rapidly arising antigenic variations due to antigenic shift and drift. In fact, current subunit or split flu vaccines rely exclusively on antibody responses for protection and do not induce cytotoxic T (Tc) cell responses, which are broadly cross-reactive between virus strains. We have previously reported that γ-ray inactivated flu virus can induce cross-reactive Tc cell responses. Methodology/Principal Finding Here, we report that intranasal administration of purified γ-ray inactivated human influenza A virus preparations (γ-Flu) effectively induces heterotypic and cross-protective immunity. A single intranasal administration of γ-A/PR8[H1N1] protects mice against lethal H5N1 and other heterotypic infections. Conclusions/Significance Intranasal γ-Flu represents a unique approach for a cross-protective vaccine against both seasonal as well as possible future pandemic influenza A virus infections. PMID:19401775

  14. Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: Role of docosahexaenoic acid.

    PubMed

    Shinde, Rajshree L; Bharkad, Gopal P; Devarajan, Padma V

    2015-10-01

    Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery. PMID:26318978

  15. Intranasal delivery of systemic-acting drugs: small-molecules and biomacromolecules.

    PubMed

    Fortuna, Ana; Alves, Gilberto; Serralheiro, Ana; Sousa, Joana; Falcão, Amílcar

    2014-09-01

    As a non-invasive route, intranasal administration offers patient comfort and compliance which are hurdled in parenteral drug therapy. In addition, the current recognition that the high permeability and vascularization of nasal mucosa coupled to the avoidance of the first-pass elimination and/or gastrointestinal decomposition ensure higher systemic drug absorption than oral route has contributed to the growing interest for intranasal delivery of drugs that require considerable systemic exposure to exert their therapeutic actions (systemic-acting drugs). Nevertheless, several features may hamper drug absorption through the nasal mucosa, particularly the drug molecular weight and intrinsic permeability, and, therefore, several strategies have been employed to improve it, propelling a constant challenge during nasal drug (formulation) development. This review will firstly provide an anatomical, histological and mechanistic overview of drug systemic absorption after nasal administration and the relevant aspects of the therapeutic interest and limitations of the intranasal systemic delivery. The current studies regarding the nasal application of systemic-acting small drugs (analgesic drugs, cardiovascular drugs and antiviral drugs) and biomacromolecular drugs (peptide/protein drugs and vaccines) will also be outlined, addressing drug pharmacokinetics and pharmacodynamic improvements. PMID:24681294

  16. Optimization of artemether-loaded NLC for intranasal delivery using central composite design.

    PubMed

    Jain, Kunal; Sood, Sumeet; Gowthamarajan, Kuppusamy

    2015-01-01

    The objective of the study was to optimize artemether-loaded nanostructured lipid carriers (ARM-NLC) for intranasal delivery using central composite design. ARM-NLC was prepared by microemulsion method with optimized formulation having particle size of 123.4 nm and zeta potential of -34.4 mV. Differential scanning calorimetry and powder X-ray diffraction studies confirmed that drug existed in amorphous form in NLC formulation. In vitro cytotoxicity assay using SVG p12 cell line and nasal histopathological studies on sheep nasal mucosa indicated the developed formulations were non-toxic and safe for intranasal administration. In vitro release studies revealed that NLC showed sustained release up to 96 h. Ex vivo diffusion studies using sheep nasal mucosa revealed that ARM-NLC had significantly lower flux compared to drug solution (ARM-SOL). Pharmacokinetic and brain uptake studies in Wistar rats showed significantly higher drug concentration in brain in animals treated intranasally (i.n.) with ARM-NLC. Brain to blood ratios for ARM-NLC (i.n.), ARM-SOL (i.n.) and ARM-SOL (i.v.) were 2.619, 1.642 and 0.260, respectively, at 0.5 h indicating direct nose to brain transport of ARM. ARM-NLC showed highest drug targeting efficiency and drug transport percentage of 278.16 and 64.02, respectively, which indicates NLC had better brain targeting efficiency compared to drug solution. PMID:24512368

  17. Effects of recombinant IL-17F intranasal inoculation against Streptococcus pneumoniae infection in a murine model.

    PubMed

    Chen, Ling; Guo, Sheng; Wu, Liangxia; Hao, Chunli; Xu, Wanting; Zhang, Jianhua

    2015-01-01

    Interleukin-17F (IL-17F) is an important member of IL-17 cytokine family, which plays important roles in host defense against microbial infections. Streptococcus pneumoniae is a common pathogen associated with several invasive and noninvasive pneumococcal diseases, and mucosal immune response plays crucial roles in defenses against pneumococcal infection. Thus, intranasal inoculation may be an alternative approach against pneumococci. In this study, BALB/c mice were intranasally inoculated with recombinant IL-17F (rIL-17F) prior to S. pneumoniae (American Type Culture Collection 6303, serotype 3) infection. As compared with the control group, numbers of total leukocyte, neutrophil, and macrophage in lungs were significantly increased in mice inoculated with rIL-17F. The levels of macrophage inflammatory protein 1α (MIP-1α), MIP-2β, and interferon γ were significantly increased in bronchoalveolar lavage fluid and culture supernatant of splenocytes from mice inoculated with rIL-17F. rIL-17F inoculation also significantly elevated β-defensin-2 expression in lung tissues. Furthermore, compared with S. pneumoniae infection group, rIL-17F inoculation prior to infection significantly reduced S. pneumoniae colonization in lungs. These findings demonstrated that rIL-17F intranasal inoculation strengthened host defense against pneumococci, which may be developed to prevent pneumococcal infection. PMID:25196250

  18. Probing the interaction induced conformation transitions in acid phosphatase with cobalt ferrite nanoparticles: Relation to inhibition and bio-activity of Chlorella vulgaris acid phosphatase.

    PubMed

    Ahmad, Farooq; Zhou, Xing; Yao, Hongzhou; Zhou, Ying; Xu, Chao

    2016-09-01

    The present study explored the interaction and kinetics of cobalt ferrite nanoparticles (NPs) with acid phosphatase (ACP) by utilizing diverse range of spectroscopic techniques. The results corroborate, the CoFe2O4 NPs cause fluorescence quenching in ACP by static quenching mechanism. The negative values of van't Hoff thermodynamic expressions (ΔH=-0.3293Jmol(-1)K(-1) and ΔG=-3.960kJmol(-1)K(-1)) corroborate the spontaneity and exothermic nature of static quenching. The positive value of ΔS (13.2893Jmol(-1)K(-1)) corroborate that major contributors of higher and stronger binding affinity among CoFe2O4 NPs with ACP were electrostatic. In addition, FTIR, UV-CD, UV-vis spectroscopy and three dimensional fluorescence (3D) techniques confirmed that CoFe2O4 NPs binding induces microenvironment perturbations leading to secondary and tertiary conformation changes in ACP to a great extent. Furthermore, synchronous fluorescence spectroscopy (SFS) affirmed the comparatively significant changes in microenvironment around tryptophan (Trp) residue by CoFe2O4 NPs. The effect of CoFe2O4 NPs on the activation kinetics of ACP was further examined in Chlorella vulgaris. Apparent Michaelis constant (Km) values of 0.57 and 26.5mM with activation energy values of 0.538 and 3.428kJmol(-1) were determined without and with 200μM CoFe2O4 NPs. Apparent Vmax value of -7Umml(-1) corroborate that enzyme active sites were completely captured by the NPs leaving no space for the substrate. The results confirmed that CoFe2O4 NPs ceased the activity by unfolding of ACP enzyme. This suggests CoFe2O4 NPs perturbed the enzyme activity by transitions in conformation and hence the metabolic activity of ACP. This study provides the pavement for novel and simple approach of using sensitive biomarkers for sensing NPs in environment. PMID:27209386

  19. Organ distribution of transgene expression following intranasal mucosal delivery of recombinant replication-defective adenovirus gene transfer vector

    PubMed Central

    Damjanovic, Daniela; Zhang, Xizhong; Mu, Jingyu; Fe Medina, Maria; Xing, Zhou

    2008-01-01

    It is believed that respiratory mucosal immunization triggers more effective immune protection than parenteral immunization against respiratory infection caused by viruses and intracellular bacteria. Such understanding has led to the successful implementation of intranasal immunization in humans with a live cold-adapted flu virus vaccine. Furthermore there has been an interest in developing effective mucosal-deliverable genetic vaccines against other infectious diseases. However, there is a concern that intranasally delivered recombinant viral-based vaccines may disseminate to the CNS via the olfactory tissue. Initial experimental evidence suggests that intranasally delivered recombinant adenoviral gene transfer vector may transport to the olfactory bulb. However, there is a lack of quantitative studies to compare the relative amounts of transgene products in the respiratory tract, lung, olfactory bulb and brain after intranasal mucosal delivery of viral gene transfer vector. To address this issue, we have used fluorescence macroscopic imaging, luciferase quantification and PCR approaches to compare the relative distribution of transgene products or adenoviral gene sequences in the respiratory tract, lung, draining lymph nodes, olfactory bulb, brain and spleen. Intranasal mucosal delivery of replication-defective recombinant adenoviral vector results in gene transfer predominantly in the respiratory system including the lung while it does lead to a moderate level of gene transfer in the olfactory bulb. However, intranasal inoculation of adenoviral vector leads to little or no viral dissemination to the major region of the CNS, the brain. These experimental findings support the efficaciousness of intranasal adenoviral-mediated gene transfer for the purpose of mucosal immunization and suggest that it may not be of significant safety concern. PMID:18261231

  20. Phospholipid micelle encapsulated gadolinium oxide nanoparticles for imaging and gene delivery

    PubMed Central

    Dixit, Suraj; Das, Mahasweta; Alwarappan, Subbiah; Goicochea, Nancy L.; Howell, Mark; Mohapatra, Subhra

    2014-01-01

    We encapsulated gadolinium oxide (Gd2O3) nanoparticles within phospholipid micelles as a novel low cytotoxic T1-weighted MRI imaging contrast agent (MGdNPs) that can also deliver small molecules such as DNA plasmids. MGdNPs show relatively good MRI relaxivity values, negligible cytotoxicity, excellent cellular uptake and expression of DNA plasmids in vivo. Biodistribution studies in mice show that intranasal and intraperitoneal administration of MGdNPs can effectively target specific organs. PMID:24724012

  1. Enhancement in bioavailability of ketorolac tromethamine via intranasal in situ hydrogel based on poloxamer 407 and carrageenan.

    PubMed

    Li, Chenxi; Li, Chunyan; Liu, Zheshuo; Li, Qiuhong; Yan, Xueying; Liu, Yu; Lu, Weiyue

    2014-10-20

    The objective of this study was to construct a new in situ gel system based on the combination of poloxamer 407 and carrageenan (carrageenan-poloxamer 407 hydrogel, CPH) for intranasal delivery of ketorolac tromethamine. CPH showed potassium ion concentration - dependent erosion characteristics which ensured slow erosion in aqueous environment containing potassium ion at the physiological level. Loading with ketorolac tromethamine influenced erosion, drug release and thermosensitive properties of CPH. CPH containing 15% ketorolac tromethamine showed suitable gelation temperature (near 35°C) and in vitro sustained release profiles. Pharmacokinetic study of intranasal CPH containing 15% ketorolac tromethamine in rats demonstrated enhanced absolute bioavailability (68.8 ± 23.3%) and prolonged mean residence time (8.8 ± 3.5h) in comparison with the intranasal solution group (24.8 ± 13.8%, 3.9 ± 0.6h). Nasal ciliotoxicity evaluation on an in situ toad palate model preliminarily showed the safety of CPH for intranasal use. All results suggested the potential of CPH as a new sustained - release platform for the intranasal delivery of ketorolac tromethamine. PMID:25138250

  2. Ancillary therapy of intranasal T-LysYal® for patients with allergic, non-allergic, and mixed rhinitis.

    PubMed

    Gelardi, M; Taliente, S; Fiorella, M L; Quaranta, N; Ciancio, G; Russo, C; Mola, P; Ciofalo, A; Zambetti, G; Caruso Armone, A; Cantone, E; Ciprandi, G

    2016-01-01

    Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction. Non-allergic rhinitis (NAR) is characterized by a non-IgE-mediated pathogenesis. Frequently, patients have the two disorders associated: such as mixed rhinitis (MR). Hyaluronic acid (HA) is a fundamental component of the human connective tissue. HA may exert anti-inflammatory and immune-modulating activities. Recently, an intranasal HA formulation was proposed: a supramolecular system containing lysine hyaluronate, thymine and sodium chloride (T-LysYal®). This randomized study investigated whether intranasal T-LysYal® (rinoLysYal®, Farmigea, Italy) was able to reduce symptom severity, endoscopic features, and nasal cytology in 89 patients (48 males and 41 females, mean age 36.3±7.1 years) with AR, NAR, and MR. Patients were treated with intranasal T-LysYal® or isotonic saline solution as adjunctive therapy to nasal corticosteroid and oral antihistamine for 4 weeks. Patients were visited at baseline, after treatment and after 4-week follow-up. Intranasal T-LysYal® treatment significantly reduced the quote of patients with symptoms, endoscopic features, and inflammatory cells. In conclusion, the present study demonstrates that intranasal T-LysYal® is able, as ancillary therapy, to significantly improve patients with AR, NAR, and MR, and its effect is long lasting. PMID:27049100

  3. Intranasal inoculation of white-tailed deer (Odocoileus virginianus) with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay.

    PubMed

    Nichols, Tracy A; Spraker, Terry R; Rigg, Tara D; Meyerett-Reid, Crystal; Hoover, Clare; Michel, Brady; Bian, Jifeng; Hoover, Edward; Gidlewski, Thomas; Balachandran, Aru; O'Rourke, Katherine; Telling, Glenn C; Bowen, Richard; Zabel, Mark D; VerCauteren, Kurt C

    2013-01-01

    Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure. PMID:23671598

  4. Intranasal Inoculation of White-Tailed Deer (Odocoileus virginianus) with Lyophilized Chronic Wasting Disease Prion Particulate Complexed to Montmorillonite Clay

    PubMed Central

    Nichols, Tracy A.; Spraker, Terry R.; Rigg, Tara D.; Meyerett-Reid, Crystal; Hoover, Clare; Michel, Brady; Bian, Jifeng; Hoover, Edward; Gidlewski, Thomas; Balachandran, Aru; O'Rourke, Katherine; Telling, Glenn C.; Bowen, Richard

    2013-01-01

    Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure. PMID:23671598

  5. Biocompatible nanoparticles and biopolyelectrolytes

    NASA Astrophysics Data System (ADS)

    Zribi, Olena

    The research presented in this manuscript encompasses a merger of two research directions: a study of aqueous nanoparticle colloids and a study of biological polyelectrolytes. The majority of biomedical applications of nanoparticles require stable aqueous colloids of nanoparticles as a starting point. A new one-step method of preparation of aqueous solutions of ultra-fine ferroelectric barium titanate nanoparticles was developed and generalized to the preparation of stable aqueous colloids of semiconductor nanoparticles. This high-energy ball milling technique is low cost, environmentally friendly, and allows for control of nanoparticle size by changing milling time. Aqueous colloids of BaTiO3 nanoparticles are stable over time, maintain ferroelectricity and can be used as second harmonic generating nanoprobes for biomedical imaging. Biopolyelectrolytes exhibit a variety of novel liquid-crystalline phases in aqueous solutions where their electrolytic nature is a driving force behind phase formation. We study medically relevant mixtures of F-actin, DNA and oppositely charged ions (such as multivalent salts and antibiotic drugs) and map out phase diagrams and laws that govern phase transitions. We combine these research directions in studies of the condensation behavior in aqueous solutions of biocompatible nanoparticles and biopolyelectrolytes.

  6. Poloxamer 407-based intranasal thermoreversible gel of zolmitriptan-loaded nanoethosomes: formulation, optimization, evaluation and permeation studies.

    PubMed

    Shelke, Santosh; Shahi, Sadhana; Jalalpure, Sunil; Dhamecha, Dinesh

    2016-12-01

    Zolmitriptan is the drug of choice for migraine, but low oral bioavailability (<50%) and recurrence of migraine lead to frequent dosing and increase in associated side effects. Increase in the residence time of drug at the site of drug absorption along with direct nose to brain targeting of zolmitriptan can be a solution to the existing problems. Hence, in the present investigation, thermoreversible intranasal gel of zolmitriptan-loaded nanoethosomes was formulated by using mucoadhesive polymers to increase the residence of the drug into the nasal cavity. The preparation of ethosomes was optimized by using 3(2) factorial design for percent drug entrapment efficiency, vesicle size, zeta potential, and polydispersity index. Optimized formulation E6 showed the vesicle size (171.67 nm) and entrapment efficiency (66%) when compared with the other formulations. Thermoreversible gels prepared by using poloxamer 407 showed the phase transition temperature at 32-33 °C which was in line with the nasal physiological temperature. The optimized ethosomes were loaded into the thermoreversible mucoadhesive gel optimized by varying concentrations of poloxamer 407, carbopol 934, HPMC K100, and evaluated for gel strength, gelation temperature, mucoadhesive strength, in vitro drug release, and ex vivo drug permeation, where G3 and G6 were found to be optimized formulations. In vitro drug release was studied by different kinetic models suggested that G3 (n = 0.582) and G6 (n = 0.648) showed Korsemeyer-Peppas (KKP) model indicating non-Fickian release profiles. A permeation coefficient of 5.92 and 5.9 µg/cm(2) for G3 and G6, respectively, revealed very little difference in release rate after 24 h between both the formulations. Non-toxic nature of the gels on columnar epithelial cells was confirmed by histopathological evaluation. PMID:26758957

  7. Synthesis of ferromagnetic nanoparticles, formic acid oxidation catalyst nanocomposites, and late-transition metal-boride intermetallics by unique synthetic methods and single-source precursors

    NASA Astrophysics Data System (ADS)

    Wellons, Matthew S.

    The design, synthesis, and characterization of magnetic alloy nanoparticles, supported formic acid oxidation catalysts, and superhard intermetallic composites are presented. Ferromagnetic equatomic alloy nanoparticles of FePt, FePd, and CoPt were synthesized utilizing single-source heteronuclear organometallic precursors supported on an inert water-soluble matrix. Direct conversion of the precursor-support composite to supported ferromagnetic nanoparticles occurs under elevated temperatures and reducing conditions with metal-ion reduction and minimal nanoparticle coalescence. Nanoparticles were easily extracted from the support by addition of water and characterized in structure and magnetic properties. Palladium and platinum based nanoparticles were synthesized with microwave-based and chemical metal-ion reduction strategies, respectively, and tested for catalytic performance in a direct formic acid fuel cell (DFAFC). A study of palladium carbide nanocomposites with various carbonaceous supports was conducted and demonstrated strong activity comparable to commercially available palladium black, but poor catalytic longevity. Platinum-lead alloy nanocomposites synthesized with chemical reduction and supported on Vulcan carbon demonstrated strong activity, excellent catalytic longevity, and were subsequently incorporated into a prototype DFAFC. A new method for the synthesis of superhard ceramics on polymer substrates called Confined Plasma Chemical Deposition (CPCD) was developed. The CPCD method utilizes a tuned Free Electron Laser to selectively decompose the single-source precursor, Re(CO)4(B3H8), in a plasma-like state resulting in the superhard intermetallic ReB2 deposited on polymer substrates. Extension of this method to the synthesis of other hard of superhard ceramics; WB4, RuB2, and B4C was demonstrated. These three areas of research show new synthetic methods and novel materials of technological importance, resulting in a substantial advance in their

  8. Microglial activation, recruitment and phagocytosis as linked phenomena in ferric oxide nanoparticle exposure.

    PubMed

    Wang, Yun; Wang, Bing; Zhu, Mo-Tao; Li, Ming; Wang, Hua-Jian; Wang, Meng; Ouyang, Hong; Chai, Zhi-Fang; Feng, Wei-Yue; Zhao, Yu-Liang

    2011-08-10

    Microglia as the resident macrophage-like cells in the central nervous system (CNS) play a pivotal role in the innate immune responses of CNS. Understanding the reactions of microglia cells to nanoparticle exposure is important in the exploration of neurobiology of nanoparticles. Here we provide a systemic mapping of microglia and the corresponding pathological changes in olfactory-transport related brain areas of mice with Fe(2)O(3)-nanoparticle intranasal treatment. We showed that intranasal exposure of Fe(2)O(3) nanoparticle could lead to pathological alteration in olfactory bulb, hippocampus and striatum, and caused microglial proliferation, activation and recruitment in these areas, especially in olfactory bulb. Further experiments with BV2 microglial cells showed the exposure to Fe(2)O(3) nanoparticles could induce cells proliferation, phagocytosis and generation of ROS and NO, but did not cause significant release of inflammatory factors, including IL-1β, IL-6 and TNF-α. Our results indicate that microglial activation may act as an alarm and defense system in the processes of the exogenous nanoparticles invading and storage in brain. PMID:21596115

  9. Intrinsic intranasal chemosensory brain networks shown by resting-state functional MRI.

    PubMed

    Tobia, Michael J; Yang, Qing X; Karunanayaka, Prasanna

    2016-05-01

    The human brain is organized into functional networks for sensory-motor and cognitive processing. Intrinsic networks are detectable in the absence of stimulation or task demands, whereas extrinsic networks are detectable when stimulated by sensory or cognitive demands. Intranasal chemosensory processing relies on two dissociable networks for processing incoming trigeminal and olfactory stimulation, but it is not known whether these networks are intrinsically organized. The aim of this study was to identify whether brain networks for intranasal chemosensory processing are detectable in functional connectivity resting-state functional MRI (fMRI). Sixteen healthy adults participated in a 5-min resting-state fMRI study. Functional connectivity seeds were defined from coordinates that anchor olfactory (i.e. bilateral piriform and orbitofrontal cortex) and trigeminal (bilateral anterior insula and cingulate cortex) networks in published task activation studies, and the resulting networks were thresholded at P less than 0.001. The olfactory network showed extended functional connectivity to the thalamus, medial prefrontal cortex, caudate, nucleus accumbens, parahippocampal gyrus, and hippocampus. The trigeminal network showed extended functional connectivity to the precuneus, thalamus, caudate, brainstem, and cerebellum. Both networks overlapped in the thalamus, caudate, medial prefrontal cortex, and insula. These results show that brain networks for intranasal chemosensory processing are intrinsically organized, not just extrinsically instantiated in response to task demands, and resemble networks for processing olfactory and trigeminal stimulation. As such, it may be possible to study the functional organization and dynamics of the olfactory network in resting-state fMRI as well as its implications for aging and disease. PMID:27031873

  10. Intranasal oxytocin administration in relationship to social behaviour in domestic pigs.

    PubMed

    Camerlink, Irene; Reimert, Inonge; Bolhuis, J Elizabeth

    2016-09-01

    Intranasal administration of oxytocin has been shown to alter positive and negative social behaviour. Positive social behaviour in pigs (Sus scrofa) may be expressed through gentle social nosing, and greater insight in the specific expression hereof might contribute to the current search for positive indicators of animal welfare. We investigated whether oxytocin alters social nosing and whether this is specific to nose-body or nose-nose contact. Sixty-four focal female pigs of 13weeks of age (out of 16 groups) were given oxytocin (24IU dose) and saline (placebo) intranasally once on two consecutive days. The frequency of nose-to-nose contact and nose-to-body contact was recorded upon pigs' return in the home pen after being for 10min located in a separate area near pen mates undergoing a positive or negative event or not. The effect of intranasal oxytocin depended on the social context in which pigs were studied. Control pigs, which were not exposed to positively or negatively aroused pen mates, gave and received less nose-nose contact after oxytocin administration than after saline administration. Pigs exposed to positively aroused pen mates also tended to give less nose contact when given oxytocin compared to saline, whereas pigs exposed to negatively aroused pen mates and administered oxytocin tended to receive more nose contact. Nose-body contact was lowest in groups of negative social context, suggesting an effect of emotional state on social nosing. In contrast to nose-nose contact, nose-body contact was unaffected by oxytocin treatment. The relationship between social nosing and oxytocin merits further research. PMID:27143253

  11. Plasma and CSF oxytocin levels after intranasal and intravenous oxytocin in awake macaques.

    PubMed

    Freeman, Sara M; Samineni, Sridhar; Allen, Philip C; Stockinger, Diane; Bales, Karen L; Hwa, Granger G C; Roberts, Jeffrey A

    2016-04-01

    Oxytocin (OT) is a neuropeptide that mediates a variety of complex social behaviors in animals and humans. Intranasal OT has been used as an experimental therapeutic for human conditions characterized by deficits in social functioning, especially autism spectrum disorder and schizophrenia. However, it is currently under intense debate whether intranasal delivery of OT reaches the central nervous system. In this study, four female rhesus macaques were implanted with chronic intrathecal catheters and used to investigate the pharmacokinetic profile of OT in the central nervous system and the peripheral vasculature following intravenous (IV) and intranasal (IN) administration of OT. In a randomized, crossover design, OT was given to four awake monkeys at three different doses based on body weight (0.1 IU/kg; 1 IU/kg; 5 IU/kg). A time course of concurrent cerebrospinal fluid (CSF) and plasma samples were taken following administration. We found a dose-dependent effect of IV OT treatment on plasma OT levels, which peaked at 5 min post-dose and gradually returned to baseline by 120 min. In contrast, a change in CSF OT was only observed at the highest IV dose (5 IU/kg) at 15 min post-dose and gradually returned to baseline by 120 min. After IN administration, there was no significant change in plasma OT at any of the three doses. However, at the highest dose level, we found a significant increase in CSF OT at 15-30 min post- dose. The results of this study in light of recent, similar publications highlight the importance of methodological consistency across studies. This study also establishes a non-human primate model that can provide a stable platform for carrying out serial sampling from the central nervous system and peripheral vasculature concurrently. PMID:26826355

  12. Effect of intranasal manganese administration on neurotransmission and spatial learning in rats

    SciTech Connect

    Blecharz-Klin, Kamilla; Piechal, Agnieszka; Joniec-Maciejak, Ilona; Pyrzanowska, Justyna; Widy-Tyszkiewicz, Ewa

    2012-11-15

    The effect of intranasal manganese chloride (MnCl{sub 2}·4H{sub 2}O) exposure on spatial learning, memory and motor activity was estimated in Morris water maze task in adult rats. Three-month-old male Wistar rats received for 2 weeks MnCl{sub 2}·4H{sub 2}O at two doses the following: 0.2 mg/kg b.w. (Mn0.2) or 0.8 mg/kg b.w. (Mn0.8) per day. Control (Con) and manganese-exposed groups were observed for behavioral performance and learning in water maze. ANOVA for repeated measurements did not show any significant differences in acquisition in the water maze between the groups. However, the results of the probe trial on day 5, exhibited spatial memory deficits following manganese treatment. After completion of the behavioral experiment, the regional brain concentrations of neurotransmitters and their metabolites were determined via HPLC in selected brain regions, i.e. prefrontal cortex, hippocampus and striatum. ANOVA demonstrated significant differences in the content of monoamines and metabolites between the treatment groups compared to the controls. Negative correlations between platform crossings on the previous platform position in Southeast (SE) quadrant during the probe trial and neurotransmitter turnover suggest that impairment of spatial memory and cognitive performance after manganese (Mn) treatment is associated with modulation of the serotonergic, noradrenergic and dopaminergic neurotransmission in the brain. These findings show that intranasally applied Mn can impair spatial memory with significant changes in the tissue level and metabolism of monoamines in several brain regions. -- Highlights: ► Intranasal exposure to manganese in rats impairs spatial memory in the water maze. ► Regional changes in levels of neurotransmitters in the brain have been identified. ► Cognitive disorder correlates with modulation of 5-HT, NA and DA neurotransmission.

  13. Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice

    PubMed Central

    Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Wei, Ling

    2015-01-01

    Apelin is a peptide originally isolated from bovine stomach tissue extracts and identified as an endogenous ligand of the APJ receptor; recent work showed that apelin ameliorates the ischemic injury in the heart and the brain. Being an analogue to the angiotensin II receptor, the apelin/APJ signaling may mediate angiogenesis process. We explored the noninvasive intranasal brain delivery method and investigated therapeutic effects of apelin-13 in a focal ischemic stroke model of mice. Intranasal administration of apelin-13 (4 mg/kg) was given 30 min after the onset of stroke and repeated once daily. Three days after stroke, mice received apelin-13 had significantly reduced infarct volume and less neuronal death in the penumbra. Western blot analyses showed upregulated levels of apelin, apelin receptor APLNR, and Bcl-2 and decreased caspase-3 activation in the apelin-13-treated brain. The proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1β, and chemokine monocyte chemoattractant protein-1 mRNA increased in the ischemic brain, which were significantly attenuated by apelin-13. Apelin-13 remarkably reduced microglia recruitment and activation in the penumbra according to morphological features of Iba-1-positive cells 3 days after ischemia. Apelin-13 significantly increased the expression of angiogenic factor vascular endothelial growth factor and matrix metalloproteinase-9 14 days after stroke. Angiogenesis illustrated by collagen IV + /5-bromo-2′-deoxyuridin + colabeled cells was significantly increased by the apelin-13 treatment 21 days after stroke. Finally, apelin-13 promoted the local cerebral blood flow restoration and long-term functional recovery. This study demonstrates a noninvasive intranasal delivery of apelin-13 after stroke, suggesting that the reduced inflammatory activities, decreased cell death, and increased angiogenesis contribute to the therapeutic benefits of apelin-13. PMID:26391329

  14. Comparison of preanesthetic sedation in pediatric patients with oral and intranasal midazolam

    PubMed Central

    Deshmukh, Purvashree Vijay; Kulkarni, Sadhana Sudhir; Parchandekar, Mukund Kachru; Sikchi, Sneha Purshottam

    2016-01-01

    Background and Aims: Preoperative anxiety in children leading to postoperative negative changes and long-term behavioral problems needs better preanesthetic sedation. Across the world, midazolam is the most commonly used premedicant in pediatric patients. The fact that no single route has achieved universal acceptance for its administration suggests that each route has its own merits and demerits. This study compares oral midazolam syrup and intranasal midazolam spray as painless and needleless systems of drug administration for preanesthetic sedation in children. Material and Methods: With randomization, Group O (30 children): Received oral midazolam syrup 0.5 mg/kg and Group IN (30 children): Received intranasal midazolam spray 0.2 mg/kg. Every child was observed for acceptance of drug, response to drug administration, sedation scale, separation score, acceptance to mask, recovery score and side effects of drug. Data were analyzed using Student's t-test, standard error of the difference between two means and Chi-square test. Results: In Group O and IN, 15/30 children (50%) and 7/30 children (23%) accepted drug easily (P < 0.05); 4/22 children (18%) in Group O and 11/20 children (55%) in Group IN cried after drug administration (P < 0.05). In both the groups, sedation at 20 min after premedication (Group O [80%] 24/30 vs. Group IN [77%] 23/30), parental separation and acceptance to mask were comparable (P > 0.05); 12/30 children (40%) in Group IN showed transient nasal irritation. Conclusion: Oral midazolam and intranasal midazolam spray produce similar anxiolysis and sedation, but acceptance of drug and response to drug administration is better with oral route. PMID:27625485

  15. Differential effects of intranasal oxytocin on sexual experiences and partner interactions in couples.

    PubMed

    Behnia, Behnoush; Heinrichs, Markus; Bergmann, Wiebke; Jung, Stefanie; Germann, Janine; Schedlowski, Manfred; Hartmann, Uwe; Kruger, Tillmann H C

    2014-03-01

    Knowledge about the effects of the neuropeptide oxytocin (OXT) on human sexual behaviors and partner interactions remains limited. Based on our previous studies, we hypothesize that OXT should be able to positively influence parameters of sexual function and couple interactions. Employing a naturalistic setting involving 29 healthy heterosexual couples (n=58 participants), we analyzed the acute effects of intranasally administered OXT (24IU) on sexual drive, arousal, orgasm and refractory aspects of sexual behavior together with partner interactions. Data were assessed by psychometric instruments (Acute Sexual Experiences Scale, Arizona Sexual Experience Scale) as well as biomarkers, such as cortisol, α-amylase and heart rate. Intranasal OXT administration did not alter "classical" parameters of sexual function, such as sexual drive, arousal or penile erection and lubrication. However, analysis of variance and a hierarchical linear model (HLM) revealed specific effects related to the orgasmic/post-orgasmic interval as well as parameters of partner interactions. According to HLM analysis, OXT increased the intensity of orgasm, contentment after sexual intercourse and the effect of study participation. According to ANOVA analysis, these effects were more pronounced in men. Men additionally indicated higher levels of sexual satiety after sexual intercourse with OXT administration. Women felt more relaxed and subgroups indicated better abilities to share sexual desires or to empathize with their partners. The effect sizes were small to moderate. Biomarkers indicated moderate psychophysiological activation but were not affected by OXT, gender or method of contraception. Using a naturalistic setting, intranasal OXT administration in couples exerted differential effects on parameters of sexual function and partner interactions. These results warrant further investigations, including subjects with sexual and relationship problems. PMID:24503174

  16. Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice.

    PubMed

    Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Wei, Ling; Yu, Shan Ping

    2015-01-01

    Apelin is a peptide originally isolated from bovine stomach tissue extracts and identified as an endogenous ligand of the APJ receptor; recent work showed that apelin ameliorates the ischemic injury in the heart and the brain. Being an analogue to the angiotensin II receptor, the apelin/APJ signaling may mediate angiogenesis process. We explored the noninvasive intranasal brain delivery method and investigated therapeutic effects of apelin-13 in a focal ischemic stroke model of mice. Intranasal administration of apelin-13 (4 mg/kg) was given 30 min after the onset of stroke and repeated once daily. Three days after stroke, mice received apelin-13 had significantly reduced infarct volume and less neuronal death in the penumbra. Western blot analyses showed upregulated levels of apelin, apelin receptor APLNR, and Bcl-2 and decreased caspase-3 activation in the apelin-13-treated brain. The proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1β, and chemokine monocyte chemoattractant protein-1 mRNA increased in the ischemic brain, which were significantly attenuated by apelin-13. Apelin-13 remarkably reduced microglia recruitment and activation in the penumbra according to morphological features of Iba-1-positive cells 3 days after ischemia. Apelin-13 significantly increased the expression of angiogenic factor vascular endothelial growth factor and matrix metalloproteinase-9 14 days after stroke. Angiogenesis illustrated by collagen IV + /5-bromo-2'-deoxyuridin + colabeled cells was significantly increased by the apelin-13 treatment 21 days after stroke. Finally, apelin-13 promoted the local cerebral blood flow restoration and long-term functional recovery. This study demonstrates a noninvasive intranasal delivery of apelin-13 after stroke, suggesting that the reduced inflammatory activities, decreased cell death, and increased angiogenesis contribute to the therapeutic benefits of apelin-13. PMID:26391329

  17. Intranasal Delivery of E-Selectin Reduces Atherosclerosis in ApoE−/− Mice

    PubMed Central

    Li, Xinhui; Johnson, Kory R.; Bryant, Mark; Elkahloun, Abdel G.; Amar, Marcelo; Remaley, Alan T.; De Silva, Ranil; Hallenbeck, John M.; Quandt, Jacqueline A.

    2011-01-01

    Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or “tolerogenic” responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE−/− mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE−/− mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke. PMID:21701687

  18. Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin.

    PubMed

    Douce, G; Fontana, M; Pizza, M; Rappuoli, R; Dougan, G

    1997-07-01

    Genetically modified derivatives of cholera toxin (CT), harboring a single amino acid substitution in and around the NAD binding cleft of the A subunit, were isolated following site-directed mutagenesis of the ctxA gene. Two mutants of CT, designated CTS106 (with a proline-to-serine change at position 106) and CTK63 (with a serine-to-lysine change at position 63), were found to have substantially reduced ADP-ribosyltransferase activity and toxicity; CTK63 was completely nontoxic in all assays, whereas CTS106 was 10(4) times less toxic than wild-type CT. The mucosal adjuvanticity and immunogenicity of derivatives of CT were assessed by intranasal immunization of mice, with either ovalbumin or fragment C of tetanus toxin as a bystander antigen. Mice immunized with wild-type CT produced both local (immunoglobulin A in mucosal washes) and systemic immune responses to both CT and bystander antigens. CTS106 showed good local and systemic responses to bystander proteins and to itself. Interestingly, mice immunized with the nontoxic derivative of CT, CTK63, generated weak immune responses to the bystander antigens which were similar to those achieved when CT B subunit was used as an adjuvant. In parallel experiments, an equivalent nontoxic mutant of the Escherichia coli heat-labile enterotoxin, LTK63 (with a serine-to-lysine change at position 63), was tested (9). In contrast to CTK63, LTK63 was found to be more immunogenic and a better intranasal adjuvant than recombinant heat-labile enterotoxin B subunit or CTK63. This information, together with data on immunoglobulin subclass responses, suggests that although highly homologous, CT and heat-labile enterotoxin should not be considered biologically identical in terms of their ability to act as intranasal adjuvants. PMID:9199455

  19. Intraoperative acridine orange photodynamic therapy and cribriform electron-beam irradiation for canine intranasal tumors: A pilot study

    PubMed Central

    Maruo, Takuya; Nagata, Koichi; Fukuyama, Yasuhiro; Nemoto, Yuki; Kawarai, Shinpei; Fujita, Yukihiro; Nakayama, Tomohiro

    2015-01-01

    Untreated canine intranasal tumors carry a poor prognosis. We retrospectively evaluated the efficacy of marginal tumor resection in combination with intraoperative acridine orange (AO) photodynamic therapy (PDT) and 1 fraction of 5 Gy megavoltage irradiation for canine intranasal malignant tumors. When cribriform plate invasion or turbinate destruction around the cribriform plate was present, an additional fraction of 20 Gy was delivered with an electron beam during surgery. The study included 6 dogs, 2 of which were classified as stage I, 1 as stage II, and 3 as stage IV. The median local disease-free survival time and overall survival after the treatment were 8.5 and 13 months, respectively. Recurrence was noted in 2 of the 6 dogs after 4 and 7 months. Adverse events were mild (subcutaneous emphysema in 1 case, and rhinitis in 3 cases). Combination AO therapy may increase the tumor control time of dogs with marginally resectable intranasal malignant tumors. PMID:26663917

  20. No relevant modulation of TRPV1-mediated trigeminal pain by intranasal carbon dioxide in healthy humans

    PubMed Central

    2013-01-01

    Background Nasal insufflation of CO2 has been shown to exert antinociceptive respectively antihyperalgesic effects in animal pain models using topical capsaicin with activation of TRPV1-receptor positive nociceptive neurons. Clinical benefit from CO2 inhalation in patients with craniofacial pain caused by a putative activation of TRPV1 receptor positive trigeminal neurons has also been reported. These effects are probably mediated via an activation of TRPV1 receptor - positive neurons in the nasal mucosa with subsequent central inhibitory effects (such as conditioned pain modulation). In this study, we aimed to examine the effects of intranasal CO2 on a human model of craniofacial pain elicited by nasal application of capsaicin. Methods In a first experiment, 48 healthy volunteers without previous craniofacial pain received intranasal capsaicin to provoke trigeminal pain elicited by activation of TRVP1 positive nociceptive neurons. Then, CO2 or air was insufflated alternatingly into the nasal cavity at a flow rate of 1 l/min for 60 sec each. In the subsequent experiment, all participants were randomized into 2 groups of 24 each and received either continuous nasal insufflation of CO2 or placebo for 18:40 min after nociceptive stimulation with intranasal capsaicin. In both experiments, pain was rated on a numerical rating scale every 60 sec. Results Contrary to previous animal studies, the effects of CO2 on experimental trigeminal pain were only marginal. In the first experiment, CO2 reduced pain ratings only minimally by 5.3% compared to air if given alternatingly with significant results for the main factor GROUP (F1,47 = 4.438; p = 0.041) and the interaction term TIME*GROUP (F2.6,121.2 = 3.3; p = 0.029) in the repeated-measures ANOVA. However, these effects were abrogated after continuous insufflation of CO2 or placebo with no significant changes for the main factors or the interaction term. Conclusions Although mild modulatory effects of low

  1. Intranasal administration of neuropeptide Y in man: systemic absorption and functional effects.

    PubMed Central

    Lacroix, J. S.; Ricchetti, A. P.; Morel, D.; Mossimann, B.; Waeber, B.; Grouzmann, E.

    1996-01-01

    1. Exogenous neuropeptide Y (NPY, 10 nmol, 50 nmol and 100 nmol) and its vehicle (NaCl 0.9%) were administered in a double blind, randomized and controlled manner by intranasal spray in 7 healthy volunteers. Variations of plasma NPY concentration over time were measured during 120 min. Forty min after the administration of 50 nmol and 100 nmol of exogenous NPY, plasma NPY increased from 5.5 +/- 1.1 pM to 9.8 +/- 2.3 pM (P < 0.05) and from 9.06 +/- 5.1 pM to 20.8 +/- 6.16 pM (P < 0.001), respectively. There was no significant modification of the mean arterial blood pressure and no subjective discomfort was reported. 2. Nasal airway resistance (NAR) was measured by anterior rhinomanometry and was reduced by 25 +/- 3% and 32 +/- 5% after the spray of 50 nmol and 100 nmol, respectively, for about 90 min. 3. Double-blind, randomized, placebo-controlled and 3-way crossover design experiments were performed in 8 healthy volunteers to evaluate the influence of intranasal pretreatment with NPY (20 nmol) and the mixed alpha 1/alpha 2-adrenoceptor agonist oxymetazoline (20 nmol) on the functional effects of subsequent local irritation evoked by capsaicin (3.3 x 10(-4) mol). Subjective evaluation of NAR and local intensity of discomfort were evaluated by means of a visual analogue scale. Nasal secretions were collected and objective NAR was recorded by rhinomanometry. 4. Subjective NAR, nasal secretions and rhinomanometry recordings were not modified by intranasal application of saline, NPY or oxymetazoline. Subjective nasal obstruction, local discomfort, nasal secretions and NAR increase evoked by capsaicin were markedly reduced by NPY pretreatment (P < 0.05) when compared to saline or oxymetazoline. 5. It is concluded that intranasal application of exogenous NPY has very low systemic absorption but induced long lasting nasal vasoconstriction without cardiovascular effects. Pretreatment of the nasal mucosa with exogenous NPY reduces both secretagogue and vasodilator responses

  2. Validation of a Best-Fit Pharmacokinetic Model for Scopolamine Disposition after Intranasal Administration

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S-L.; Tam, V.; Putcha, L.

    2015-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Motion Sickness. Bioavailability and pharmacokinetics (PK) were determined per Investigative New Drug (IND) evaluation guidance by the Food and Drug Administration. Earlier, we reported the development of a PK model that can predict the relationship between plasma, saliva and urinary scopolamine (SCOP) concentrations using data collected from an IND clinical trial with INSCOP. This data analysis project is designed to validate the reported best fit PK model for SCOP by comparing observed and model predicted SCOP concentration-time profiles after administration of INSCOP.

  3. Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y.

    PubMed

    Sabban, Esther L; Laukova, Marcela; Alaluf, Lishay G; Olsson, Emelie; Serova, Lidia I

    2015-12-01

    Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments. Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze

  4. Brief Report: Oxytocin Enhances Paternal Sensitivity to a Child with Autism--A Double-Blind Within-Subject Experiment with Intranasally Administered Oxytocin

    ERIC Educational Resources Information Center

    Naber, Fabienne B. A.; Poslawsky, Irina E.; van Ijzendoorn, Marinus H.; van Engeland, Herman; Bakermans-Kranenburg, Marian J.

    2013-01-01

    Oxytocin seems associated with parenting style, and experimental work showed positive effects of intranasally administered oxytocin on parenting style of fathers. Here, the first double-blind, placebo-controlled, within-subject experiment with intranasal oxytocin administration to fathers of children with autism spectrum disorder (ASD) is…

  5. A role for the intranasal formulation of azelastine hydrochloride/fluticasone propionate in the treatment of allergic rhinitis.

    PubMed

    Ridolo, Erminia; Montagni, Marcello; Melli, Valerie; Bonzano, Laura; Incorvaia, Cristoforo; Canonica, Giorgio Walter

    2015-01-01

    Rhinitis is a very common disease and represents a health problem for both children and adults globally. Rhinitis can be allergic or occur without any IgE-mediated sensitization to aeroallergens. Common symptoms include nasal congestion, postnasal drainage, nasal itching, rhinorrhea and sneezing. The most effective drugs for the treatment of rhinitis are antihistamines and topical glucocorticoids. MP29-02 (Dymista(®)) is a novel intranasal formulation combining the second-generation antihistamine, azelastine hydrochloride, with fluticasone propionate in a single device that has recently been developed. Here, we review the efficacy and safety profile of this intranasal formulation in the treatment of allergic and nonallergic rhinitis. PMID:25913181

  6. Ribavirin Protects Syrian Hamsters against Lethal Hantavirus Pulmonary Syndrome — After Intranasal Exposure to Andes Virus

    PubMed Central

    Ogg, Monica; Jonsson, Colleen B.; Camp, Jeremy V.; Hooper, Jay W.

    2013-01-01

    Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route. PMID:24217424

  7. Intranasal oxytocin attenuates attentional bias for eating and fat shape stimuli in patients with anorexia nervosa.

    PubMed

    Kim, Youl-Ri; Kim, Chan-Hyung; Cardi, Valentina; Eom, Jin-Sup; Seong, Yoori; Treasure, Janet

    2014-06-01

    We examined the impact of oxytocin on attentional processes for eating, shape, and weight stimuli in patients with anorexia nervosa (AN). A double-blind, placebo-controlled within-subject crossover design was used. Intranasal oxytocin or placebo followed by a visual probe detection task with food, weight, and shape images was administered to 64 female subjects: 31 patients with AN and 33 control students. The AN group showed significant reductions in the attentional biases toward eating-related stimuli (p=0.030, d=0.516) and toward negative shape stimuli (p=0.015, d=0.498) under the influence of intranasal oxytocin. The effect of oxytocin was correlated with autistic spectrum traits in the AN group. Oxytocin had no effect on the amount of juice consumed in either group. The results of this study suggest that oxytocin attenuates the attentional vigilance to eating and fat shape stimuli in patients with AN. Further studies using oxytocin as a form of intervention for patients with AN are needed. PMID:24703429

  8. Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes.

    PubMed

    Every, Alison L; Kramer, David R; Mannering, Stuart I; Lew, Andrew M; Harrison, Leonard C

    2006-04-15

    Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (T(reg)) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4+ T(reg) that suppressed diabetes development, both after adoptive cotransfer with "diabetogenic" spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4+ CD25+ T(reg), CD4+ T(reg) induced by proinsulin DNA were both CD25+ and CD25- and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of T(reg) and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective T(reg), but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity. PMID:16585551

  9. A Unique Case of Intranasal Metastasis from Occult Poorly Differentiated Thyroid Carcinoma

    PubMed Central

    Kum, Rauf Oğuzhan; Aygenç, Erdinç; Somuk, Battal Tahsin; Börcek, Pelin; Özdem, Cafer

    2015-01-01

    Background: Poorly differentiated thyroid carcinomas (PDTCs) lie, both morphologically and behaviorally, between well-differentiated and undifferentiated carcinomas. Metastasis of poorly differentiated thyroid carcinoma to the intranasal cavity has not been reported previously in the literature. Case Report: A 48-year-old male patient presented with massive epistaxis and nasal obstruction. On nasal examination, a bleeding, vascular mass was seen filling the left nasal cavity. The histopathological report of the nasal mass was well-differentiated thyroid carcinoma metastasis. Whole body scintigraphy, ultrasonography and positron emission tomography were done to rule out other possible metastases in the body and determine the origin of the tumor, which was identified as the left lobe of the thyroid gland, and there were multiple metastases involving the lung, sacroiliac area, and left humerus. Histopathological examination of a thyroidectomy specimen revealed PDTC consisting of insular, follicular, and papillary components. Postoperatively, the patient received radioactive iodine ablation therapy (iodine-131) and a course of external beam radiation therapy to the sacroiliac area and other metastatic regions. No recurrences were observed in a follow-up period of 5 years after surgery. Conclusion: The metastasis of differentiated thyroid carcinoma as a component of PDTC to the intranasal cavity has not been reported before. It is interesting that the well-differentiated component of the tumor was metastasized in our patient. Due to the aggressiveness of PDTC and the poor survival rates in patients who undergo surgery alone, a multidisciplinary treatment approach is required. PMID:26185723

  10. Food consumption and activity levels increase in rats following intranasal Hypocretin-1.

    PubMed

    Dhuria, Shyeilla V; Fine, Jared M; Bingham, Deborah; Svitak, Aleta L; Burns, Rachel B; Baillargeon, Amanda M; Panter, Scott S; Kazi, Abdul N; Frey, William H; Hanson, Leah R

    2016-08-01

    Hypocretin-1 (HC, orexin-A) is a neuropeptide involved in regulating physiological functions of sleep, appetite and arousal, and it has been shown that intranasal (IN) administration can target HC to the brain. Recent clinical studies have shown that IN HC has functional effects in human clinical trials. In this study, we use rats to determine whether IN HC has an immediate effect on food consumption and locomotor activity, whether distribution in the brain after IN delivery is dose-dependent, and whether MAPK and PDK1 are affected after IN delivery. Food intake and wheel-running activity were quantified for 24h after IN delivery. Biodistribution was determined 30min after IN delivery of both a high and low dose of 125I-radiolabelled HC throughout the brain and other bodily tissues, while Western blots were used to quantify changes in cell signaling pathways (MAPK and PDK1) in the brain. Intranasal HC significantly increased food intake and wheel activity within 4h after delivery, but balanced out over the course of 24h. The distribution studies showed dose-dependent delivery in the CNS and peripheral tissues, while PDK1 was significantly increased in the brain 30min after IN delivery of HC. This study adds to the growing body of evidence that IN administration of HC is a promising strategy for treatment of HC related behaviors. PMID:27264485

  11. Intranasal Immunization of Mice to Avoid Interference of Maternal Antibody against H5N1 Infection

    PubMed Central

    Zhang, Fenghua; Peng, Bo; Chang, Haiyan; Zhang, Ran; Lu, Fangguo; Wang, Fuyan; Fang, Fang

    2016-01-01

    Maternally-derived antibodies (MDAs) can protect offspring against influenza virus infection but may also inhibit active immune responses. To overcome MDA- mediated inhibition, active immunization of offspring with an inactivated H5N1 whole-virion vaccine under the influence of MDAs was explored in mice. Female mice were vaccinated twice via the intraperitoneal (IP) or intranasal (IN) route with the vaccine prior to mating. One week after birth, the offspring were immunized twice via the IP or IN route with the same vaccine and then challenged with a lethal dose of a highly homologous virus strain. The results showed that, no matter which immunization route (IP or IN) was used for mothers, the presence of MDAs severely interfered with the active immune response of the offspring when the offspring were immunized via the IP route. Only via the IN immunization route did the offspring overcome the MDA interference. These results suggest that intranasal immunization could be a suitable inoculation route for offspring to overcome MDA interference in the defense against highly pathogenic H5N1 virus infection. This study may provide references for human and animal vaccination to overcome MDA-induced inhibition. PMID:27280297

  12. Intranasal immunisation with inactivated RSV and bacterial adjuvants induces mucosal protection and abrogates eosinophilia upon challenge.

    PubMed

    Etchart, Nathalie; Baaten, Bas; Andersen, Svein Rune; Hyland, Lisa; Wong, Simon Y C; Hou, Sam

    2006-05-01

    We have previously shown that following intranasal exposure to influenza virus, specific plasma cells are generated in the nasal-associated lymphoid tissue (NALT) and maintained for the life of the animal. However, we also showed that following infection with respiratory syncytial virus (RSV), specific plasma cells are generated in the NALT but wane quickly and are not maintained even after challenge, even though RSV-specific serum antibody responses remain robust. Only infection with influenza virus generated sterilising immunity, implying a role for these long-lived plasma cells in protection. We show here that the RSV-specific IgA NALT plasma cell population and lung antibody levels can be substantially boosted, both at acute and memory time points, by intranasal immunisation with inactivated RSV (iRSV) in combination with bacterial outer membrane vesicles (OMV) compared to live RSV alone. Finally, challenge with live RSV showed that immunisation with iRSV and OMV protect against both virus replication in the lung and the eosinophil infiltrate generated by either live RSV or iRSV alone. These data show that immunisation with iRSV and OMV maintains a NALT RSV-specific plasma cell population and generates an efficient protective immune response following RSV infection. PMID:16619288

  13. Pharmacokinetics of Intranasal Scopolamine Gel Formation During Antiorthostatic Bedrest - A Microgravity Analog

    NASA Technical Reports Server (NTRS)

    Lakshmi, Putcha; Singh, R. P.; Crady, V. A.; Derendorf, H.

    2011-01-01

    Space Motion sickness (SMS) is an age old problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is the most frequently used drug for the treatment of motion sickness (MS) which is currently available in transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability thus allowing precise and reduced dosing options in addition to offering rescue and treatment options. As such, an intranasal gel dosage formulation of scopolamine (INSCOP) was developed and Pharmacokinetics (PK) and bioavailability were determined under IND guidelines. The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostatic bedrest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 and 0.4 mg doses of INSCOP during AMB and ABR in a four-way crossover design. Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose. Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration versus time curve (AUC) during ABR after the 0.4 mg dose. This difference in AUC and Cls at the higher but not the lower dose during ABR may suggest that ABR may affect metabolism and/or clearance at higher doses of INSCOP. These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

  14. Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives

    PubMed Central

    Xu, Yingying; Yuen, Pak-Wai; Lam, Jenny Ka-Wing

    2014-01-01

    Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal-associated lymphoid tissues (NALT). Different kinds of DNA vaccines are investigated to provide protection against respiratory infectious diseases including tuberculosis, coronavirus, influenza and respiratory syncytial virus (RSV) etc. DNA vaccines have several attractive development potential, such as producing cross-protection towards different virus subtypes, enabling the possibility of mass manufacture in a relatively short time and a better safety profile. The biggest obstacle to DNA vaccines is low immunogenicity. One of the approaches to enhance the efficacy of DNA vaccine is to improve DNA delivery efficiency. This review provides insight on the development of intranasal DNA vaccine for respiratory infections, with special attention paid to the strategies to improve the delivery of DNA vaccines using non-viral delivery agents. PMID:25014738

  15. Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome.

    PubMed

    Hall, Scott S; Lightbody, Amy A; McCarthy, Brigid E; Parker, Karen J; Reiss, Allan L

    2012-04-01

    Fragile X syndrome (FXS) is a rare inherited genetic disorder causing severe intellectual disability and autistic-like symptoms. Individuals with FXS, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations. We investigated whether oxytocin (OT), a hormone with prosocial and anxiolytic effects, could alleviate symptoms of social anxiety in this population. A randomized double-blind placebo-controlled single-dose trial was performed with intranasal administration of placebo, 24 IU OT and 48 IU OT. Measures of eye gaze frequency, heart rate, respiratory sinus arrhythmia (RSA), heart rate variability (HRV) and salivary cortisol were obtained during a structured social challenge conducted 50 min following OT administration. Ten low-functioning males with FXS (aged 13-28 years) traveled to Stanford for the initial visit: 8 completed the study. Eye gaze frequency improved significantly in response to the 24 IU OT dose and salivary cortisol levels decreased significantly in response to the 48 IU OT dose. There was no effect of OT on heart rate, RSA or HRV although individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others. These findings suggest that intranasal administration of OT may ameliorate some symptoms of social anxiety in patients with FXS. Further double-blind placebo-controlled studies of OT, conducted in combination with behavioral treatment programs, may be warranted. PMID:21862226

  16. Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children.

    PubMed

    Yilmaz, G; Varan, B; Yilmaz, T; Gürakan, B

    2000-01-01

    We investigated the clinical value of intranasal budesonide in acute sinusitis in 52 children with acute maxillary sinusitis. We randomly divided them into two groups: group 1 received oral pseudoephedrine (2 x 30 mg) and cefaclor (40 mg/kg) for 10 days, and group 2 received intranasal budesonide (2 x 100 microg) and cefaclor (40 mg/kg) for 10 days. Symptoms of headache, cough, and nasal stuffiness and signs of nasal discharge were graded before and after treatment. The patients whose symptoms and signs completely normalized after treatment were considered to have recovered, and those with persisting symptoms and signs after treatment as having not recovered. The results of the two treatment groups were compared. The recovery rate of the children in group 2 were significantly higher than those in group 1 (P < 0.05). No adverse drug effects were determined during the study period. These findings suggest that topical steroids may be a useful adjunctive agent in the treatment of acute sinusitis of children without apparent side effects and can possibly hasten the resolution of symptoms. PMID:10923938

  17. Study of sodium hyaluronate-based intranasal formulations containing micro- or nanosized meloxicam particles.

    PubMed

    Bartos, Csilla; Ambrus, Rita; Sipos, Péter; Budai-Szűcs, Mária; Csányi, Erzsébet; Gáspár, Róbert; Márki, Árpád; Seres, Adrienn B; Sztojkov-Ivanov, Anita; Horváth, Tamás; Szabó-Révész, Piroska

    2015-08-01

    This article reports on the micro- and nanonization of meloxicam (MEL) with the aim of developing pre-dispersions as intermediates for the design of intranasal formulations. As a new approach, combined wet milling technology was developed in order to reduce the particle size of the MEL. Different milling times resulted in micro- or nanosized MEL in the pre-dispersions with polyvinyl alcohol as stabilizer agent, which were directly used for preparing intranasal liquid formulations with the addition of sodium hyaluronate as mucoadhesive agent. Reduction of the MEL particle size into the nano range led to increased saturation solubility and dissolution velocities, and increased adhesiveness to surfaces as compared with microsized MEL particles. A linear correlation was demonstrated between the specific surface area of MEL and the AUC. The in vitro and in vivo studies indicated that the longer residence time and the uniform distribution of nano MEL spray throughout an artificial membrane and the nasal mucosa resulted in better diffusion and a higher AUC. Nanosized MEL may be suggested for the development of an innovative dosage form with a different dose of the drug, as a possible administration route for pain management. PMID:26142244

  18. Effects of intranasal oxytocin administration on memory for infant cues: moderation by childhood emotional maltreatment.

    PubMed

    Bhandari, Ritu; van der Veen, Rixt; Parsons, Christine E; Young, Katherine S; Voorthuis, Alexandra; Bakermans-Kranenburg, Marian J; Stein, Alan; Kringelbach, Morten L; van IJzendoorn, Marinus H

    2014-01-01

    Oxytocin has been implicated in parent-infant attachment and social recognition. With respect to emotion recognition memory, both memory-enhancing and impairing effects have been observed, suggesting an influence of individual factors. We assessed the effects of oxytocin on memory for infant cues, and whether these effects are moderated by self-reported childhood emotional maltreatment. Nulliparous females (N = 102) participated in a randomized, double-blind, between-subjects study with intranasal oxytocin or placebo administration. Participants' memory was tested using the Baby Social Reward Task, where participants were asked to select the happier infant from a pair of two infants based on the information that they received about the infants' mood in the previous phase. Participants reporting more childhood emotional maltreatment were less accurate in this task after inhaling oxytocin. Our findings add to a growing body of literature showing that the effects of intranasal oxytocin on memory and social behavior are moderated by adverse early life experiences. PMID:24968101

  19. Intranasal Delivery of Recombinant NT4-NAP/AAV Exerts Potential Antidepressant Effect.

    PubMed

    Ma, Xian-Cang; Chu, Zheng; Zhang, Xiao-Ling; Jiang, Wen-Hui; Jia, Min; Dang, Yong-Hui; Gao, Cheng-Ge

    2016-06-01

    The present study was designed to construct a recombinant adeno-associated virus (rAAV) which can express NAP in the brain and examine whether this virus can produce antidepressant effects on C57 BL/6 mice that had been subjected to open field test and forced swimming test, via nose-to-brain pathway. When the recombinant plasmid pGEM-T Easy/NT4-NAP was digested by EcoRI, 297 bp fragments can be obtained and NT4-NAP sequence was consistent with the designed sequence confirmed by DNA sequencing. When the recombinant plasmid pSSCMV/NT4-NAP was digested by EcoRI, 297 bp fragments is visible. Immunohistochemical staining of fibroblasts revealed that expression of NAP was detected in NT4-NAP/AAV group. Intranasal delivery of NT4-NAP/AAV significantly reduced immobility time when the FST was performed after 1 day from the last administration. The effects observed in the FST could not be attributed to non-specific increases in activity since intranasal delivery of NT4-NAP/AAV did not alter the behavior of the mice during the open field test. The results indicated that a recombinant AAV vector which could express NAP in cells was successfully constructed and NAP may be a potential target for therapeutic action of antidepressant treatment. PMID:26846142

  20. Effects of positive and negative human contacts and intranasal oxytocin on cerebrospinal fluid oxytocin.

    PubMed

    Rault, Jean-Loup

    2016-07-01

    Despite the popularity of oxytocin (OT) research for its role in social behavior, the relationship between the social environment and endogenous central OT remains poorly understood. This study investigated the effects of positive and negative human contacts and intranasal OT administration on OT concentration in the cerebrospinal fluid (CSF). The pig was used as a model, with repeated CSF sampling through a spinal catheter using a within-subject design. Positive human contact led to sustained CSF OT elevation in pigs over 120min which outlasted the 15min interaction. Furthermore, the frequency of positive interactions was correlated with CSF OT increase. This provides a neurophysiological basis to positive human-animal relationships, with OT preserving bonds within but also between species through interactions. Conversely, CSF OT concentration did not vary during or after negative contact with an unfamiliar person, supporting CSF OT as a biomarker of positive valence in the human-animal relationship context. Intranasal OT administration resulted in peak CSF OT within 10min, with approximately 0.001% of the administered dose reaching the CSF. The sensitivity of the oxytocinergic system to variations in the social environment is a worthy area of investigation for its scientific and clinical implications. In particular, positive interactions result in outlasting central OT release. PMID:27032064

  1. Intranasal pyrrolidine dithiocarbamate decreases brain inflammatory mediators and provides neuroprotection after brain hypoxia-ischemia in neonatal rats

    PubMed Central

    Wang, Zhi; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2013-01-01

    Brain injury due to birth asphyxia is the major cause of death and long-term disabilities in newborns. We determined whether intranasal pyrrolidine dithiocarbamate (PDTC) could provide neuroprotection in neonatal rats after brain hypoxia-ischemia (HI). Seven-day old male and female Sprague-Dawley rats were subjected to brain HI. They were then treated by intranasal PDTC. Neurological outcome were evaluated 7 or 30 days after the brain HI. Brain tissues were harvested 6 or 24 h after the brain HI for biochemical analysis. Here, PDTC dose-dependently reduced brain HI-induced brain tissue loss with an effective dose (ED)50 at 27 mg/kg. PDTC needed to be applied within 45 min after the brain HI for this neuroprotection. This treatment reduced brain tissue loss and improved neurological and cognitive functions assessed 30 days after the HI. PDTC attenuated brain HI-induced lipid oxidative stress, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells, and various inflammatory mediators in the brain tissues. Inhibition of inducible nitric oxide synthase after brain HI reduced brain tissue loss. Our results suggest that intranasal PDTC provides neuroprotection possibly via reducing inflammation and oxidative stress. Intranasal PDTC may have a potential to provide neuroprotection to human neonates after birth asphyxia. PMID:23994718

  2. Intranasal Insulin Prevents Cognitive Decline, Cerebral Atrophy and White Matter Changes in Murine Type I Diabetic Encephalopathy

    ERIC Educational Resources Information Center

    Francis, George J.; Martinez, Jose A.; Liu, Wei Q.; Xu, Kevin; Ayer, Amit; Fine, Jared; Tuor, Ursula I.; Glazner, Gordon; Hanson, Leah R.; Frey, William H., II; Toth, Cory

    2008-01-01

    Insulin deficiency in type I diabetes may lead to cognitive impairment, cerebral atrophy and white matter abnormalities. We studied the impact of a novel delivery system using intranasal insulin (I-I) in a mouse model of type I diabetes (streptozotocin-induced) for direct targeting of pathological and cognitive deficits while avoiding potential…

  3. Limited susceptibility and lack of systemic infection by an H3N2 swine influenza virus in intranasally inoculated chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chickens were intranasally inoculated with the swine influenza virus A/swine/NC/307408/04 (H3N2) (NC/04 SIV) to determine the infectivity of a North American SIV for chickens, as well as the possibility of chicken meat serving as a transmission vehicle for SIV. White Leghorn (WL) layer-type chicken...

  4. Intranasal Vaccination Affords Localization and Persistence of Antigen-Specific CD8+ T Lymphocytes in the Female Reproductive Tract

    PubMed Central

    Singh, Shailbala; Schluns, Kimberly S.; Yang, Guojun; Anthony, Scott M.; Barry, Michael A.; Sastry, K. Jagannadha

    2016-01-01

    Immunization strategies generating large numbers of antigen-specific T cells in the female reproductive tract (FRT) can provide barrier protection against sexually-transmitted pathogens, such as the human immunodeficiency virus (HIV) and human papillomaviruses (HPV). The kinetics and mechanisms of regulation of vaccine-induced adaptive T cell-mediated immune responses in FRT are less well defined. We present here evidence for intranasal delivery of the model antigen ovalbumin (OVA) along with alpha-galactosylceramide adjuvant as a protein vaccine to induce significantly higher levels of antigen-specific effector and memory CD8+ T cells in the FRT, relative to other systemic and mucosal tissues. Antibody blocking of the CXCR3 receptor significantly reduced antigen-specific CD8+ T cells subsequent to intranasal delivery of the protein vaccine suggesting an important role for the CXCR3 chemokine-receptor signaling for T cell trafficking. Further, intranasal vaccination with an adenoviral vector expressing OVA or HIV-1 envelope was as effective as intramuscular vaccination for generating OVA- or ENV-specific immunity in the FRT. These results support the application of the needle-free intranasal route as a practical approach to delivering protein as well as DNA/virus vector-based vaccines for efficient induction of effector and memory T cell immunity in the FRT. PMID:26999228

  5. Effects of cold pressor pain on the abuse liability of intranasal oxycodone in male and female prescription opioid abusers

    PubMed Central

    Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.

    2012-01-01

    Background Approximately 1.9 million persons in the U.S. have prescription opioid use disorders often with concomitant bodily pain, but systematic data on the impact of pain on abuse liability of opioids is lacking. The purpose of this study was to determine whether pain alters the intranasal abuse liability of oxycodone, a commonly prescribed and abused analgesic, in males and females. Methods Sporadic prescription opioid abusers (10 females, 10 males) participated in this mixed (between and within-subject), randomized inpatient study. Experimental sessions (n=6) tested intranasal placebo, oxycodone 15 or 30 mg/70 kg during cold pressor testing (CPT) and a warm water control. Observer- and subject-rated drug effect measures, analgesia, physiologic and cognitive effects were assessed. Results The CPT significantly increased blood pressure, heart rate, pain, stress, and “opiate desire” compared to the no-pain control but did not alter opioid liking, high or street value. Intranasal oxycodone produced effects within 10 minutes, significantly decreasing pain and significantly increasing subjective measures of abuse liability (e.g., high). Females had higher ratings of street value, high, and liking for one or both active doses. Conclusions The CPT was a reliably painful and stressful stimulus that did not diminish the abuse liability of intranasal Oxycodone®. Females were more sensitive to oxycodone on several abuse liability measures that warrant further follow-up. Snorting oxycodone rapidly produced psychoactive effects indicative of substantial abuse liability. PMID:22209386

  6. Safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC by intranasal administration of multiple escalating dose in healthy male subjects.

    PubMed

    Thennati, Rajamannar; Khanna, Aman; Khanna, Mallika; Sonaiya, Tushar; Mehta, Tejas; Mehta, Kalpana; Shahi, Pradeep; Patel, Jigneshkumar

    2014-11-01

    A novel corticosteroid compound (short form of IUPAC name: SFDAC) has been discovered by Sun Pharma Advanced Research Company (SPARC) Ltd. A randomized, observer-blind, active-controlled, parallel-groups, intranasal multiple escalating dose study was conducted in healthy male subjects to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC formulated as an aqueous suspension for intranasal administration. Intranasal sprays of SFDAC, active control fluticasone propionate (FP) and placebo were administered once in a day for 14 days as per randomization. Various clinical evaluations including 24-hour serum cortisol and urinary free cortisol (UFC) profiles were carried out. Blood samples were collected at pre-defined time-points and analyzed using a validated chromatographic method for estimation of SFDAC and its metabolite. The results of the study indicate that multiple dose of SFDAC intranasal spray upto 3,200 µg is safe and tolerated. Clinically significant suppression of hypothalamic pituitary adrenal (HPA) axis was not observed. The plasma concentration of SFDAC was found to be below the lower limit of quantification (LLQ) at most time-points for all subjects. SFDAC M1 metabolite was detected only at picogram level in plasma. The safety and pharmacokinetic characteristics of SFDAC observed in this study support further clinical development of the SFDAC nasal spray. PMID:27129118

  7. Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.

    PubMed

    Opler, Lewis A; Opler, Mark G A; Arnsten, Amy F T

    2016-02-01

    This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia. PMID:25619798

  8. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans

    PubMed Central

    Feng, Chunliang; Lori, Adriana; Waldman, Irwin D.; Binder, Elisabeth B.; Haroon, Ebrahim; Rilling, James K.

    2015-01-01

    Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment. PMID:26178189

  9. Dispersion-Aggregation and Wetting-Dewetting Phase Transitions in Mixtures of Polymer Grafted Nanoparticles and a Chemically Dissimilar Polymer Matrix

    NASA Astrophysics Data System (ADS)

    Martin, Tyler; Mongcopa, Katrina; Ashkar, Rana; Butler, Paul; Krishnamoorti, Ramanan; Jayaraman, Arthi

    Significant efforts have been focused towards controlling morphology of the nanoscale fillers and matrix polymer in polymer nanocomposites as the composite morphology is directly related to the macroscopic properties of that material. For nanocomposites with chemically identical graft and matrix polymers, it is well understood that the polymer grafted particle dispersion to aggregation transition is directly linked to and synonymous with wetting/dewetting of the graft and matrix polymer. Our recent work has focused on exploring composites with chemically different graft and matrix polymers, specifically those with attractive graft-matrix interactions that lead to a dispersed filler state at low temperature and aggregated filler state at high temperatures. We show, using coarse-grained molecular simulations, that the sharp phase transition from dispersed to aggregated states is distinct from the continuous wetting-dewetting transition. The onset of wetting to dewetting occurs at temperatures lower than the dispersion to aggregation transition, and dewetting continues at temperatures above the transition temperature in the aggregated state. Furthermore, the graft and matrix chain composition can be varied to tune the dispersion-aggregation transition temperature and the degree of wetting of the grafted layer. Experiments using SANS and SAXS of deuterated poly(styrene) grafted silica particles in a poly(vinyl methyl ether) matrix show remarkable agreement with our simulations.

  10. Building robust architectures of carbon-wrapped transition metal nanoparticles for high catalytic enhancement of the 2LiBH4-MgH2 system for hydrogen storage cycling performance.

    PubMed

    Huang, Xu; Xiao, Xuezhang; Shao, Jie; Zhai, Bing; Fan, Xiulin; Cheng, Changjun; Li, Shouquan; Ge, Hongwei; Wang, Qidong; Chen, Lixin

    2016-08-21

    Nanoscale catalyst doping is regarded as one of the most effective strategies to improve the kinetics performance of hydrogen storage materials, but the agglomeration of nanoparticles is usually unavoidable during the repeated de/rehydrogenation processes. Herein, hierarchically structured catalysts (Fe/C, Co/C and Ni/C) were designed and fabricated to overcome the agglomeration issue of nanocatalysts applied to the 2LiBH4-MgH2 system for the first time. Uniform transition metal (TM) nanoparticles (∼10 nm) wrapped by few layers of carbon are synthesized by pyrolysis of the corresponding metal-organic frameworks (MOFs), and introduced into the 2LiBH4-MgH2 reactive hydride composites (RHCs) by ball milling. The particular features of the carbon-wrapped architecture effectively avoid the agglomeration of the TM nanoparticles during hydrogen storage cycling, and high catalysis is maintained during the subsequent de/rehydrogenation processes. After de/rehydrogenation cycling, FeB, CoB and MgNi3B2 can be formed as the catalytically active components with a particle size of 5-15 nm, which show a homogeneous distribution in the hydride matrix. Among the three catalysts, in situ-formed MgNi3B2 shows the best catalytic efficiency. The incubation period of the Fe/C, Co/C and Ni/C-doped 2LiBH4-MgH2 system between the two dehydrogenation steps was reduced to about 8 h, 4 h and 2 h, respectively, which is about 8 h, 12 h and 14 h shorter than that of the undoped 2LiBH4-MgH2 sample. In addition, the two-step dehydrogenation peak temperatures of the Ni/C-doped 2LiBH4-MgH2 system drop to 323.4 °C and 410.6 °C, meanwhile, the apparent activation energies of dehydrogenated MgH2 and LiBH4 decrease by 58 kJ mol(-1) and 71 kJ mol(-1), respectively. In particular, the cycling hydrogen desorption of the Ni/C-doped 2LiBH4-MgH2 sample exhibits very good stability compared with the undoped sample. The present approach, which ideally addresses the agglomeration of nanoparticles with

  11. Morphological Transition of Paracoccidioides brasiliensis Conidia to Yeast Cells: In Vivo Inhibition in Females

    PubMed Central

    Aristizabal, Beatriz H.; Clemons, Karl V.; Stevens, David A.; Restrepo, Angela

    1998-01-01

    Clinical paracoccidioidomycosis is 13 times more common in men than in women. Estrogen inhibits the transition of mycelia or conidia (the saprophytic form of Paracoccidoides brasiliensis) to yeasts (the parasitic form) in vitro. Here, we show that, in male mice that were infected intranasally (mimicking natural infection) the transition of conidia in bronchoalveolar lavage fluids to intermediate forms and yeasts occurred over 24 to 96 h; CFU and yeasts (shown by histopathology) increased subsequently. In females, transition did not occur and infection cleared. These events in vivo are consistent with epidemiological and in vitro observations, suggesting that female hormones block transition and are responsible for resistance. PMID:9784579

  12. The neuronal correlates of intranasal trigeminal function-an ALE meta-analysis of human functional brain imaging data.

    PubMed

    Albrecht, Jessica; Kopietz, Rainer; Frasnelli, Johannes; Wiesmann, Martin; Hummel, Thomas; Lundström, Johan N

    2010-03-01

    Almost every odor we encounter in daily life has the capacity to produce a trigeminal sensation. Surprisingly, few functional imaging studies exploring human neuronal correlates of intranasal trigeminal function exist, and results are to some degree inconsistent. We utilized activation likelihood estimation (ALE), a quantitative voxel-based meta-analysis tool, to analyze functional imaging data (fMRI/PET) following intranasal trigeminal stimulation with carbon dioxide (CO(2)), a stimulus known to exclusively activate the trigeminal system. Meta-analysis tools are able to identify activations common across studies, thereby enabling activation mapping with higher certainty. Activation foci of nine studies utilizing trigeminal stimulation were included in the meta-analysis. We found significant ALE scores, thus indicating consistent activation across studies, in the brainstem, ventrolateral posterior thalamic nucleus, anterior cingulate cortex, insula, precentral gyrus, as well as in primary and secondary somatosensory cortices-a network known for the processing of intranasal nociceptive stimuli. Significant ALE values were also observed in the piriform cortex, insula, and the orbitofrontal cortex, areas known to process chemosensory stimuli, and in association cortices. Additionally, the trigeminal ALE statistics were directly compared with ALE statistics originating from olfactory stimulation, demonstrating considerable overlap in activation. In conclusion, the results of this meta-analysis map the human neuronal correlates of intranasal trigeminal stimulation with high statistical certainty and demonstrate that the cortical areas recruited during the processing of intranasal CO(2) stimuli include those outside traditional trigeminal areas. Moreover, through illustrations of the considerable overlap between brain areas that process trigeminal and olfactory information; these results demonstrate the interconnectivity of flavor processing. PMID:19913573

  13. Comparison of Oral and Intranasal Midazolam/Ketamine Sedation in 3-6-year-old Uncooperative Dental Patients

    PubMed Central

    Fallahinejad Ghajari, Masoud; Ansari, Ghassem; Soleymani, Ali Asghar; Shayeghi, Shahnaz; Fotuhi Ardakani, Faezeh

    2015-01-01

    Background and aims. There are several known sedative drugs, with midazolam and ketamine being the most commonly used drugs in children. The aim of this study was to compare the effect of intranasal and oral midazolam plus ketamine in children with high levels of dental anxiety. Materials and methods.A crossover double-blind clinical trial was conducted on 23 uncooperative children aged 3-6 (negative or definitely negative by Frankel scale), who required at least two similar dental treatment visits. Cases were randomly given ketamine (10 mg/kg) and midazolam (0.5 mg/kg) through oral or intranasal routes in each visit. The sedative efficacy of the agents was assessed by an overall success rate judged by two independent pediatric dentists based on Houpt’s scale for sedation. Data analysis was carried out using Wilcoxon test and paired t-test. Results. Intranasal administration was more effective in reduction of crying and movement during dental procedures compared to oral sedation (P<0.05). Overall behavior control was scored higher in nasal compared to oral routes at the time of LA injection and after 15 minutes (P<0.05). The difference was found to be statistically significant at the start and during treatment. However, the difference was no longer significant after 30 minutes, with the vital signs remaining within physiological limits. Recovery time was longer in the intranasal group (P<0.001) with a more sleepy face (P=0.004). Conclusion.. Intranasal midazolam/ketamine combination was more satisfactory and effective than the oral route when sedating uncooperative children. PMID:26236429

  14. Intranasal haloperidol-loaded miniemulsions for brain targeting: Evaluation of locomotor suppression and in-vivo biodistribution.

    PubMed

    El-Setouhy, Doaa Ahmed; Ibrahim, A B; Amin, Maha M; Khowessah, Omneya M; Elzanfaly, Eman S

    2016-09-20

    Haloperidol is a commonly prescribed antipsychotic drug currently administered as oral and injectable preparations. This study aimed to prepare haloperidol intranasal miniemulsion helpful for psychiatric emergencies and exhibiting lower systemic exposure and side effects associated with non-target site delivery. Haloperidol miniemulsions were successfully prepared by spontaneous emulsification adopting 2(3) factorial design. The effect of three independent variables at two levels each namely; oil type (Capmul®-Capryol™90), lipophilic emulsifier type (Span 20-Span 80) and HLB value (12-14) on globule size, PDI and percent locomotor activity inhibition in mice was evaluated. The optimized formula (F4, Capmul®, Tween 80/Span 20, HLB 14) showed globule size of 209.5±0.98nm, PDI of 0.402±0.03 and locomotor inhibition of 83.89±9.15% with desirability of 0.907. Biodistribution study following intranasal and intravenous administration of the radiolabeled (99m)Tc mucoadhesive F4 revealed that intranasal administration achieved 1.72-fold higher and 6 times faster peak brain levels compared with intravenous administration. Drug targeting efficiency percent and brain/blood exposure ratios remained above 100% and 1 respectively after intranasal instillation compared to a maximum brain/blood exposure ratio of 0.8 post intravenous route. Results suggested the CNS delivery of major fraction of haloperidol via direct transnasal to brain pathway that can be a promising alternative to oral and parenteral routes in chronic and acute situations. Haloperidol concentration of 275.6ng/g brain 8h post intranasal instillation, higher than therapeutic concentration range of haloperidol (0.8 to 5.15ng/ml), suggests possible sustained delivery of the drug through nasal route. PMID:27154259

  15. Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection

    PubMed Central

    Marriott, Anthony C.; Dennis, Mike; Kane, Jennifer A.; Gooch, Karen E.; Hatch, Graham; Sharpe, Sally; Prevosto, Claudia; Leeming, Gail; Zekeng, Elsa-Gayle; Staples, Karl J.; Hall, Graham; Ryan, Kathryn A.; Bate, Simon; Moyo, Nathifa; Whittaker, Catherine J.; Hallis, Bassam; Silman, Nigel J.; Lalvani, Ajit; Wilkinson, Tom M.; Hiscox, Julian A.; Stewart, James P.; Carroll, Miles W.

    2016-01-01

    Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections. PMID

  16. Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.

    PubMed

    Marriott, Anthony C; Dennis, Mike; Kane, Jennifer A; Gooch, Karen E; Hatch, Graham; Sharpe, Sally; Prevosto, Claudia; Leeming, Gail; Zekeng, Elsa-Gayle; Staples, Karl J; Hall, Graham; Ryan, Kathryn A; Bate, Simon; Moyo, Nathifa; Whittaker, Catherine J; Hallis, Bassam; Silman, Nigel J; Lalvani, Ajit; Wilkinson, Tom M; Hiscox, Julian A; Stewart, James P; Carroll, Miles W

    2016-01-01

    Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections. PMID

  17. Intranasal and intramuscular proteosome-staphylococcal enterotoxin B (SEB) toxoid vaccines: immunogenicity and efficacy against lethal SEB intoxication in mice.

    PubMed Central

    Lowell, G H; Kaminski, R W; Grate, S; Hunt, R E; Charney, C; Zimmer, S; Colleton, C

    1996-01-01

    Intranasal or intramuscular (i.m.) immunization of mice and i.m. immunization of rabbits with formalinized staphylococcal enterotoxin B (SEB) toxoid in saline elicited higher anti-SEB serum immunoglobulin G (IgG) titers when the toxoid was formulated with proteosomes. In addition, intranasal immunization of mice with this proteosome-toxoid vaccine elicited high levels of anti-SEB IgA in lung and intestinal secretions, whereas the toxoid without proteosomes did not. Two i.m. immunizations with proteosome-toxoid plus alum also induced higher murine serum responses than alum-adjuvanted toxoid without proteosomes. Furthermore, proteosome-toxoid delivered intranasally in saline or i.m. with either saline or alum afforded significant protection against lethal SEB challenge in two D-galactosamine-sensitized murine models of SEB intoxication, i.e., the previously described i.m. challenge model and a new respiratory challenge model of mucosal SEB exposure. Efficacy correlated with the induction of high serum levels of anti-SEB IgG. In contrast, intranasal or i.m. immunization with toxoid in saline without proteosomes was not significantly protective in either challenge model. Proteosome-toxoid plus alum given i.m. also elicited more significant protection against respiratory challenge than the alum-adjuvanted toxoid alone. The capacity of proteosomes to enhance both i.m. and intranasal immunogenicity and efficacy of SEB toxoid indicates that testing such proteosome-SEB toxoid vaccines in the nonhuman primate aerosol challenge model of SEB intoxication prior to immunogenicity trials in humans is warranted. These data expand the applicability of the proteosome mucosal vaccine delivery system to protein toxoids and suggest that respiratory delivery of proteosome vaccines may be practical for enhancement of both mucosal and systemic immunity against toxic or infectious diseases. PMID:8613381

  18. Intranasal priming with recombinant Bordetella pertussis for the induction of a systemic immune response against a heterologous antigen.

    PubMed Central

    Mielcarek, N; Cornette, J; Schacht, A M; Pierce, R J; Locht, C; Capron, A; Riveau, G

    1997-01-01

    One of the current goals in vaccine development is the noninvasive administration of protective antigens via mucosal surfaces. In this context, the gut-associated lymphoid tissues have already been extensively explored. Vaccination via the nasal route has only recently been the focus of intensive investigation, and no live vector specifically designed for the respiratory mucosa is yet available. In this study we show that intranasal administration of the recombinant Bordetella pertussis BPGR60, producing the Schistosoma mansoni 28-kDa glutathione S-transferase (Sm28GST) protective antigen fused to filamentous hemagglutinin, induces priming in mice for the production of serum antibodies. In addition to significant levels of anti-Sm28GST immunoglobulin A (IgA) antibodies, high levels of anti-Sm28GST serum antibodies were obtained after intranasal boost with the purified antigen or infection with S. mansoni following intranasal priming with BPGR60. These antibodies were of the IgG1, IgG2a, and IgG2b isotypes, suggesting a mixed immune response. No priming was observed in animals that had received nonrecombinant B. pertussis or purified Sm28GST, indicating specific priming by BPGR60. This priming was also evident in immune protection against S. mansoni challenge. Significant protection against worm burden and egg output was obtained in mice primed with BPGR60 and intranasally boosted with purified Sm28GST. A lower but still significant degree of protection against egg output was also obtained in mice infected with a single dose of BPGR60. These results indicate that intranasal administration of recombinant B. pertussis can prime for serum antibody responses against a foreign antigen and for heterologous protection. PMID:9009311

  19. Chitosan nanoparticle encapsulated hemagglutinin-split influenza virus mucosal vaccine.

    PubMed

    Sawaengsak, Chompoonuch; Mori, Yasuko; Yamanishi, Koichi; Mitrevej, Ampol; Sinchaipanid, Nuttanan

    2014-04-01

    Subunit/split influenza vaccines are less reactogenic compared with the whole virus vaccines. However, their immunogenicity is relatively low and thus required proper adjuvant and/or delivery vehicle for immunogenicity enhancement. Influenza vaccines administered intramuscularly induce minimum, if any, mucosal immunity at the respiratory mucosa which is the prime site of the infection. In this study, chitosan (CS) nanoparticles were prepared by ionic cross-linking of the CS with sodium tripolyphosphate (TPP) at the CS/TPP ratio of 1:0.6 using 2 h mixing time. The CS/TPP nanoparticles were used as delivery vehicle of an intranasal influenza vaccine made of hemagglutinin (HA)-split influenza virus product. Innocuousness, immunogenicity, and protective efficacy of the CS/TPP-HA vaccine were tested in influenza mouse model in comparison with the antigen alone vaccine. The CS/TPP-HA nanoparticles had required characteristics including nano-sizes, positive charges, and high antigen encapsulation efficiency. Mice that received two doses of the CS/TPP-HA vaccine intranasally showed no adverse symptoms indicating the vaccine innocuousness. The animals developed higher systemic and mucosal antibody responses than vaccine made of the HA-split influenza virus alone. The CS/TPP-HA vaccine could induce also a cell-mediated immune response shown as high numbers of IFN-γ-secreting cells in spleens while the HA vaccine alone could not. Besides, the CS nanoparticle encapsulated HA-split vaccine reduced markedly the influenza morbidity and also conferred 100% protective rate to the vaccinated mice against lethal influenza virus challenge. Overall results indicated that the CS nanoparticles invented in this study is an effective and safe delivery vehicle/adjuvant for the influenza vaccine. PMID:24343789

  20. Surface-induced phase behavior of polymer/nanoparticle blends with attractions.

    PubMed

    Frischknecht, Amalie L; Padmanabhan, Venkat; Mackay, Michael E

    2012-04-28

    In an athermal blend of nanoparticles and homopolymer near a hard wall, there is a first order phase transition in which the nanoparticles segregate to the wall and form a densely packed monolayer above a certain nanoparticle density. Previous investigations of this phase transition employed a fluids density functional theory (DFT) at constant packing fraction. Here we report further DFT calculations to probe the robustness of this phase transition. We find that the phase transition also occurs in athermal systems at constant pressure, the more natural experimental condition than constant packing fraction. Adding nanoparticle-polymer attractions increases the nanoparticle transition density, while sufficiently strong attractions suppress the first-order transition entirely. In this case the systems display a continuous transition to a bulk layered state. Adding attractions between the polymers and the wall has a similar effect of delaying and then suppressing the first-order nanoparticle segregation transition, but does not lead to any continuous phase transitions. PMID:22559503

  1. Intranasal treatment with luteinising hormone releasing hormone agonist in women with endometriosis.

    PubMed Central

    Shaw, R W; Fraser, H M; Boyle, H

    1983-01-01

    An agonist analogue of luteinising hormone releasing hormone (buserelin) was successfully used to treat women with endometriosis. A dose of 200 micrograms administered intranasally thrice daily was found to be effective in five patients, in whom the endometriotic lesions resolved after six months' treatment. Failure occurred in a sixth patient, who received only 400 micrograms once daily. Anovulation was induced in all subjects together with suppression of menstruation after the first month of treatment. Symptoms of abdominal pain, dysmenorrhoea, and dyspareunia were relieved during treatment, and one previously infertile patient conceived within two months of stopping treatment. No side effects were reported with this dosage, and the results suggest a new form of treatment for patients with endometriosis. PMID:6416542

  2. The acute effects of intranasal oxytocin on automatic and effortful attentional shifting to emotional faces.

    PubMed

    Ellenbogen, Mark A; Linnen, Anne-Marie; Grumet, Robin; Cardoso, Christopher; Joober, Ridha

    2012-01-01

    Oxytocin is known to promote social affiliation. The mechanism by which this occurs is unknown, but it may involve changes in social information processing. In a placebo-controlled study, we examined the influence of intranasal oxytocin on effortful and automatic attentional shifting in 57 participants using a spatial cueing task with emotional and neutral faces. For effortful processing, oxytocin decreased the speed of shifting attention to sad faces presented for 750 ms and facilitated disengagement from right hemifield sad and angry faces presented for 200 ms. For automatic processing, symptoms of depression moderated the relationship between drug and disengagement. Oxytocin attenuated an attentional bias to masked angry faces on disengagement trials in persons with high depression scores. Oxytocin's influence on social behavior may occur, in part, by eliciting flexible attentional shifting in the early stages of information processing. PMID:22092248

  3. Effects of intranasal oxytocin on pupil dilation indicate increased salience of socioaffective stimuli.

    PubMed

    Prehn, Kristin; Kazzer, Philipp; Lischke, Alexander; Heinrichs, Markus; Herpertz, Sabine C; Domes, Gregor

    2013-06-01

    To investigate the mechanisms by which oxytocin improves socioaffective processing, we measured behavioral and pupillometric data during a dynamic facial emotion recognition task. In a double-blind between-subjects design, 47 men received either 24 IU intranasal oxytocin (OXT) or a placebo (PLC). Participants in the OXT group recognized all facial expressions at lower intensity levels than did participants in the PLC group. Improved performance was accompanied by increased task-related pupil dilation, indicating an increased recruitment of attentional resources. We also found increased pupil dilation during the processing of female compared with male faces. This gender-specific stimulus effect diminished in the OXT group, in which pupil size specifically increased for male faces. Results suggest that improved emotion recognition after OXT treatment might be due to an intensified processing of stimuli that usually do not recruit much attention. PMID:23551070

  4. Size-dependent magnetic transitions in CoFe0.1Cr1.9O4 nanoparticles studied by magnetic and neutron-polarization analysis

    NASA Astrophysics Data System (ADS)

    Kumar, D.; Galivarapu, J. K.; Banerjee, A.; Nemkovski, K. S.; Su, Y.; Rath, Chandana

    2016-04-01

    Multiferroic, CoCr2O4 bulk material undergoes successive magnetic transitions such as a paramagnetic to collinear and non-collinear ferrimagnetic state at the Curie temperature (T C) and spiral ordering temperature (T S) respectively and finally to a lock-in-transition temperature (T l). In this paper, the rich sequence of magnetic transitions in CoCr2O4 after mixing the octahedral site with 10% of iron are investigated by varying the size of the particle from 10 to 50 nm. With the increasing size, while the T C increases from 110 to 119 K which is higher than the T C (95 K) of pure CoCr2O4, the T S remains unaffected. In addition, a compensation of magnetization at 34 K and a lock-in transition at 10 K are also monitored in 50 nm particles. Further, we have examined the magnetic-ordering temperatures through neutron scattering using a polarized neutron beam along three orthogonal directions after separating the magnetic scattering from nuclear-coherent and spin-incoherent contributions. While a sharp long-range ferrimagnetic ordering down to 110 K and a short-range spiral ordering down to 50 K are obtained in 50 nm particles, in 10 nm particles, the para to ferrimagnetic transition is found to be continuous and spiral ordering is diffused in nature. Frequency-dependent ac susceptibility (χ) data fitted with different phenomenological models such as the Neel-Arrhenius, Vogel-Fulcher and power law, while ruling out the canonical spin-glass, cluster-glass and interacting superparamagnetism, reveal that both particles show spin-glass behavior with a higher relaxation time in 10 nm particles than in 50 nm. The smaller spin flip time in 50 nm particles confirms that spin dynamics does not slow down on approaching the glass transition temperature (T g).

  5. Size-dependent magnetic transitions in CoFe0.1Cr1.9O4 nanoparticles studied by magnetic and neutron-polarization analysis.

    PubMed

    Kumar, D; Galivarapu, J K; Banerjee, A; Nemkovski, K S; Su, Y; Rath, Chandana

    2016-04-29

    Multiferroic, CoCr2O4 bulk material undergoes successive magnetic transitions such as a paramagnetic to collinear and non-collinear ferrimagnetic state at the Curie temperature (TC) and spiral ordering temperature (TS) respectively and finally to a lock-in-transition temperature (Tl). In this paper, the rich sequence of magnetic transitions in CoCr2O4 after mixing the octahedral site with 10% of iron are investigated by varying the size of the particle from 10 to 50 nm. With the increasing size, while the TC increases from 110 to 119 K which is higher than the TC (95 K) of pure CoCr2O4, the TS remains unaffected. In addition, a compensation of magnetization at 34 K and a lock-in transition at 10 K are also monitored in 50 nm particles. Further, we have examined the magnetic-ordering temperatures through neutron scattering using a polarized neutron beam along three orthogonal directions after separating the magnetic scattering from nuclear-coherent and spin-incoherent contributions. While a sharp long-range ferrimagnetic ordering down to 110 K and a short-range spiral ordering down to 50 K are obtained in 50 nm particles, in 10 nm particles, the para to ferrimagnetic transition is found to be continuous and spiral ordering is diffused in nature. Frequency-dependent ac susceptibility (χ) data fitted with different phenomenological models such as the Neel-Arrhenius, Vogel-Fulcher and power law, while ruling out the canonical spin-glass, cluster-glass and interacting superparamagnetism, reveal that both particles show spin-glass behavior with a higher relaxation time in 10 nm particles than in 50 nm. The smaller spin flip time in 50 nm particles confirms that spin dynamics does not slow down on approaching the glass transition temperature (Tg). PMID:26978515

  6. Medical costs and adherence in patients receiving aqueous versus pressurized aerosol formulations of intranasal corticosteroids.

    PubMed

    Hankin, Cheryl S; Cox, Linda; Lang, David; Bronstone, Amy; Wang, Zhaohui; Lepore, Mark S; Buck, Philip O

    2012-01-01

    Intranasal corticosteroid (INS) formulations have different sensory attributes that influence patient preferences, and thereby possibly adherence and health outcomes. This study compares health care use and costs and medication adherence in matched cohorts of patients with allergic rhinitis (AR) using a chlorofluorocarbon-propelled pressurized metered-dose inhaler (pMDI) or aqueous intranasal corticosteroid (A-INS). Florida Medicaid retrospective claims analysis was performed of enrollees aged ≥12 years with at least 1 year of continuous enrollment before their initial AR diagnosis, 1 year for continuous enrollment before their index INS claim, and 18 months of continuous enrollment after their index INS claim during which they received either pMDI or A-INS. pMDI and A-INS patients were matched 1:2 using propensity scores. Nonparametric analyses compared outcomes between matched cohorts at 6, 12, and 18 months of follow-up. A total of 585 patients were matched (pMDI = 195, A-INS = 390). pMDI patients were more adherent to INS, as reflected in their higher median medication possession ratio (53.2% versus 32.7%; p < 0.0001) and fewer median days between fills (73 days versus 111 days; p = 0.0003). Significantly lower median per patient pharmacy fills (34.0 versus 50.5; p < 0.05) and costs ($1282 versus $2178; p < 0.01) were observed among pMDI patients versus A-INS patients 18 months after INS initiation and were maintained when analyses excluded INS fills. Adherence to INS and health care utilization and costs following INS initiation for AR differed by type of formulation received. Our findings suggest patient preferences for INS sensory attributes can drive adherence and affect disease control, and ultimately impact health care costs. PMID:22737709

  7. Chitosan-Based Intranasal Vaccine against Escherichia coli O157:H7

    PubMed Central

    Doavi, Tahere; Mousavi, Seyed Latif; Kamali, Mehdi; Amani, Jafar; Fasihi Ramandi, Mahdi

    2016-01-01

    Background: Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an infectious zoonotic pathogen causing human infections. These infections, in some cases, can lead to hemolytic uremic syndrome and its life-threatening complications and even death worldwide. The first intimate bacterial adhesion, intimin (I), with its own receptor translocated intimin receptor (Tir) and E. coli secreted protein A, acting as Tir conduit, are highly immunogenic proteins for vaccine development against E. coli O157:H7. Methods: A chimeric trivalent recombinant protein was previously found to be a suitable strategy for developing vaccines against E. coli O157:H7. In this study, the recombinant EIT (rEIT) was used to design a protective EHEC nasal nanovaccine. Chitosan and its water-soluble derivative, trimethylated chitosan (TMC), as muco-adhesive biopolymers, are good candidates for preparation of nanovaccines.  Using the electrospraying technique, as a novel method, we could obtain particles of rEIT loaded with chitosan and TMC on a nanometer scale. Mice were immunized with intranasal administration or intrapretoneal injection of rEIT. Results: The rEIT-specific immune responses (IgG and IgA) were measured by indirect ELISA. Only nasal administration of chitosan electrospray and TMC formulation produced significant secretion IgA. Intranasal administration of nanovaccine reduced the duration of bacterial fecal shedding on mice challenged with E. coli O157:H7. Conclusion: Since development of mucosal vaccines for the prevention of infectious diseases requires efficient antigen delivery; therefore, this research could be a new strategy for developing vaccine against E. coli O157:H7. PMID:26724233

  8. Analysis on correlation between SP and NK-1R and intranasal mucosal contact point headache.

    PubMed

    Zhao, Guomin; Yin, Jinshu; Peng, Hong; Wang, Jing

    2016-05-01

    Conclusion Distribution of SP and NK-1R, especially NK-1R, in nasal mucosal tissue at contact point was higher compared with non-contact point. It was suggested that SP and NK-1R were associated with mucosal contact point headache. Objectives To observe difference of substance P (SP) and NK-1 receptor (NK-1R) expression in tissues at contact point and non-contact point among the patients with intranasal mucosal contact point headache and speculate the role of SP and NK-1R in mucosal contact point headache. Methods SP and NK-1R in tissues of contact point and non-contact point among 40 patients with intranasal mucosal contact point headache were stained histologically by immunohistochemistry, and the mRNA level was detected by RT-PCR. Results SP was located in cytoplasm of acini epithelial cells, distributed in nasal mucosa tissues at both contact point and non-contact point. However, stain intensity was significantly increased at contact point (Z = -2.554, p < 0.05). NK-1R was located in the cytoplasm of acinar epithelial cells, inflammatory cells, and nerve fibers of contact point; only in cytoplasm of acinar epithelial cells and nerve fibers of non-contact point. Tinctorial rate of NK-1R increased significantly at contact point (χ(2) = 40.438, p < 0.01). mRNA level of SP and NK-1R was up-regulated in nasal mucosa at contact point compared with non-contact point. PMID:26817501

  9. Mucosal Immune Responses and Protection against Tetanus Toxin after Intranasal Immunization with Recombinant Lactobacillus plantarum

    PubMed Central

    Grangette, Corinne; Müller-Alouf, Heide; Goudercourt, Denise; Geoffroy, Marie-Claude; Turneer, Mireille; Mercenier, Annick

    2001-01-01

    The use of live microorganisms as an antigen delivery system is an effective means to elicit local immune responses and thus represents a promising strategy for mucosal vaccination. In this respect, lactic acid bacteria represent an original and attractive approach, as they are safe organisms that are used as food starters and probiotics. To determine whether an immune response could be elicited by intranasal delivery of recombinant lactobacilli, a Lactobacillus plantarum strain of human origin (NCIMB8826) was selected as the expression host. Cytoplasmic production of the 47-kDa fragment C of tetanus toxin (TTFC) was achieved at different levels depending on the plasmid construct. All recombinant strains proved to be immunogenic by the intranasal route in mice and able to elicit very high systemic immunoglobulin G (IgG1, IgG2b, and IgG2a) responses which correlated to the antigen dose. No significant differences in enzyme-linked immunosorbent assay IgG titers were observed when mice were immunized with live or mitomycin C-treated recombinant lactobacilli. Nevertheless, protection against the lethal effect of tetanus toxin was obtained only with the strains producing the highest dose of antigen and was greater following immunization with live bacteria. Significant TTFC-specific mucosal IgA responses were measured in bronchoalveolar lavage fluids, and antigen-specific T-cell responses were detected in cervical lymph nodes, both responses being higher in mice receiving a double dose of bacteria (at a 24-h interval) at each administration. These results demonstrate that recombinant lactobacilli can induce specific humoral (protective) and mucosal antibodies and cellular immune response against protective antigens upon nasal administration. PMID:11179325

  10. Comparison of intranasal administration of xylazine, diazepam, and midazolam in budgerigars (Melopsittacus undulatus): clinical evaluation.

    PubMed

    Sadegh, Amin Bigham

    2013-06-01

    Effective sedation methods are important to facilitate safe handling for diagnostic and clinical procedures for small and often delicate birds such as budgerigars (Melopsittacus undulatus). The aim of this study was to directly compare the time of onset and duration of sedation produced by intranasal administration of xylazine, diazepam, or midazolam in budgerigars. Fifteen (seven male, eight female) clinically healthy mature budgerigars weighing 28.9 +/- 6.1 g were involved in the study Each bird was used three times in a randomized crossover study design with 7 days between treatments. Birds received xylazine (25.6 +/- 2.2 mg/kg), diazepam (13.6 +/- 1.1 mg/kg), or midazolam (13.2 +/- 1.3 mg/kg) intranasally (i.n.) using a micropipette. The onset time and dorsal recumbency duration time were measured and recorded. Sedation was produced in all birds after i.n. administration of xylazine, diazepam, and midazolam. Time to onset of sedation was significantly shorter after midazolam (1.3 +/- 0.44 min) compared with that after xylazine (2.6 +/- 0.89 min) and diazepam (2.8 +/- 0.88 min). Xylazine produced significantly longer duration of sedation (286.0 +/- 28.8 min) than that produced by diazepam (165.40 +/- 19.2 min) and midazolam (71.60 +/- 8.9 min). This study demonstrated that i.n. drug administration could provide fast and reliable sedation in budgerigars. Although i.n. midazolam or diazepam can provide adequate sedation for diagnostic and minor therapeutic procedures, xylazine at the dose used in this study is not recommended because the quality of sedation may be insufficient to perform a clinical procedure. PMID:23805540

  11. Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial

    PubMed Central

    Sabzghabaee, Ali Mohammad; Eizadi-Mood, Nastaran; Zandifar, Samaneh

    2014-01-01

    Introduction This study was designed to compare the effects of intranasal (IN) and intravenous (IV) administration of naloxone in patients who had overdosed on opioids. Material and methods This randomized clinical trial study was conducted in the Department of Poisoning Emergencies at Noor and Ali Asghar (PBUH) University Hospital. One hundred opioid overdose patients were assigned by random allocation software into two study groups (n = 50). Both groups received 0.4 mg naloxone: one group IN and the other IV. Outcomes included change in the level of consciousness (measured using a descriptive scale and the Glasgow Coma Scale (GCS)), time to response, vital signs (blood pressure, heart rate and respiratory rate), arterial blood O2 saturation before and after naloxone administration, side-effects (agitation) and length of hospital stay. Results Patients who had been administered IN naloxone demonstrated significantly higher levels of consciousness than those in the IV group using both descriptive and GCS scales (p < 0.001). There was a significant difference in the heart rate between IN and IV groups (p = 0.003). However, blood pressure, respiratory rate and arterial O2 saturation were not significantly different between the two groups after naloxone administration (p = 0.18, p = 0.17, p = 0.32). There was also no significant difference in the length of hospital stay between the two groups (p = 0.14). Conclusions Intranasal naloxone is as effective as IV naloxone in reversing both respiratory depression and depressive effects on the central nervous system caused by opioid overdose. PMID:24904666

  12. Bystander suppression to unrelated allergen sensitization through intranasal administration of tolerogenic exosomes in mouse.

    PubMed

    Prado, Noela; Cañamero, Marta; Villalba, Mayte; Rodríguez, Rosalía; Batanero, Eva

    2010-07-01

    Exosomes represent a new family of bioactive nanovesicles (30-100 nm in diameter) secreted by different cell types whose appealing features can be exploited for designing vaccines in the context of several human diseases. We previously reported the potential of bronchoalveolar lavage fluid (BALF)-derived tolerogenic exosomes (Exo(Tol)) to be used as a nasal allergy vaccine in a mouse model of sensitization to Ole e 1, the main allergen of olive pollen. The aim of the study was to investigate whether such nanovesicles specific to Ole e 1 can also prevent the sensitization to other unrelated allergen, as Bet v 1 from birch pollen. Exo(Tol) were isolated from BALF of mice tolerized against Ole e 1 and used in a prophylactic approach. BALB/c mice were intranasally pretreated with Exo(Tol) one week before sensitization/challenge with Bet v 1, and the magnitude of allergen-specific response was analyzed. Intranasal pretreatment with Exo(Tol) resulted in significant inhibition of both specific IgE and IgG1 antibodies levels. Moreover, T cells from mice pretreated with Exo(Tol) showed a reduction in IL-5 and IL-13 (Th2 cytokines) production. Lung inflammatory response triggered by unrelated allergen-challenge was also significantly reduced after pretreatment: perivascular/peribronchial inflammatory cell infiltration, eosinophilia and mucus secretion. In conclusion, Exo(Tol) specific to Ole e 1, in addition to inhibit specific immune response to this allergen, blocked the allergic response to a second unrelated allergen such as Bet v 1. The in vivo "bystander suppression" that we herein describe for Exo(Tol) may have implications for the treatment of allergy based on mucosal tolerance induction. PMID:20478618

  13. Pharmacokinetics of Intranasal Scopolamine Gel Formulation During Antiorthostatic Bed Rest, a Microgravity Analog

    NASA Technical Reports Server (NTRS)

    Singh, Rajendra P.; Daniels, Vernie R.; Crady, Camille J.; Derendorf, H.; Putcha, L.

    2011-01-01

    Statement of Purpose, Innovation or Hypothesis: Space Motion sickness (SMS) is a long-standing problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is frequently used for the treatment of motion sickness (MS), and is available as transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability, thus allowing precise and reduced dosing in addition to offering rescue and treatment options. An intranasal gel dosage formulation of scopolamine (INSCOP) was developed and pharmacokinetics (PK) and bioavailability were determined in clinical trials with human subjects under IND guidelines.Description of Methods and Materials: The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostaticbed rest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 mg and 0.4 mg doses of INSCOP during AMB and ABR in a 4-way crossover design.Data and Results: Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose, Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration-versus-time curve (AUC) during ABR after the 0.4 mg dose.Interpretation, Conclusion or Significance: The difference in AUC and Cls at the higher (0.4 mg) but not the lower dose (0.2 mg) during ABR suggests that ABR may affect metabolism and/or clearance of INSCOP at higher doses . These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

  14. Formulation and evaluation of in situ gelling systems for intranasal administration of gastrodin.

    PubMed

    Cai, Zheng; Song, Xiangrong; Sun, Feng; Yang, Zhaoxiang; Hou, Shixiang; Liu, Zhongqiu

    2011-12-01

    Gastrodin is the major bioactive constituent of the traditional Chinese drug "Tianma." It is used in the treatment of some nervous system diseases and can be transported to the brain via intranasal administration. In the current paper, the development of a novel ion-activated in situ gelling system for the nasal delivery of gastrodin is discussed. An in situ perfusion model was used to determine the absorption-rate constant of gastrodin through rat nasal mucosa. The optimal formulation was determined by measuring the critical cation concentration, anti-dilution capacity, gel expansion coefficient, water-holding capacity, and adhesive capacity. The best formulation consisted of 10% gastrodin, 0.5% deacetylated gellan gum as the gelatinizer, and 0.03% ethylparaben as the preservative. The rheological properties of gastrodin nasal in situ gels were also investigated. The viscosity and elasticity sharply increased at temperatures below 25°C. When physiological concentrations of cations were added into the preparation, the mixture gelled into a semi-solid. The results of an accelerated stability test show that gastrodin nasal in situ gels can be stable for more than 2 years. Mucociliary toxicity was evaluated using the in situ toad palate model and the rat nasal mucociliary method; both models demonstrated no measurable ciliotoxicity. Pharmacodynamic studies suggest that similar acesodyne and sedative effects were induced following intranasal administration of 50 mg/kg gastrodin nasal in situ gels or oral administration of 100 mg/kg gastrodin solution. The in situ gel preparation is a safe and effective nasal delivery system for gastrodin. PMID:21879392

  15. Kinetics of Satratoxin G Tissue Distribution and Excretion Following Intranasal Exposure in the Mouse

    PubMed Central

    Amuzie, Chidozie J.; Islam, Zahidul; Kim, Jae Kyung; Seo, Ji-Hyun; Pestka, James J.

    2010-01-01

    Intranasal exposure of mice to satratoxin G (SG), a macrocyclic trichothecene produced by the indoor air mold Stachybotrys chartarum, selectively induces apoptosis in olfactory sensory neurons (OSNs) of the nose and brain. The purpose of this study was to measure the kinetics of distribution and clearance of SG in the mouse. Following intranasal instillation of female C57B16 mice with SG (500 μg/kg bw), the toxin was detectable from 5 to 60 min in blood and plasma, with the highest concentrations, 30 and 19 ng/ml, respectively, being observed at 5 min. SG clearance from plasma was rapid and followed single-compartment kinetics (t1/2 = 20 min) and differed markedly from that of other tissues. SG concentrations were maximal at 15–30 min in nasal turbinates (480 ng/g), kidney (280 ng/g), lung (250 ng/g), spleen (200 ng/g), liver (140 ng/g), thymus (90 ng/g), heart (70 ng/g), olfactory bulb (14 ng/g), and brain (3 ng/g). The half-lives of SG in the nasal turbinate and thymus were 7.6 and 10.1 h, respectively, whereas in other organs, these ranged from 2.3 to 4.4 h. SG was detectable in feces and urine, but cumulative excretion over 5 days via these routes accounted for less than 0.3% of the total dose administered. Taken together, SG was rapidly taken up from the nose, distributed to tissues involved in respiratory, immune, and neuronal function, and subsequently cleared. However, a significant amount of the toxin was retained in the nasal turbinate, which might contribute to SG’s capacity to evoke OSN death. PMID:20466779

  16. Building robust architectures of carbon-wrapped transition metal nanoparticles for high catalytic enhancement of the 2LiBH4-MgH2 system for hydrogen storage cycling performance

    NASA Astrophysics Data System (ADS)

    Huang, Xu; Xiao, Xuezhang; Shao, Jie; Zhai, Bing; Fan, Xiulin; Cheng, Changjun; Li, Shouquan; Ge, Hongwei; Wang, Qidong; Chen, Lixin

    2016-08-01

    Nanoscale catalyst doping is regarded as one of the most effective strategies to improve the kinetics performance of hydrogen storage materials, but the agglomeration of nanoparticles is usually unavoidable during the repeated de/rehydrogenation processes. Herein, hierarchically structured catalysts (Fe/C, Co/C and Ni/C) were designed and fabricated to overcome the agglomeration issue of nanocatalysts applied to the 2LiBH4-MgH2 system for the first time. Uniform transition metal (TM) nanoparticles (~10 nm) wrapped by few layers of carbon are synthesized by pyrolysis of the corresponding metal-organic frameworks (MOFs), and introduced into the 2LiBH4-MgH2 reactive hydride composites (RHCs) by ball milling. The particular features of the carbon-wrapped architecture effectively avoid the agglomeration of the TM nanoparticles during hydrogen storage cycling, and high catalysis is maintained during the subsequent de/rehydrogenation processes. After de/rehydrogenation cycling, FeB, CoB and MgNi3B2 can be formed as the catalytically active components with a particle size of 5-15 nm, which show a homogeneous distribution in the hydride matrix. Among the three catalysts, in situ-formed MgNi3B2 shows the best catalytic efficiency. The incubation period of the Fe/C, Co/C and Ni/C-doped 2LiBH4-MgH2 system between the two dehydrogenation steps was reduced to about 8 h, 4 h and 2 h, respectively, which is about 8 h, 12 h and 14 h shorter than that of the undoped 2LiBH4-MgH2 sample. In addition, the two-step dehydrogenation peak temperatures of the Ni/C-doped 2LiBH4-MgH2 system drop to 323.4 °C and 410.6 °C, meanwhile, the apparent activation energies of dehydrogenated MgH2 and LiBH4 decrease by 58 kJ mol-1 and 71 kJ mol-1, respectively. In particular, the cycling hydrogen desorption of the Ni/C-doped 2LiBH4-MgH2 sample exhibits very good stability compared with the undoped sample. The present approach, which ideally addresses the agglomeration of nanoparticles with efficient

  17. Responsive foams for nanoparticle delivery.

    PubMed

    Tang, Christina; Xiao, Edward; Sinko, Patrick J; Szekely, Zoltan; Prud'homme, Robert K

    2015-09-01

    We have developed responsive foam systems for nanoparticle delivery. The foams are easy to make, stable at room temperature, and can be engineered to break in response to temperature or moisture. Temperature-responsive foams are based on the phase transition of long chain alcohols and could be produced using medical grade nitrous oxide as a propellant. These temperature-sensitive foams could be used for polyacrylic acid (PAA)-based nanoparticle delivery. We also discuss moisture-responsive foams made with soap pump dispensers. Polyethylene glycol (PEG)-based nanoparticles or PMMA latex nanoparticles were loaded into Tween 20 foams and the particle size was not affected by the foam formulation or foam break. Using biocompatible detergents, we anticipate this will be a versatile and simple approach to producing foams for nanoparticle delivery with many potential pharmaceutical and personal care applications. PMID:26091943

  18. Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels

    PubMed Central

    Perez, Ana Paula; Mundiña-Weilenmann, Cecilia; Romero, Eder Lilia; Morilla, Maria Jose

    2012-01-01

    Background Molecules taken up by olfactory and trigeminal nerve neurons directly access the brain by the nose-to-brain pathway. In situ-forming mucoadhesive gels would increase the residence time of intranasal material, favoring the nose-to-brain delivery. In this first approach, brain radioactivity after intranasal administration of 32P-small interference RNA (siRNA) complexed with poly(amidoamine) G7 dendrimers (siRNA dendriplexes) within in situ-forming mucoadhesive gels, was determined. Materials 32P-siRNA dendriplexes were incorporated into in situ-forming mucoadhesive gels prepared by blending thermosensitive poloxamer (23% w/w) with mucoadhesive chitosan (1% w/w, PxChi) or carbopol (0.25% w/w, PxBCP). Rheological properties, radiolabel release profile, and local toxicity in rat nasal mucosa were determined. The best-suited formulation was intranasally administered to rats, and blood absorption and brain distribution of radioactivity were measured. Results The gelation temperature of both formulations was 23°C. The PxChi liquid showed non-Newtonian pseudoplastic behavior of high consistency and difficult manipulation, and the gel retained 100% of radiolabel after 150 minutes. The PxCBP liquid showed a Newtonian behavior of low viscosity and easy manipulation, while in the gel phase showed apparent viscosity similar to that of the mucus but higher than that of aqueous solution. The gel released 35% of radiolabel and the released material showed silencing activity in vitro. Three intranasal doses of dendriplexes in PxCBP gel did not damage the rat nasal mucosa. A combination of 32P-siRNA complexation with dendrimers, incorporation of the dendriplexes into PxCBP gel, and administration of two intranasal doses was necessary to achieve higher brain radioactivity than that achieved by intravenous dendriplexes or intranasal naked siRNA. Conclusion The increased radioactivity within the olfactory bulb suggested that the combination above mentioned favored the

  19. Genome Sequences of Four Strains of Mycobacterium avium subsp. hominissuis, Isolated from Swine and Humans, Differing in Virulence in a Murine Intranasal Infection Model.

    PubMed

    Bruffaerts, N; Vluggen, C; Duytschaever, L; Mathys, V; Saegerman, C; Chapeira, O; Huygen, K

    2016-01-01

    This paper announces the genome sequences of four strains of Mycobacterium avium subsp. hominissuis, isolated from cases of lymphadenopathy in swine and humans, differing in virulence in a murine intranasal infection model. PMID:27313293

  20. Genome Sequences of Four Strains of Mycobacterium avium subsp. hominissuis, Isolated from Swine and Humans, Differing in Virulence in a Murine Intranasal Infection Model

    PubMed Central

    Bruffaerts, N.; Vluggen, C.; Duytschaever, L.; Mathys, V.; Saegerman, C.; Chapeira, O.

    2016-01-01

    This paper announces the genome sequences of four strains of Mycobacterium avium subsp. hominissuis, isolated from cases of lymphadenopathy in swine and humans, differing in virulence in a murine intranasal infection model. PMID:27313293

  1. The adjuvants MF59 and LT-K63 enhance the mucosal and systemic immunogenicity of subunit influenza vaccine administered intranasally in mice.

    PubMed

    Barchfeld, G L; Hessler, A L; Chen, M; Pizza, M; Rappuoli, R; Van Nest, G A

    1999-02-26

    Commercial influenza vaccines generate serum antibody, but not local IgA. Influenza vaccines that induce both serum and secretory antibody are more likely to protect against infection and disease progression. The adjuvants MF59 and LT-K63 were tested intramuscularly and intranasally with subunit HA. In naive mice, intranasal adjuvant effect was more apparent when included with the first than second immunization. In previously infected mice, intranasal adjuvants had little effect on serum antibodies and were most effective for nasal antibodies after the second immunization. Overall, both adjuvants enhanced anti-HA IgA and IgG by intranasal vaccination whereas, by intramuscular vaccination, they only enhanced serum IgG. PMID:10067675

  2. Platinum nanoparticles decorated robust binary transition metal nitride-carbon nanotubes hybrid as an efficient electrocatalyst for the methanol oxidation reaction

    NASA Astrophysics Data System (ADS)

    Zhan, Guohe; Fu, Zhenggao; Sun, Dalei; Pan, Zhanchang; Xiao, Chumin; Wu, Shoukun; Chen, Chun; Hu, Guanghui; Wei, Zhigang

    2016-09-01

    Titanium cobalt nitride (TiCoN)-CNTs hybrid support is prepared by a facile and efficient method, including a one-pot solvothermal process followed by a nitriding process, and this hybrid support is further decorated with Pt nanoparticles to catalyze the oxidation of methanol. The catalyst is characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and electrochemical measurements. Notably, Pt/CNTs@TiCoN catalyst exhibits a much higher mass activity and durability than that of the conventional Pt/C (JM) for methanol oxidation. The experimental data indicates that the CNTs@TiCoN hybrid support combines the merits of the CNTs's high conductivity and the superb corrosion resistance of external TiCoN coating.

  3. Intranasal application of vasopressin fails to elicit changes in brain immediate early gene expression, neural activity and behavioral performance of rats

    PubMed Central

    Ludwig, Mike; Tobin, Vicky A.; Callahan, Michael F.; Papadaki, Eirini; Becker, Axel; Engelmann, Mario; Leng, Gareth

    2013-01-01

    Intranasal administration has been widely used to investigate effects of the neuropeptides vasopressin and oxytocin on human behaviors and neurological disorders, but exactly what happens when these neuropeptides are administered intranasally is far from clear. In particular, it is not clear whether a physiological significant amount of peptide enters the brain to account for the observed effects. Here, we investigated whether intranasal administration of vasopressin and oxytocin to rats induces expression of the immediate-early gene product Fos in brain areas that are sensitive to centrally administered peptide, whether it alters neuronal activity in the way that centrally administered peptide does, and whether it affects behavior in ways expected from studies of centrally administered peptide. We found that, whereas intracerebroventricular (icv) injection of very low doses of vasopressin or oxytocin increased Fos expression in several distinct brain regions, intranasal administration of large doses of the peptides had no significant effect. In contrast to the effects of vasopressin applied topically to the main olfactory bulb, we saw no changes in the electrical activity of olfactory bulb mitral cells after intranasal vasopressin administration. In addition, vasopressin given intranasally had no significant effects on social recognition or short-term recognition memory. Finally, intranasal infusions of vasopressin had no significant effects on the parameters monitored on the elevated plus maze, a rodent model of anxiety. Our data in rats suggest that, after intranasal administration, significant amounts of vasopressin and oxytocin do not reach areas in the brain at levels sufficient to change immediate early gene expression, neural activity or behavior in the ways described for central administration of the peptides. PMID:23656518

  4. Building robust architectures of carbon-wrapped transition metal nanoparticles for high catalytic enhancement of the 2LiBH4-MgH2 system for hydrogen storage cycling performance

    NASA Astrophysics Data System (ADS)

    Huang, Xu; Xiao, Xuezhang; Shao, Jie; Zhai, Bing; Fan, Xiulin; Cheng, Changjun; Li, Shouquan; Ge, Hongwei; Wang, Qidong; Chen, Lixin

    2016-08-01

    Nanoscale catalyst doping is regarded as one of the most effective strategies to improve the kinetics performance of hydrogen storage materials, but the agglomeration of nanoparticles is usually unavoidable during the repeated de/rehydrogenation processes. Herein, hierarchically structured catalysts (Fe/C, Co/C and Ni/C) were designed and fabricated to overcome the agglomeration issue of nanocatalysts applied to the 2LiBH4-MgH2 system for the first time. Uniform transition metal (TM) nanoparticles (~10 nm) wrapped by few layers of carbon are synthesized by pyrolysis of the corresponding metal-organic frameworks (MOFs), and introduced into the 2LiBH4-MgH2 reactive hydride composites (RHCs) by ball milling. The particular features of the carbon-wrapped architecture effectively avoid the agglomeration of the TM nanoparticles during hydrogen storage cycling, and high catalysis is maintained during the subsequent de/rehydrogenation processes. After de/rehydrogenation cycling, FeB, CoB and MgNi3B2 can be formed as the catalytically active components with a particle size of 5-15 nm, which show a homogeneous distribution in the hydride matrix. Among the three catalysts, in situ-formed MgNi3B2 shows the best catalytic efficiency. The incubation period of the Fe/C, Co/C and Ni/C-doped 2LiBH4-MgH2 system between the two dehydrogenation steps was reduced to about 8 h, 4 h and 2 h, respectively, which is about 8 h, 12 h and 14 h shorter than that of the undoped 2LiBH4-MgH2 sample. In addition, the two-step dehydrogenation peak temperatures of the Ni/C-doped 2LiBH4-MgH2 system drop to 323.4 °C and 410.6 °C, meanwhile, the apparent activation energies of dehydrogenated MgH2 and LiBH4 decrease by 58 kJ mol-1 and 71 kJ mol-1, respectively. In particular, the cycling hydrogen desorption of the Ni/C-doped 2LiBH4-MgH2 sample exhibits very good stability compared with the undoped sample. The present approach, which ideally addresses the agglomeration of nanoparticles with efficient

  5. Intranasal administration of oxytocin modulates behavioral and amygdala responses to infant crying in females with insecure attachment representations.

    PubMed

    Riem, Madelon M E; Bakermans-Kranenburg, Marian J; van IJzendoorn, Marinus H

    2016-06-01

    The current study examined the effects of oxytocin administration on the response to infant crying in individuals with secure or insecure attachment representations as assessed with the Adult Attachment Interview. We measured feelings of irritation and the use of excessive force as indicated by grip strength using a handgrip dynamometer during exposure to infant crying in 42 women without children who were administered intranasal oxytocin or a placebo. In addition, amygdala responses to infant crying and control sounds were measured with functional magnetic resonance imaging (fMRI). The effects of oxytocin on reactivity to crying were moderated by attachment security. Oxytocin decreased the use of excessive handgrip force and amygdala reactivity in response to crying in individuals with insecure attachment representations. Our findings indicate that insecure individuals, who show emotional, behavioral, and neural hyperreactivity to crying, benefit the most from intranasal oxytocin. PMID:26982874

  6. Adjuvant action of Chenopodium quinoa saponins on the induction of antibody responses to intragastric and intranasal administered antigens in mice.

    PubMed

    Estrada, A; Li, B; Laarveld, B

    1998-07-01

    Saponins extracted from the seed of Chenopodium quinoa (quinoa) were studied for their ability to act as mucosal adjuvants upon their intragastric or intranasal administration together with model antigens in mice. Quinoa saponins, co-administered intragastrically or intranasally with cholera toxin or ovalbumin, potentiated specific IgG and IgA antibody responses to the antigens in serum, intestinal and lung secretions. The potentiating effect of the saponins appeared, to some extent, mediated by increased permeability of the mucosa, allowing increased uptake of the antigen. The intragastric administration of 99mTc-radio-labeled human serum albumin together with quinoa saponins revealed an increased presence of the radiolabeled protein in blood, liver, spleen and lungs of mice. This study indicates the potential of quinoa saponins as adjuvants for mucosally administered vaccines. PMID:9681245

  7. Non-invasive intranasal delivery of quetiapine fumarate loaded microemulsion for brain targeting: Formulation, physicochemical and pharmacokinetic consideration.

    PubMed

    Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

    2016-08-25

    Systemic drug delivery in schizophrenia is a major challenge due to presence of obstacles like, blood-brain barrier and P-glycoprotein, which prohibit entry of drugs into the brain. Quetiapine fumarate (QF), a substrate to P-glycoprotein under goes extensive first pass metabolism leading to limited absorption thus necessitating frequent oral administration. The aim of this study was to develop QF based microemulsion (ME) with and without chitosan (CH) to investigate its potential use in improving the bioavailability and brain targeting efficiency following non-invasive intranasal administration. QF loaded ME and mucoadhesive ME (MME) showed globule size, pH and viscosity in the range of 29-47nm, 5.5-6.5 and 17-40cP respectively. CH-ME with spherical globules having mean size of 35.31±1.71nm, pH value of 5.61±0.16 showed highest ex-vivo nasal diffusion (78.26±3.29%) in 8h with no sign of structural damage upon histopathological examination. Circular plume with an ovality ratio closer to 1.3 for CH-ME depicted ideal spray pattern. Significantly higher brain/blood ratio of CH-ME in comparison to QF-ME and drug solution following intranasal administration revealed prolonged retention of QF at site of action suggesting superiority of CH as permeability enhancer. Following intranasal administration, 2.7 and 3.8 folds higher nasal bioavailability in brain with CH-ME compared to QF-ME and drug solution respectively is indicative of preferential nose to brain transport (80.51±6.46%) bypassing blood-brain barrier. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery. PMID:27174656

  8. Immunogenicity and protective efficacy of an elastase-dependent live attenuated swine influenza virus vaccine administered intranasally in pigs.

    PubMed

    Masic, Aleksandar; Lu, Xinya; Li, Junwei; Mutwiri, George K; Babiuk, Lorne A; Brown, Earl G; Zhou, Yan

    2010-10-01

    Influenza A virus is an important respiratory pathogen of swine that causes significant morbidity and economic impact on the swine industry. Vaccination is the first choice for prevention and control of influenza infections. Live attenuated influenza vaccines (LAIV) are approved for use in humans and horses and their application provides broad protective immunity, however no LAIV against swine influenza virus (SIV) exists in the market. Previously we reported that an elastase-dependent mutant SIV A/Sw/Sk-R345V (R345V) derived from A/Sw/Saskatchewan/18789/02 (H1N1) (SIV/Sk02) is highly attenuated in pigs. Two intratracheal administrations of R345V induced strong cell-mediated and humoral immune responses and provided a high degree of protection to antigenically different SIV infection in pigs. Here we evaluated the immunogenicity and the protective efficacy of R345V against SIV infection by intranasal administration, the more practical route for vaccination of pigs in the field. Our data showed that intranasally administered R345V live vaccine is capable of inducing strong antigen-specific IFN-γ response from local tracheo-bronchial lymphocytes and antibody responses in serum and respiratory mucosa after two applications. Intranasal vaccination of R345V provided pigs with complete protection not only from parental wild type virus infection, but also from homologous antigenic variant A/Sw/Indiana/1726/88 (H1N1) infection. Moreover, intranasal administration of R345V conferred partial protection from heterologous subtypic H3N2 SIV infection in pigs. Thus, R345V elastase-dependent mutant SIV can serve as a live vaccine against antigenically different swine influenza viruses in pigs. PMID:20708697

  9. Intranasal Dexmedetomidine as a Sedative Premedication for Patients Undergoing Suspension Laryngoscopy: A Randomized Double-Blind Study

    PubMed Central

    Lu, Chengxiang; Zhang, Li-Ming; Zhang, Yuehong; Ying, Yanlu; Li, Ling; Xu, Lixin; Ruan, Xiangcai

    2016-01-01

    Background Intranasal dexmedetomidine, a well-tolerated and convenient treatment option, has been shown to induce a favorable perioperative anxiolysis in children. We investigate intranasal dexmedetomidine as a sedative premedication for anesthesia recovery in an adult population. Methods A prospective randomized controlled trial; 81 adult patients scheduled for elective suspension laryngoscopy received intranasal dexmedetomidine (1 μg∙kg–1) or a placebo 45–60 min before anesthetic induction. Extubation time was used as the primary outcome measure. Secondary variables included the levels of sedation (Observer’s Assessment of Alertness/Sedation scale, OAA/S) and anxiety (4-point anxiety score), anesthetic and analgesic requirements, hemodynamic fluctuations, and anesthesia recovery as well as side effects. Results The levels of sedation and anxiety differed significantly between the two groups at anesthesia pre-induction (p < 0.001 and = 0.001, respectively). Repeated-measure general linear model determined no significant interaction effect between group and time on the targeted concentration of propofol (F = 1.635, p = 0.200), but a significant main effect of group existed (F = 6.880, p = 0.010). A moderate but significant decrease in the heart rate was recorded in the dexmedetomidine group at pre-induction. Episodes of tachycardia and hypertension after tracheal intubation and extubation were more frequent in the placebo group. Conclusions Intranasal dexmedetomidine as a sedative premedication induced a favorable perioperative anxiolysis without prolongation in anesthesia recovery; the hemodynamic effect was modest. Trial Registration ClinicalTrials.gov NCT 02108171 PMID:27196121

  10. Comparison of immune responses to intranasal and intrapulmonary vaccinations with the attenuated Mycoplasma hyopneumoniae 168 strain in pigs.

    PubMed

    Li, Pengcheng; Li, Yunfeng; Shao, Guoqing; Yu, Qinghua; Yang, Qian

    2015-05-01

    The aim of this study was to evaluate the immune responses to intranasal and intrapulmonary vaccinations with the attenuated Mycoplasma hyopneumoniae (Mhp) 168 strain in the local respiratory tract in pigs. Twenty-four pigs were randomly divided into 4 groups: an intranasal immunization group, an intrapulmonary immunization group, an intramuscular immunization group and a control group. The levels of local respiratory tract cellular and humoral immune responses were investigated. The levels of interleukin (IL)-6 in the early stage of immunization (P<0.01), local specific secretory IgA (sIgA) in nasal swab samples (P<0.01); and IgA- and IgG-secreting cells in the nasal mucosa and trachea were higher after intranasal vaccination (P<0.01) than in the control group. Interestingly, intrapulmonary immunization induced much stronger immune responses than intranasal immunization. Intrapulmonary immunization also significantly increased the secretion of IL-6 and local specific sIgA and the numbers of IgA- and IgG-secreting cells. The levels of IL-10 and interferon-γ in the nasal swab samples and the numbers of CD4(+) and CD8(+) T lymphocytes in the lung and hilar lymph nodes were significantly increased by intrapulmonary immunization compared with those in the control group (P<0.01). These data suggest that intrapulmonary immunization with attenuated Mhp is effective in evoking local cellular and humoral immune responses in the respiratory tract. Intrapulmonary immunization with Mhp may be a promising route for defense against Mhp in pigs. PMID:25649413

  11. Comparison of immune responses to intranasal and intrapulmonary vaccinations with the attenuated Mycoplasma hyopneumoniae 168 strain in pigs

    PubMed Central

    LI, Pengcheng; LI, Yunfeng; SHAO, Guoqing; YU, Qinghua; YANG, Qian

    2015-01-01

    The aim of this study was to evaluate the immune responses to intranasal and intrapulmonary vaccinations with the attenuated Mycoplasma hyopneumoniae (Mhp) 168 strain in the local respiratory tract in pigs. Twenty-four pigs were randomly divided into 4 groups: an intranasal immunization group, an intrapulmonary immunization group, an intramuscular immunization group and a control group. The levels of local respiratory tract cellular and humoral immune responses were investigated. The levels of interleukin (IL)-6 in the early stage of immunization (P<0.01), local specific secretory IgA (sIgA) in nasal swab samples (P<0.01); and IgA- and IgG-secreting cells in the nasal mucosa and trachea were higher after intranasal vaccination (P<0.01) than in the control group. Interestingly, intrapulmonary immunization induced much stronger immune responses than intranasal immunization. Intrapulmonary immunization also significantly increased the secretion of IL-6 and local specific sIgA and the numbers of IgA- and IgG-secreting cells. The levels of IL-10 and interferon-γ in the nasal swab samples and the numbers of CD4+ and CD8+ T lymphocytes in the lung and hilar lymph nodes were significantly increased by intrapulmonary immunization compared with those in the control group (P<0.01). These data suggest that intrapulmonary immunization with attenuated Mhp is effective in evoking local cellular and humoral immune responses in the respiratory tract. Intrapulmonary immunization with Mhp may be a promising route for defense against Mhp in pigs. PMID:25649413

  12. Intranasal administration of glial-derived neurotrophic factor (GDNF) rapidly and significantly increases whole-brain GDNF level in rats.

    PubMed

    Bender, T S; Migliore, M M; Campbell, R B; John Gatley, S; Waszczak, B L

    2015-09-10

    Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) exerts significant neuroprotective effects on substantia nigra (SN) neurons in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this study we used enzyme-linked immunosorbent assay (ELISA) to determine GDNF brain levels and distribution to target regions (i.e. striatum and SN) following intranasal administration of GDNF at different time points after administration. Brain levels increased significantly within 1h following a single 50-μg dose of GDNF in a liposomal formulation, returning to baseline by 24h. In a second study, different doses of GDNF (10-150 μg) in phosphate-buffered saline (PBS) were studied at the 1-h time point. Dose-dependent increases in brain GDNF levels were observed with apparent saturation of uptake at doses above 100 μg. Liposomes delivered 10-fold more GDNF to brain than PBS despite yielding similar neuroprotective efficacy in the 6-OHDA model, suggesting incomplete release of GDNF from liposomes in tissue. In a third study, autoradiography was performed on brain sections taken 1h after intranasal (125)I-labeled GDNF. Radioactivity was detected throughout the brain along the rostral-to-caudal axis, indicating that nasally administered GDNF can reach target areas. Collectively, these results demonstrate that intranasal administration of GDNF in liposomes or PBS achieves significant increases in GDNF in target brain areas, supporting use of intranasal administration as a non-invasive means of delivering GDNF to the brain to protect dopamine neurons and arrest disease progression in PD. PMID:26166725

  13. Intranasal Vaccination against HIV-1 with Adenoviral Vector-Based Nanocomplex Using Synthetic TLR-4 Agonist Peptide as Adjuvant.

    PubMed

    Li, Man; Jiang, Yuhong; Gong, Tao; Zhang, Zhirong; Sun, Xun

    2016-03-01

    Recombinant type 5 adenovirus (rAd5) vaccines hold the promise to prevent HIV-1 infections. Intranasal vaccination not only stimulates systemic immunity but also elicits mucosal immunity that provides first defense for mucosally transmitted diseases like HIV-1. Adjuvants such as TLR agonists are usually codelivered with antigens to enhance the immunogenicity of vaccines. Here, we present a rAd5 vaccine delivery system using DEG-PEI as the carrier. Adenovirus encoding HIV gag was used as antigen, and was complexed with DEG-PEI polymer via electrostatic interaction. A novel synthetic TLR-4 agonist, RS09, was either chemically linked with DEG-PEI (DP-RS09) or physically mixed with it(DP/RS09) to enhance the immunogenticity of rAd5 vaccine. After intranasal immunization, the systemic antigen-specific immune responses and cytotoxicity T lymphocytes responses induced by DP-RS09-rAd5 and DP/RS09-rAd5 were analyzed. The mucosal secretory IgA level was detected in both nasal and vaginal washes to determine the mucosal immunity. Furthermore, cytokine productions on RAW264.7 cells were tested after preincubation with TLR-4 pathway inhibitors. The results indicated that DEG-PEI could facilitate the intranasal delivery of rAd5 vaccine. Both chemically linked (DP-RS09) and physically mixed RS09 (DP/RS09) could further enhance the mucosal immunity of rAd5 vaccine via TLR-4 pathway. This RS09 adjuvanted DEG-PEI polymer represents a potential intranasal vaccine delivery system and may have a wider application for other viral vectors. PMID:26824411

  14. Nanoparticle-based measurements of pH and O2 dynamics in the rhizosphere of Zostera marina L.: effects of temperature elevation and light-dark transitions.

    PubMed

    Elgetti Brodersen, Kasper; Koren, Klaus; Lichtenberg, Mads; Kühl, Michael

    2016-07-01

    Seagrasses can modulate the geochemical conditions in their immediate rhizosphere through the release of chemical compounds from their below-ground tissue. This is a vital chemical defence mechanism, whereby the plants detoxify the surrounding sediment. Using novel nanoparticle-based optical O2 and pH sensors incorporated in reduced and transparent artificial sediment, we investigated the spatio-temporal dynamics of pH and O2 within the entire rhizosphere of Zostera marina L. during experimental manipulations of light and temperature. We combined such measurements with O2 microsensor measurements of the photosynthetic productivity and respiration of seagrass leaves. We found pronounced pH and O2 microheterogeneity within the immediate rhizosphere of Z. marina, with higher below-ground tissue oxidation capability and rhizoplane pH levels during both light exposure of the leaf canopy and elevated temperature, where the temperature-mediated stimuli of biogeochemical processes seemed to predominate. Low rhizosphere pH microenvironments appeared to correlate with plant-derived oxic microzones stimulating local sulphide oxidation and thus driving local proton generation, although the rhizoplane pH levels generally where much higher than the bulk sediment pH. Our data show that Z. marina can actively alter its rhizosphere pH microenvironment alleviating the local H2 S toxicity and enhancing nutrient availability in the adjacent sediment via geochemical speciation shift. PMID:27003238

  15. Intranasal Delivery of Recombinant Parvovirus-Like Particles Elicits Cytotoxic T-Cell and Neutralizing Antibody Responses

    PubMed Central

    Sedlik, C.; Dridi, A.; Deriaud, E.; Saron, M. F.; Rueda, P.; Sarraseca, J.; Casal, J. I.; Leclerc, C.

    1999-01-01

    We previously demonstrated that chimeric porcine parvovirus-like particles (PPV:VLP) carrying heterologous epitopes, when injected intraperitoneally into mice without adjuvant, activate strong CD4+ and CD8+ T-cell responses specific for the foreign epitopes. In the present study, we investigated the immunogenicity of PPV:VLP carrying a CD8+ T-cell epitope from the lymphocytic choriomeningitis virus (LCMV) administered by mucosal routes. Mice immunized intranasally with recombinant PPV:VLP, in the absence of adjuvant, developed high levels of PPV-specific immunoglobulin G (IgG) and/or IgA in their serum, as well as in mucosal sites such as the bronchoalveolar and intestinal fluids. Antibodies in sera from mice immunized parenterally or intranasally with PPV:VLP were strongly neutralizing in vitro. Intranasal immunization with PPV:VLP carrying the LCMV CD8+ T-cell epitope also elicited a strong peptide-specific cytotoxic-T-cell (CTL) response. In contrast, mice orally immunized with recombinant PPV:VLP did not develop any antibody or CTL responses. We also showed that mice primed with PPV:VLP are still able to develop strong CTL responses after subsequent immunization with chimeric PPV:VLP carrying a foreign CD8+ T-cell epitope. These results highlight the attractive potential of PPV:VLP as a safe, nonreplicating antigen carrier to stimulate systemic and mucosal immunity after nasal administration. PMID:10074120

  16. Effect of intranasal oxytocin administration on psychiatric symptoms: A meta-analysis of placebo-controlled studies.

    PubMed

    Hofmann, Stefan G; Fang, Angela; Brager, Daniel N

    2015-08-30

    Clinical trials of intranasal administration of oxytocin for treating psychiatric problems have yielded mixed results. To conduct a quantitative review of placebo-controlled clinical trials of intranasally-administered oxytocin (OT) for psychiatric symptoms, manual and electronic searches using PubMed and PsycINFO were conducted. Of 1828 entries, 16 placebo-controlled studies totaling 330 participants were included in the analysis. The overall placebo-controlled effect size was moderately strong (Hedges' g=0.67) and robust as suggested by the fail-safe N and funnel plot analysis. OT reduced symptoms of depression, anxiety, autism/repetitive behaviors, psychotic symptoms, and general psychopathology. In the combined sample, symptom reduction was moderated by frequency of administration. Publication year and diagnostic category did not moderate the effect of OT on the clinical outcome measures. We conclude that intranasal administration of OT is a potentially useful intervention for reducing psychiatric symptoms. However, more studies are needed to determine the best treatment target and to identify the mechanism of treatment change. PMID:26094200

  17. Attitudes of Australian Heroin Users to Peer Distribution of Naloxone for Heroin Overdose: Perspectives on Intranasal Administration

    PubMed Central

    Dietze, Paul; Kelly, Anne-Maree; Jolley, Damien

    2008-01-01

    Naloxone distribution to injecting drug users (IDUs) for peer administration is a suggested strategy to prevent fatal heroin overdose. The aim of this study was to explore attitudes of IDUs to administration of naloxone to others after heroin overdose, and preferences for method of administration. A sample of 99 IDUs (median age 35 years, 72% male) recruited from needle and syringe programs in Melbourne were administered a questionnaire. Data collected included demographics, attitudes to naloxone distribution, and preferences for method of administration. The primary study outcomes were attitudes of IDUs to use of naloxone for peer administration (categorized on a five-point scale ranging from “very good idea” to “very bad idea”) and preferred mode of administration (intravenous, intramuscular, and intranasal). The majority of the sample reported positive attitudes toward naloxone distribution (good to very good idea: 89%) and 92% said they were willing to participate in a related training program. Some participants raised concerns about peer administration including the competence of IDUs to administer naloxone in an emergency, victim response on wakening and legal implications. Most (74%) preferred intranasal administration in comparison to other administration methods (21%). There was no association with age, sex, or heroin practice. There appears to be strong support among Australian IDU for naloxone distribution to peers. Intranasal spray is the preferred route of administration. PMID:18347990

  18. Nanogel-based PspA intranasal vaccine prevents invasive disease and nasal colonization by Streptococcus pneumoniae.

    PubMed

    Kong, Il Gyu; Sato, Ayuko; Yuki, Yoshikazu; Nochi, Tomonori; Takahashi, Haruko; Sawada, Shinichi; Mejima, Mio; Kurokawa, Shiho; Okada, Kazunari; Sato, Shintaro; Briles, David E; Kunisawa, Jun; Inoue, Yusuke; Yamamoto, Masafumi; Akiyoshi, Kazunari; Kiyono, Hiroshi

    2013-05-01

    To establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge with Streptococcus pneumoniae Xen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection. PMID:23460513

  19. Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae

    PubMed Central

    Kong, Il Gyu; Sato, Ayuko; Nochi, Tomonori; Takahashi, Haruko; Sawada, Shinichi; Mejima, Mio; Kurokawa, Shiho; Okada, Kazunari; Sato, Shintaro; Briles, David E.; Kunisawa, Jun; Inoue, Yusuke; Yamamoto, Masafumi; Akiyoshi, Kazunari

    2013-01-01

    To establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge with Streptococcus pneumoniae Xen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection. PMID:23460513

  20. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways.

    PubMed

    Li, Man; Zhao, Mengnan; Fu, Yao; Li, You; Gong, Tao; Zhang, Zhirong; Sun, Xun

    2016-04-28

    Facing the threat of highly variable virus infection, versatile vaccination systems are urgently needed. Intranasal mRNA vaccination provides a flexible and convenient approach. However, the nasal epithelium remains a major biological barrier to deliver antigens to nasal associated lymphoid tissue (NALT). To address this issue, a potent polymer-based intranasal mRNA vaccination system for HIV-1 treatment was synthesized using cationic cyclodextrin-polyethylenimine 2k conjugate (CP 2k) complexed with anionic mRNA encoding HIV gp120. The delivery vehicle containing CP 2k and mRNA overcame the epithelial barrier by reversibly opening the tight junctions, enhanced the paracellular delivery of mRNA and consequently minimized absorption of toxins in the nasal cavity. Together with the excellent intracellular delivery and prolonged nasal residence time, strong system and mucosal anti-HIV immune responses as well as cytokine productions were achieved with a balanced Th1/Th2/Th17 type. Our study provided the first proof of evidence that cationic polymers can be used as safe and potent intranasal mRNA vaccine carriers to overcome the nasal epithelial barrier. The safe and versatile polymeric delivery system represents a promising vaccination platform for infectious diseases. PMID:26941035

  1. Brain cytokine and chemokine mRNA expression in mice induced by intranasal instillation with ultrafine carbon black.

    PubMed

    Tin-Tin-Win-Shwe; Yamamoto, Shoji; Ahmed, Sohel; Kakeyama, Masaki; Kobayashi, Takahiro; Fujimaki, Hidekazu

    2006-05-25

    Ambient air ultrafine particles (UFPs) have gained enormous attention to many researchers with recent evidence showing them to have more hazardous effects on human health than larger ambient particles. Studies focusing the possibility of effects on brain are quite limited. To examine the effect of ultrafine carbon black (ufCB) on mice brain, we instilled 125 microg of 14 nm or 95 nm CB into the nostrils of 8-week-old male BALB/c mice, once a week for 4 weeks. Four hours after the last instillation, we collected olfactory bulb and hippocampus and detected the expression of cytokine and chemokine mRNA by quantitative real-time PCR method. In this study, we found the induction of proinflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha and chemokines (monocyte chemoattractant protein-1/CCL2, macrophage inflammatory protein-1 alpha/CCL3), and monokine induced interferon-gamma/CXC chemokine ligand (CXCL9) mRNA in brain olfactory bulb, not in the hippocampus of mice instilled with 14 nm ufCB intranasally. We suggest that the intranasal instillation of ufCB may influence the brain immune function depending on their size. To our knowledge, this is the first study to demonstrate region-specific brain cytokine and chemokine mRNA-induction in mice triggered by intranasal instillation of specific-sized ufCB, in a physiologically relevant condition. PMID:16293374

  2. Diesel-exhaust particulates inoculated by the intranasal route have an adjuvant activity for IgE production in mice

    SciTech Connect

    Takafuji, S.; Suzuki, S.; Koizumi, K.; Tadokoro, K.; Miyamoto, T.; Ikemori, R.; Muranaka, M.

    1987-04-01

    Our previous study indicated that the IgE antibody responses in mice immunized with intraperitoneal injection of the antigens mixed with diesel-exhaust particulates (DEP) were higher than those in the animals immunized with the antigens alone. We examined the adjuvant activity of DEP inoculated by the intranasal route, i.e., the natural entrance of DEP. In 3-week interval immunization, the IgE antibody responses in mice immunized with intranasal inoculation of ovalbumin (OA) mixed with DEP were higher than responses in the animals immunized with OA alone. DEP had an adjuvant activity for anti-OA IgE antibody production, even in a small dose such as 1 micrograms administered with a 3-week interval. Also in 1-week interval immunization, the enhancing effect of DEP on anti-OA IgE antibody production was demonstrated when mice were immunized with intranasal inoculation of OA and DEP. The possibility cannot be excluded that DEP, which are kept buoyant in the environmental atmosphere of urban districts, may exert an adjuvant activity for IgE antibody production after being inhaled into the human body and have some relation to the mechanism of the outbreak of allergic rhinitis caused by pollens in Japan.

  3. Intranasal Administration of Chitosan Against Influenza A (H7N9) Virus Infection in a Mouse Model.

    PubMed

    Zheng, Mei; Qu, Di; Wang, Haiming; Sun, Zhiping; Liu, Xueying; Chen, Jianjun; Li, Changgui; Li, Xuguang; Chen, Ze

    2016-01-01

    Influenza virus evolves constantly in an unpredictable fashion, making it necessary to vaccinate people annually for effective prevention and control of influenza. In general, however, during the first wave of an influenza outbreak caused by a newly emerging virus strain, influenza morbidity and mortality have been observed to rise sharply due to the lack of a matching vaccine. This necessitates the exploration of novel intervention approaches, particularly those prophylactic or therapeutic agents that have a broad range of antiviral activities and are also proven to be non-toxic. Here, we reported that stimulation of the innate immune system by intranasal administration of chitosan as a single agent was sufficient to completely protect BALB/c mice from lethal infection by H7N9 virus, a newly emerged viral strain that is highly pathogenic to humans. Remarkably, animals could still be protected against lethal challenge by H7N9 (10×LD50), even ten days after the intranasal chitosan administration. The significantly enhanced infiltration of leukocytes in the bronchoalveolar lavage and elevated levels of proinflammatory cytokines in the bronchia/lung tissues revealed the potent activation of mucosal immune responses by intranasally delivered chitosan. We also observed that chitosan can protect mice from three other virus strains. The marked breadth and magnitude of protection against diverse viral strains makes chitosan an attractive candidate as a universal anti-influenza agent. PMID:27353250

  4. Intranasal Administration of Chitosan Against Influenza A (H7N9) Virus Infection in a Mouse Model

    PubMed Central

    Zheng, Mei; Qu, Di; Wang, Haiming; Sun, Zhiping; Liu, Xueying; Chen, Jianjun; Li, Changgui; Li, Xuguang; Chen, Ze

    2016-01-01

    Influenza virus evolves constantly in an unpredictable fashion, making it necessary to vaccinate people annually for effective prevention and control of influenza. In general, however, during the first wave of an influenza outbreak caused by a newly emerging virus strain, influenza morbidity and mortality have been observed to rise sharply due to the lack of a matching vaccine. This necessitates the exploration of novel intervention approaches, particularly those prophylactic or therapeutic agents that have a broad range of antiviral activities and are also proven to be non-toxic. Here, we reported that stimulation of the innate immune system by intranasal administration of chitosan as a single agent was sufficient to completely protect BALB/c mice from lethal infection by H7N9 virus, a newly emerged viral strain that is highly pathogenic to humans. Remarkably, animals could still be protected against lethal challenge by H7N9 (10×LD50), even ten days after the intranasal chitosan administration. The significantly enhanced infiltration of leukocytes in the bronchoalveolar lavage and elevated levels of proinflammatory cytokines in the bronchia/lung tissues revealed the potent activation of mucosal immune responses by intranasally delivered chitosan. We also observed that chitosan can protect mice from three other virus strains. The marked breadth and magnitude of protection against diverse viral strains makes chitosan an attractive candidate as a universal anti-influenza agent. PMID:27353250

  5. Intranasal delivery of recombinant parvovirus-like particles elicits cytotoxic T-cell and neutralizing antibody responses.

    PubMed

    Sedlik, C; Dridi, A; Deriaud, E; Saron, M F; Rueda, P; Sarraseca, J; Casal, J I; Leclerc, C

    1999-04-01

    We previously demonstrated that chimeric porcine parvovirus-like particles (PPV:VLP) carrying heterologous epitopes, when injected intraperitoneally into mice without adjuvant, activate strong CD4(+) and CD8(+) T-cell responses specific for the foreign epitopes. In the present study, we investigated the immunogenicity of PPV:VLP carrying a CD8(+) T-cell epitope from the lymphocytic choriomeningitis virus (LCMV) administered by mucosal routes. Mice immunized intranasally with recombinant PPV:VLP, in the absence of adjuvant, developed high levels of PPV-specific immunoglobulin G (IgG) and/or IgA in their serum, as well as in mucosal sites such as the bronchoalveolar and intestinal fluids. Antibodies in sera from mice immunized parenterally or intranasally with PPV:VLP were strongly neutralizing in vitro. Intranasal immunization with PPV:VLP carrying the LCMV CD8(+) T-cell epitope also elicited a strong peptide-specific cytotoxic-T-cell (CTL) response. In contrast, mice orally immunized with recombinant PPV:VLP did not develop any antibody or CTL responses. We also showed that mice primed with PPV:VLP are still able to develop strong CTL responses after subsequent immunization with chimeric PPV:VLP carrying a foreign CD8(+) T-cell epitope. These results highlight the attractive potential of PPV:VLP as a safe, nonreplicating antigen carrier to stimulate systemic and mucosal immunity after nasal administration. PMID:10074120

  6. Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression.

    PubMed

    Zhuang, Xiaoying; Teng, Yun; Samykutty, Abhilash; Mu, Jingyao; Deng, Zhongbin; Zhang, Lifeng; Cao, Pengxiao; Rong, Yuan; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2016-02-01

    The lack of access to the brain is a major obstacle for central nervous system drug development. In this study, we demonstrate the capability of a grapefruit-derived nanovector (GNV) to carry miR17 for therapeutic treatment of mouse brain tumor. We show that GNVs coated with folic acid (FA-GNVs) are enhanced for targeting the GNVs to a folate receptor-positive GL-26 brain tumor. Additionally, FA-GNV-coated polyethylenimine (FA-pGNVs) not only enhance the capacity to carry RNA, but the toxicity of the polyethylenimine is eliminated by the GNVs. Intranasal administration of miR17 carried by FA-pGNVs led to rapid delivery of miR17 to the brain that was selectively taken up by GL-26 tumor cells. Mice treated intranasally with FA-pGNV/miR17 had delayed brain tumor growth. Our results demonstrate that this strategy may provide a noninvasive therapeutic approach for treating brain-related disease through intranasal delivery. PMID:26444082

  7. Treatment with intranasal iloprost reduces disease manifestations in a murine model of previously established COPD.

    PubMed

    Lammi, Matthew R; Ghonim, Mohamed A; Pyakurel, Kusma; Naura, Amarjit S; Ibba, Salome V; Davis, Christian J; Okpechi, Samuel C; Happel, Kyle I; deBoisblanc, Bennett P; Shellito, Judd; Boulares, A Hamid

    2016-04-01

    Pulmonary endothelial prostacyclin appears to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The effect of treatment with a prostacyclin analog in animal models of previously established COPD is unknown. We evaluated the short- and long-term effect of iloprost on inflammation and airway hyperresponsiveness (AHR) in a murine model of COPD. Nineteen mice were exposed to LPS/elastase, followed by either three doses of intranasal iloprost or saline. In the long-term treatment experiment, 18 mice were exposed to LPS/elastase and then received 6 wk of iloprost or were left untreated as controls. In the short-term experiment, iloprost did not change AHR but significantly reduced serum IL-5 and IFN-γ. Long-term treatment with iloprost for both 2 and 6 wk significantly improved AHR. After 6 wk of iloprost, there was a reduction in bronchoalveolar lavage (BALF) neutrophils, serum IL-1β (30.0 ± 9.2 vs. 64.8 ± 7.4 pg/ml, P = 0.045), IL-2 (36.5 ± 10.6 vs. 83.8 ± 0.4 pg/ml, P = 0.01), IL-10 (75.7 ± 9.3 vs. 96.5 ± 3.5 pg/ml, P = 0.02), and nitrite (15.1 ± 5.4 vs. 30.5 ± 10.7 μmol, P = 0.01). Smooth muscle actin (SMA) in the lung homogenate was also significantly reduced after iloprost treatment (P = 0.02), and SMA thickness was reduced in the small and medium blood vessels after iloprost (P < 0.001). In summary, short- and long-term treatment with intranasal iloprost significantly reduced systemic inflammation in an LPS/elastase COPD model. Long-term iloprost treatment also reduced AHR, serum nitrite, SMA, and BALF neutrophilia. These data encourage future investigations of prostanoid therapy as a novel treatment for COPD patients. PMID:26851260

  8. Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

    PubMed

    Rais, Rana; Wozniak, Krystyna; Wu, Ying; Niwa, Minae; Stathis, Marigo; Alt, Jesse; Giroux, Marc; Sawa, Akira; Rojas, Camilo; Slusher, Barbara S

    2015-01-01

    Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support

  9. Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration

    PubMed Central

    Rais, Rana; Wozniak, Krystyna; Wu, Ying; Niwa, Minae; Stathis, Marigo; Alt, Jesse; Giroux, Marc; Sawa, Akira; Rojas, Camilo; Slusher, Barbara S.

    2015-01-01

    Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support

  10. Transition-Metal-Doped p-Type ZnO Nanoparticle-Based Sensory Array for Instant Discrimination of Explosive Vapors.

    PubMed

    Qu, Jiang; Ge, Yuru; Zu, Baiyi; Li, Yuxiang; Dou, Xincun

    2016-03-01

    The development of portable, real-time, and cheap platforms to monitor ultratrace levels of explosives is of great urgence and importance due to the threat of terrorism attacks and the need for homeland security. However, most of the previous chemiresistor sensors for explosive detection are suffering from limited responses and long response time. Here, a transition-metal-doping method is presented to remarkably promote the quantity of the surface defect states and to significantly reduce the charge transfer distance by creating a local charge reservoir layer. Thus, the sensor response is greatly enhanced and the response time is remarkably shortened. The resulting sensory array can not only detect military explosives, such as, TNT, DNT, PNT, PA, and RDX with high response, but also can fully distinguish some of the improvised explosive vapors, such as AN and urea, due to the huge response reaching to 100%. Furthermore, this sensory array can discriminate ppb-level TNT and ppt-level RDX from structurally similar and high-concentration interfering aromatic gases in less than 12 s. Through comparison with the previously reported chemiresistor or Schottky sensors for explosive detection, the present transition-metal-doping method resulting ZnO sensor stands out and undoubtedly challenges the best. PMID:26763156

  11. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats.

    PubMed

    Pang, Y; Lin, S; Wright, C; Shen, J; Carter, K; Bhatt, A; Fan, L-W

    2016-03-24

    Protection of substantia nigra (SN) dopaminergic (DA) neurons by neurotrophic factors (NTFs) is one of the promising strategies in Parkinson's disease (PD) therapy. A major clinical challenge for NTF-based therapy is that NTFs need to be delivered into the brain via invasive means, which often shows limited delivery efficiency. The nose to brain pathway is a non-invasive brain drug delivery approach developed in recent years. Of particular interest is the finding that intranasal insulin improves cognitive functions in Alzheimer's patients. In vitro, insulin has been shown to protect neurons against various insults. Therefore, the current study was designed to test whether intranasal insulin could afford neuroprotection in the 6-hydroxydopamine (6-OHDA)-based rat PD model. 6-OHDA was injected into the right side of striatum to induce a progressive DA neuronal lesion in the ipsilateral SN pars compact (SNc). Recombinant human insulin was applied intranasally to rats starting from 24h post lesion, once per day, for 2 weeks. A battery of motor behavioral tests was conducted on day 8 and 15. The number of DA neurons in the SNc was estimated by stereological counting. Our results showed that 6-OHDA injection led to significant motor deficits and 53% of DA neuron loss in the ipsilateral side of injection. Treatment with insulin significantly ameliorated 6-OHDA-induced motor impairments, as shown by improved locomotor activity, tapered/ledged beam-walking performance, vibrissa-elicited forelimb-placing, initial steps, as well as methamphetamine-induced rotational behavior. Consistent with behavioral improvements, insulin treatment provided a potent protection of DA neurons in the SNc against 6-OHDA neurotoxicity, as shown by a 74.8% increase in tyrosine hydroxylase (TH)-positive neurons compared to the vehicle group. Intranasal insulin treatment did not affect body weight and blood glucose levels. In conclusion, our study showed that intranasal insulin provided strong

  12. Sniff and mimic - Intranasal oxytocin increases facial mimicry in a sample of men.

    PubMed

    Korb, Sebastian; Malsert, Jennifer; Strathearn, Lane; Vuilleumier, Patrik; Niedenthal, Paula

    2016-08-01

    The neuropeptide oxytocin (OT) has many potential social benefits. For example, intranasal administration of OT appears to trigger caregiving behavior and to improve the recognition of emotional facial expressions. But the mechanism for these effects is not yet clear. Recent findings relating OT to action imitation and to the visual processing of the eye region of faces point to mimicry as a mechanism through which OT improves processing of emotional expression. To test the hypothesis that increased levels of OT in the brain enhance facial mimicry, 60 healthy male participants were administered, in a double-blind between-subjects design, 24 international units (IUs) of OT or placebo (PLA) through nasal spray. Facial mimicry and emotion judgments were recorded in response to movie clips depicting changing facial expressions. As expected, facial mimicry was increased in the OT group, but effects were strongest for angry infant faces. These findings provide further evidence for the importance of OT in social cognitive skills, and suggest that facial mimicry mediates the effects of OT on improved emotion recognition. PMID:27283377

  13. Intranasal Antibody Gene Transfer in Mice and Ferrets Elicits Broad Protection Against Pandemic Influenza

    PubMed Central

    Limberis, Maria P.; Adam, Virginie S.; Wong, Gary; Gren, Jason; Kobasa, Darwyn; Ross, Ted M.; Kobinger, Gary P.; Tretiakova, Anna; Wilson, James M.

    2015-01-01

    The emergence of a new influenza pandemic remains a threat that could result in a substantial loss of life and economic disruption worldwide. Advances in human antibody isolation have led to the discovery of monoclonal antibodies (mAbs) that have broad neutralizing activity against various influenza strains, although their direct use for prophylaxis is impractical. To overcome this limitation, our approach is to deliver antibody via adeno-associated virus (AAV) vectors to the site of initial infection, which, for respiratory viruses such as influenza, is the nasopharyngeal mucosa. AAV vectors based on serotype 9 were engineered to express a modified version of the previously isolated broadly neutralizing mAb to influenza A, FI6. We demonstrate that intranasal delivery of AAV9.FI6 into mice afforded complete protection and log reductions in viral load to 100 LD50 (median lethal dose) of three clinical isolates of H5N1 and two clinical isolates of H1N1, all of which have been associated with historic human pandemics (including H1N1 1918). Similarly, complete protection was achieved in ferrets challenged with lethal doses of H5N1 and H1N1. This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available. PMID:23720583

  14. Verbal memory after three months of intranasal vasopressin in healthy old humans.

    PubMed

    Perras, B; Droste, C; Born, J; Fehm, H L; Pietrowsky, R

    1997-08-01

    In animals, evidence has been accumulated that vasopressin (VP) improves learning and memory. In humans, this effect was not consistently demonstrated, and attempts to restore age-related memory deficits by VP also remained inconsistent. Assuming that in old subjects a beneficial effect on memory occurs only after prolonged treatment with VP, we conducted a study in 26 healthy elderly persons receiving 40 IU of VP for three months through the intranasal route. The trial was randomized, placebo-controlled and held double-blind. Memory was assessed by the Auditory Verbal Learning Test (AVLT) requiring the subject to learn repeatedly presented lists of 15 words. Results demonstrated no general effect of long-term treatment with VP on memory in aged humans. However, recall of an interfering word list was improved, indicating a diminished proactive interference by the peptide. Additionally, VP influenced recall depending on the serial position of an item: it improved the primacy effect (i.e. recall of the first words of a list) and impaired the recency effect. This result may indicate an improved semantic encoding (i.e. a primary effect on processes of attention) after long-term administration of VP. PMID:9364618

  15. Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

    PubMed Central

    Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

    2016-01-01

    The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain. PMID:27345430

  16. Protective Enterotoxigenic Escherichia coli Antigens in a Murine Intranasal Challenge Model.

    PubMed

    Kumar, Amit; Hays, Mike; Lim, Francis; Foster, Leonard J; Zhou, Mingxu; Zhu, Guoqiang; Miesner, Tracy; Hardwidge, Philip R

    2015-01-01

    Enterotoxigenic Escherichia coli (ETEC) is an endemic health threat in underdeveloped nations. Despite the significant effort extended to vaccine trials using ETEC colonization factors, these approaches have generally not been especially effective in mediating cross-protective immunity. We used quantitative proteomics to identify 24 proteins that differed in abundance in membrane protein preparations derived from wild-type vs. a type II secretion system mutant of ETEC. We expressed and purified a subset of these proteins and identified nine antigens that generated significant immune responses in mice. Sera from mice immunized with either the MltA-interacting protein MipA, the periplasmic chaperone seventeen kilodalton protein, Skp, or a long-chain fatty acid outer membrane transporter, ETEC_2479, reduced the adherence of multiple ETEC strains differing in colonization factor expression to human intestinal epithelial cells. In intranasal challenge assays of mice, immunization with ETEC_2479 protected 88% of mice from an otherwise lethal challenge with ETEC H10407. Immunization with either Skp or MipA provided an intermediate degree of protection, 68 and 64%, respectively. Protection was significantly correlated with the induction of a secretory immunoglobulin A response. This study has identified several proteins that are conserved among heterologous ETEC strains and may thus potentially improve cross-protective efficacy if incorporated into future vaccine designs. PMID:26244636

  17. Diverse Profiles of Ricin-Cell Interactions in the Lung Following Intranasal Exposure to Ricin

    PubMed Central

    Sapoznikov, Anita; Falach, Reut; Mazor, Ohad; Alcalay, Ron; Gal, Yoav; Seliger, Nehama; Sabo, Tamar; Kronman, Chanoch

    2015-01-01

    Ricin, a plant-derived exotoxin, inhibits protein synthesis by ribosomal inactivation. Due to its wide availability and ease of preparation, ricin is considered a biothreat, foremost by respiratory exposure. We examined the in vivo interactions between ricin and cells of the lungs in mice intranasally exposed to the toxin and revealed multi-phasic cell-type-dependent binding profiles. While macrophages (MΦs) and dendritic cells (DCs) displayed biphasic binding to ricin, monophasic binding patterns were observed for other cell types; epithelial cells displayed early binding, while B cells and endothelial cells bound toxin late after intoxication. Neutrophils, which were massively recruited to the intoxicated lung, were refractive to toxin binding. Although epithelial cells bound ricin as early as MΦs and DCs, their rates of elimination differed considerably; a reduction in epithelial cell counts occurred late after intoxication and was restricted to alveolar type II cells only. The differential binding and cell-elimination patterns observed may stem from dissimilar accessibility of the toxin to different cells in the lung and may also reflect unequal interactions of the toxin with different cell-surface receptors. The multifaceted interactions observed in this study between ricin and the various cells of the target organ should be considered in the future development of efficient post-exposure countermeasures against ricin intoxication. PMID:26593946

  18. [Development of the disease in marmot at the intranasal infection with the monkeypox virus].

    PubMed

    Sergeev, A A; Kabanov, A S; Bulychev, L E; Sergeev, Ar A; Pyankov, O V; Bodnev, S A; Galakhova, D O; Zamedyanskaya, A S; Titova, K A; Shishkina, L N; Agafonov, A P; Sergeev, A N

    2015-01-01

    In experimental study the sensitivity of the Marmota bobak species to the monkeypox virus (MPXV) with the intranasal (i/n) infection was tested. It was demonstrated that 50% of the infective dose (ID50) of the MPXV on external clinical signs of the disease was 2.2 Ig plaque forming units (PFU). The percentage of the marmot mortality is slightly dependent on the infecting dose of the MPXV, therefore it is not possible to correctly determine the value of 50 % fatal dose (FD50) for these animals. The most pronounced external clinical signs of the disease were obtained in the marmots: pox-like skin rash throughout the surface of the body and mucous membranes, purulent discharge from the nose, lymphadenitis, discoordination, tremor of the extremities, fever, increased aggression, and ruffled fur. In the course of experiments intended to determine the dynamics of the accumulation of the MPXV in various organs, tissues, and blood serum of marmot infected i/n with dose of 3.7 Ig PFU, it was found that the trachea, lungs, and the bifurcation lymph nodes are the primary target organs. The trachea, lungs, nasal mucosa membrane, and skin are the organs with maximal virus replication recorded at 5, 7, 9, and 12 days after the infection. The transfer of the MPXV into the secondary target organs (nasal mucosa membrane, brain, spleen, duodenum, adrenal glands, and skin) was carried out in marmots with lymphogenic and hematogenic ways of the dissemination of the infection. PMID:27024916

  19. Efficient post-exposure prophylaxis against rabies by applying a four-dose DNA vaccine intranasally.

    PubMed

    Tesoro Cruz, Emiliano; Feria Romero, Iris Angélica; López Mendoza, Juan Gabriel; Orozco Suárez, Sandra; Hernández González, Rafael; Favela, Francisco Blanco; Pérez Torres, Armando; José Alvaro Aguilar Setién

    2008-12-01

    We tested two post-exposure prophylaxes (PEPs) for rabies in laboratory animals; one was a traditional antirabies vaccine for humans via intramuscular route (IM), and the other was a DNA vaccine administered by intranasal route (IN). In contrast to The World Health Organization's recommended five-dose PEP, we gave only four doses without hyper-immune antirabies sera, making the PEP more rigorous. All animals were challenged with challenge virus strain (CVS); 16h later, PEP was applied. All animals that received the PEP with DNA/IN survived, and 87% of the rabbits and 80% of the mice that received the PEP with traditional antirabies vaccine/IM survived. Negative controls succumbed to infection. The expression of G protein was detected in the NALT, cerebellum, cerebral cortex (neocortex), cerebellum and hippocampus, mainly in the glial cells (microglia) and microvessels. On the other hand, plasmid construct was detected in brain and its mRNA expression in medium and posterior encephalon. The efficiency of this DNA/IN PEP is probably due to the early expression of the antigen in the brain stimulating the immune system locally. PMID:18940223

  20. Smallpox DNA vaccine delivered by novel skin electroporation device protects mice against intranasal poxvirus challenge.

    PubMed

    Hooper, Jay W; Golden, Joseph W; Ferro, Anthony M; King, Alan D

    2007-02-26

    Previously, we demonstrated that an experimental smallpox DNA vaccine comprised of four vaccinia virus genes (4pox) administered by gene gun elicited protective immunity in mice challenged with vaccinia virus, and in nonhuman primates challenged with monkeypox virus (Hooper JW, et al. Smallpox DNA vaccine protects nonhuman primates against lethal monkeypox. J Virol 2004;78:4433-43). Here, we report that this 4pox DNA vaccine can be efficiently delivered by a novel method involving skin electroporation using plasmid DNA-coated microneedle arrays. Mice vaccinated with the 4pox DNA vaccine mounted robust antibody responses against the four immunogens-of-interest, including neutralizing antibody titers that were greater than those elicited by the traditional live virus vaccine administered by scarification. Moreover, vaccinated mice were completely protected against a lethal (>10LD(50)) intranasal challenge with vaccinia virus strain IHD-J. To our knowledge, this is the first demonstration of a protective immune response being elicited by microneedle-mediated skin electroporation. PMID:17240007

  1. Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors.

    PubMed

    Balyasnikova, Irina V; Prasol, Melanie S; Ferguson, Sherise D; Han, Yu; Ahmed, Atique U; Gutova, Margarita; Tobias, Alex L; Mustafi, Devkumar; Rincón, Esther; Zhang, Lingjiao; Aboody, Karen S; Lesniak, Maciej S

    2014-01-01

    Treatment options of glioblastoma multiforme are limited due to the blood-brain barrier (BBB). In this study, we investigated the utility of intranasal (IN) delivery as a means of transporting stem cell-based antiglioma therapeutics. We hypothesized that mesenchymal stem cells (MSCs) delivered via nasal application could impart therapeutic efficacy when expressing TNF-related apoptosis-inducing ligand (TRAIL) in a model of human glioma. ¹¹¹In-oxine, histology and magnetic resonance imaging (MRI) were utilized to track MSCs within the brain and associated tumor. We demonstrate that MSCs can penetrate the brain from nasal cavity and infiltrate intracranial glioma xenografts in a mouse model. Furthermore, irradiation of tumor-bearing mice tripled the penetration of (¹¹¹In)-oxine-labeled MSCs in the brain with a fivefold increase in cerebellum. Significant increase in CXCL12 expression was observed in irradiated xenograft tissue, implicating a CXCL12-dependent mechanism of MSCs migration towards irradiated glioma xenografts. Finally, MSCs expressing TRAIL improved the median survival of irradiated mice bearing intracranial U87 glioma xenografts in comparison with nonirradiated and irradiated control mice. Cumulatively, our data suggest that IN delivery of stem cell-based therapeutics is a feasible and highly efficacious treatment modality, allowing for repeated application of modified stem cells to target malignant glioma. PMID:24002694

  2. Pediatric intranasal lobular capillary hemangioma: Report of two new cases and review of the literature

    PubMed Central

    Mariño-Sánchez, Franklin; Lopez-Chacon, Mauricio; Jou, Cristina; Haag, Oliver

    2016-01-01

    Background Lobular capillary hemangioma (LCH) is an acquired benign vascular tumor of unknown origin. It usually affects skin and mucous membranes of the oropharynx. It rarely involves the nasal cavity which most commonly manifests as epistaxis. To our knowledge, only fifteen pediatric intranasal LCH cases have been reported in the literature. None of these occurred in the inferior turbinate. We report two new pediatric cases of LCH, one of them on the inferior turbinate and the other one on the anterior nasal septum. Our principal aim was to highlight the importance of considering this lesion as a differential diagnosis for pediatric unilateral nasal obstruction and epistaxis. Methods Retrospective case series and review of current literature regarding the possible causes, diagnosis, and treatment of nasal LCH. Description of cases Two adolescents presented with symptoms of unilateral nasal obstruction and epistaxis. Plain and contrast enhanced computed tomography revealed a well-defined intensely enhancing lesion in both cases. Patients underwent transnasal endoscopic excision and bipolar electrocautery at the base of the tumor for hemostasis. Histopathological examination confirmed the diagnosis of LCH. Discussion Current epidemiological and pathophysiological data suggests that the development of LCH may be associated to previous nasal trauma or endocrine disorders. LCH should be considered in the differential diagnosis of all pediatric endonasal masses associated with unilateral epistaxis and nasal obstruction. Endoscopic total excision with bipolar electrocautery for hemostasis is an appropriate treatment. PMID:27144115

  3. Intranasal Immunization with Nontypeable Haemophilus influenzae Outer Membrane Vesicles Induces Cross-Protective Immunity in Mice

    PubMed Central

    Roier, Sandro; Leitner, Deborah R.; Iwashkiw, Jeremy; Schild-Prüfert, Kristina; Feldman, Mario F.; Krohne, Georg; Reidl, Joachim; Schild, Stefan

    2012-01-01

    Abstract Haemophilus influenzae is a Gram-negative human-restricted bacterium that can act as a commensal and a pathogen of the respiratory tract. Especially nontypeable H. influenzae (NTHi) is a major threat to public health and is responsible for several infectious diseases in humans, such as pneumonia, sinusitis, and otitis media. Additionally, NTHi strains are highly associated with exacerbations in patients suffering from chronic obstructive pulmonary disease. Currently, there is no licensed vaccine against NTHi commercially available. Thus, this study investigated the utilization of outer membrane vesicles (OMVs) as a potential vaccine candidate against NTHi infections. We analyzed the immunogenic and protective properties of OMVs derived from various NTHi strains by means of nasopharyngeal immunization and colonization studies with BALB/c mice. The results presented herein demonstrate that an intranasal immunization with NTHi OMVs results in a robust and complex humoral and mucosal immune response. Immunoprecipitation revealed the most important immunogenic proteins, such as the heme utilization protein, protective surface antigen D15, heme binding protein A, and the outer membrane proteins P1, P2, P5 and P6. The induced immune response conferred not only protection against colonization with a homologous NTHi strain, which served as an OMV donor for the immunization mixtures, but also against a heterologous NTHi strain, whose OMVs were not part of the immunization mixtures. These findings indicate that OMVs derived from NTHi strains have a high potential to act as a vaccine against NTHi infections. PMID:22880074

  4. The Murine Lung Microbiome Changes During Lung Inflammation and Intranasal Vancomycin Treatment

    PubMed Central

    Barfod, Kenneth Klingenberg; Vrankx, Katleen; Mirsepasi-Lauridsen, Hengameh Chloé; Hansen, Jitka Stilund; Hougaard, Karin Sørig; Larsen, Søren Thor; Ouwenhand, Arthur C.; Krogfelt, Karen Angeliki

    2015-01-01

    Most microbiome research related to airway diseases has focused on the gut microbiome. This is despite advances in culture independent microbial identification techniques revealing that even healthy lungs possess a unique dynamic microbiome. This conceptual change raises the question; if lung diseases could be causally linked to local dysbiosis of the local lung microbiota. Here, we manipulate the murine lung and gut microbiome, in order to show that the lung microbiota can be changed experimentally. We have used four different approaches: lung inflammation by exposure to carbon nano-tube particles, oral probiotics and oral or intranasal exposure to the antibiotic vancomycin. Bacterial DNA was extracted from broncho-alveolar and nasal lavage fluids, caecum samples and compared by DGGE. Our results show that: the lung microbiota is sex dependent and not just a reflection of the gut microbiota, and that induced inflammation can change lung microbiota. This change is not transferred to offspring. Oral probiotics in adult mice do not change lung microbiome detectible by DGGE. Nasal vancomycin can change the lung microbiome preferentially, while oral exposure does not. These observations should be considered in future studies of the causal relationship between lung microbiota and lung diseases. PMID:26668669

  5. Chimeric Alphavirus Vaccine Candidates Protect Mice from Intranasal Challenge with Western Equine Encephalitis Virus

    PubMed Central

    Atasheva, Svetlana; Wang, Eryu; Adams, A. Paige; Plante, Kenneth S.; Ni, Sai; Taylor, Katherine; Miller, Mary E.; Frolov, Ilya; Weaver, Scott C.

    2011-01-01

    We developed two types of chimeric Sindbis virus (SINV)/western equine encephalitis virus (WEEV) alphaviruses to investigate their potential use as live virus vaccines against WEE. The first-generation vaccine candidate, SIN/CO92, was derived from structural protein genes of WEEV strain CO92-1356, and two second-generation candidates were derived from WEEV strain McMillan. For both first- and second-generation vaccine candidates, the nonstructural protein genes were derived from SINV strain AR339. Second-generation vaccine candidates SIN/SIN/McM and SIN/EEE/McM included the envelope glycoprotein genes from WEEV strain McMillan; however, the amino-terminal half of the capsid, which encodes the RNA-binding domain, was derived from either SINV or eastern equine encephalitis virus (EEEV) strain FL93-939. All chimeric viruses replicated efficiently in mammalian and mosquito cell cultures and were highly attenuated in 6-week-old mice. Vaccinated mice developed little or no detectable disease and showed little or no evidence of challenge virus replication; however, all developed high titers of neutralizing antibodies. Upon intranasal challenge with high doses of virulent WEEV strains, mice vaccinated with ≥105 PFU of SIN/CO92 or ≥104 PFU of SIN/SIN/McM or SIN/EEE/McM were completely protected from disease. These findings support the potential use of these live-attenuated vaccine candidates as safe and effective vaccines against WEE. PMID:19446595

  6. Evidence for Status Epilepticus and Pro-Inflammatory Changes after Intranasal Kainic Acid Administration in Mice.

    PubMed

    Sabilallah, Mounira; Fontanaud, Pierre; Linck, Nathalie; Boussadia, Badreddine; Peyroutou, Ronan; Lasgouzes, Thibault; Rassendren, François A; Marchi, Nicola; Hirbec, Helene E

    2016-01-01

    Kainic acid (KA) is routinely used to elicit status epilepticus (SE) and epileptogenesis. Among the available KA administration protocols, intranasal instillation (IN) remains understudied. Dosages of KA were instilled IN in mice. Racine Scale and Video-EEG were used to assess and quantify SE onset. Time spent in SE and spike activity was quantified for each animal and confirmed by power spectrum analysis. Immunohistochemistry and qPCR were performed to define brain inflammation occurring after SE, including activated microglial phenotypes. Long term video-EEG recording was also performed. Titration of IN KA showed that a dose of 30 mg/kg was associated with low mortality while eliciting SE. IN KA provoked at least one behavioral and electrographic SE in the majority of the mice (>90%). Behavioral and EEG SE were accompanied by a rapid and persistent microglial-astrocytic cell activation and hippocampal neurodegeneration. Specifically, microglial modifications involved both pro- (M1) and anti-inflammatory (M2) genes. Our initial long-term video-EEG exploration conducted using a small cohort of mice indicated the appearance of spike activity or SE. Our study demonstrated that induction of SE is attainable using IN KA in mice. Typical pro-inflammatory brain changes were observed in this model after SE, supporting disease pathophysiology. Our results are in favor of the further development of IN KA as a means to study seizure disorders. A possibility for tailoring this model to drug testing or to study mechanisms of disease is offered. PMID:26963100

  7. Evidence for Status Epilepticus and Pro-Inflammatory Changes after Intranasal Kainic Acid Administration in Mice

    PubMed Central

    Sabilallah, Mounira; Fontanaud, Pierre; Linck, Nathalie; Boussadia, Badreddine; Peyroutou, Ronan; Lasgouzes, Thibault; Rassendren, François A.

    2016-01-01

    Kainic acid (KA) is routinely used to elicit status epilepticus (SE) and epileptogenesis. Among the available KA administration protocols, intranasal instillation (IN) remains understudied. Dosages of KA were instilled IN in mice. Racine Scale and Video-EEG were used to assess and quantify SE onset. Time spent in SE and spike activity was quantified for each animal and confirmed by power spectrum analysis. Immunohistochemistry and qPCR were performed to define brain inflammation occurring after SE, including activated microglial phenotypes. Long term video-EEG recording was also performed. Titration of IN KA showed that a dose of 30 mg/kg was associated with low mortality while eliciting SE. IN KA provoked at least one behavioral and electrographic SE in the majority of the mice (>90%). Behavioral and EEG SE were accompanied by a rapid and persistent microglial-astrocytic cell activation and hippocampal neurodegeneration. Specifically, microglial modifications involved both pro- (M1) and anti-inflammatory (M2) genes. Our initial long-term video-EEG exploration conducted using a small cohort of mice indicated the appearance of spike activity or SE. Our study demonstrated that induction of SE is attainable using IN KA in mice. Typical pro-inflammatory brain changes were observed in this model after SE, supporting disease pathophysiology. Our results are in favor of the further development of IN KA as a means to study seizure disorders. A possibility for tailoring this model to drug testing or to study mechanisms of disease is offered. PMID:26963100

  8. Effects of intranasal oxytocin on neural processing within a socially relevant neural circuit.

    PubMed

    Singh, Fiza; Nunag, Jason; Muldoon, Glennis; Cadenhead, Kristin S; Pineda, Jaime A; Feifel, David

    2016-03-01

    Dysregulation of the Mirror Neuron System (MNS) in schizophrenia (SCZ) may underlie the cognitive and behavioral manifestations of social dysfunction associated with that disorder. In healthy subjects intranasal (IN) oxytocin (OT) improves neural processing in the MNS and is associated with improved social cognition. OT's brain effects can be measured through its modulation of the MNS by suppressing EEG mu-band electrical activity (8-13Hz) in response to motion perception. Although IN OT's effects on social cognition have been tested in SCZ, OT's impact on the MNS has not been evaluated to date. Therefore, we designed a study to investigate the effects of two different OT doses on biological motion-induced mu suppression in SCZ and healthy subjects. EEG recordings were taken after each subject received a single IN administration of placebo, OT-24IU and OT-48IU in randomized order in a double-blind crossover design. The results provide support for OT's regulation of the MNS in both healthy and SCZ subjects, with the optimal dose dependent on diagnostic group and sex of subject. A statistically significant response was seen in SCZ males only, indicating a heightened sensitivity to those effects, although sex hormone related effects cannot be ruled out. In general, OT appears to have positive effects on neural circuitry that supports social cognition and socially adaptive behaviors. PMID:26727038

  9. Protective Enterotoxigenic Escherichia coli Antigens in a Murine Intranasal Challenge Model

    PubMed Central

    Kumar, Amit; Hays, Mike; Lim, Francis; Foster, Leonard J.; Zhou, Mingxu; Zhu, Guoqiang; Miesner, Tracy; Hardwidge, Philip R.

    2015-01-01

    Enterotoxigenic Escherichia coli (ETEC) is an endemic health threat in underdeveloped nations. Despite the significant effort extended to vaccine trials using ETEC colonization factors, these approaches have generally not been especially effective in mediating cross-protective immunity. We used quantitative proteomics to identify 24 proteins that differed in abundance in membrane protein preparations derived from wild-type vs. a type II secretion system mutant of ETEC. We expressed and purified a subset of these proteins and identified nine antigens that generated significant immune responses in mice. Sera from mice immunized with either the MltA-interacting protein MipA, the periplasmic chaperone seventeen kilodalton protein, Skp, or a long-chain fatty acid outer membrane transporter, ETEC_2479, reduced the adherence of multiple ETEC strains differing in colonization factor expression to human intestinal epithelial cells. In intranasal challenge assays of mice, immunization with ETEC_2479 protected 88% of mice from an otherwise lethal challenge with ETEC H10407. Immunization with either Skp or MipA provided an intermediate degree of protection, 68 and 64%, respectively. Protection was significantly correlated with the induction of a secretory immunoglobulin A response. This study has identified several proteins that are conserved among heterologous ETEC strains and may thus potentially improve cross-protective efficacy if incorporated into future vaccine designs. PMID:26244636

  10. Intranasal Immunization Strategy To Impede Pilin-Mediated Binding of Pseudomonas aeruginosa to Airway Epithelial Cells

    PubMed Central

    Hsieh, Jennifer C.; Tham, Doris M.; Feng, Weijun; Huang, Fan; Embaie, Selamawit; Liu, Keyi; Dean, Deborah; Hertle, Ralf; FitzGerald, David J.; Mrsny, Randall J.

    2005-01-01

    Prevention of pulmonary Pseudomonas aeruginosa infections represents a critical unmet medical need for cystic fibrosis (CF) patients. We have examined the tenet that a mucosal immunization approach can reduce interactions of a piliated form of this opportunistic pathogen with respiratory epithelial cells. Vaccinations were performed using ntPEpilinPAK, a protein chimera composed of a nontoxic form of P. aeruginosa exotoxin A (ntPE), where the C-terminal loop amino acid sequence of the PAK strain pilin protein was inserted in place of the ntPE Ib domain. Intranasal (i.n.) immunization of BALB/c mice with ntPEpilinPAK generated both serum and saliva immune responses. A series of in vitro studies showed that diluted samples of saliva obtained from immunized mice reduced pilin-dependent P. aeruginosa binding to polarized human tracheal epithelial cells, protected human pulmonary epithelial cells from cytotoxic actions associated with bacterial challenge, and reduced exotoxin A toxicity. Overall, i.n. administration of ntPEpilinPAK induced mucosal and systemic immune responses that may be beneficial for blocking early stage adhesion and/or infection events of epithelial cell-P. aeruginosa interactions at oropharyngeal surfaces. PMID:16239575

  11. Histopathological effects of intranasal phototherapy and nasal corticosteroids in allergic rhinitis in a rabbit model.

    PubMed

    Yurttas, Veysel; Şereflican, Murat; Erkoçoğlu, Mustafa; Terzi, Elçin Hakan; Kükner, Aysel; Oral, Mesut

    2015-08-01

    Allergic rhinitis is one of the most common health problems and has a major effect on quality of life. Although new-generation antihistamines and nasal steroids are the main treatment options, complete resolution cannot be obtained in some patients. Besides common side effects such as nasal irritation and epistaxis, the use of these drugs is controversial in some patients, such as pregnant or breastfeeding women. These findings highlight the need for new treatment options. Although phototherapy has been successfully used in the treatment of atopic dermatitis, which is an IgE-mediated disease and shares several common pathogenic features with allergic rhinitis, there are limited studies about its role in the treatment of allergic rhinitis. In this study, we aimed to evaluate and compare the histopathological effects of intranasal phototherapy (Rhinolight) and nasal corticosteroid treatment on the nasal mucosa in allergic rhinitis in a rabbit model and we found that both treatment options significantly reduced inflammation in the nasal mucosa without increasing apoptosis of mucosal cells. PMID:26123190

  12. Diverse profiles of ricin-cell interactions in the lung following intranasal exposure to ricin.

    PubMed

    Sapoznikov, Anita; Falach, Reut; Mazor, Ohad; Alcalay, Ron; Gal, Yoav; Seliger, Nehama; Sabo, Tamar; Kronman, Chanoch

    2015-11-01

    Ricin, a plant-derived exotoxin, inhibits protein synthesis by ribosomal inactivation. Due to its wide availability and ease of preparation, ricin is considered a biothreat, foremost by respiratory exposure. We examined the in vivo interactions between ricin and cells of the lungs in mice intranasally exposed to the toxin and revealed multi-phasic cell-type-dependent binding profiles. While macrophages (MΦs) and dendritic cells (DCs) displayed biphasic binding to ricin, monophasic binding patterns were observed for other cell types; epithelial cells displayed early binding, while B cells and endothelial cells bound toxin late after intoxication. Neutrophils, which were massively recruited to the intoxicated lung, were refractive to toxin binding. Although epithelial cells bound ricin as early as MΦs and DCs, their rates of elimination differed considerably; a reduction in epithelial cell counts occurred late after intoxication and was restricted to alveolar type II cells only. The differential binding and cell-elimination patterns observed may stem from dissimilar accessibility of the toxin to different cells in the lung and may also reflect unequal interactions of the toxin with different cell-surface receptors. The multifaceted interactions observed in this study between ricin and the various cells of the target organ should be considered in the future development of efficient post-exposure countermeasures against ricin intoxication. PMID:26593946

  13. Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor.

    PubMed

    Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E

    2016-01-01

    The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain. PMID:27345430

  14. IgG4-related disease in the sinonasal cavity accompanied by intranasal structure loss.

    PubMed

    Inoue, Akiko; Wada, Kota; Matsuura, Kentaro; Osafune, Hiroshi; Ida, Yutaro; Kosakai, Arifumi; Edamatsu, Hideo

    2016-02-01

    IgG4-related disease was recently proposed under the classification of systemic chronic inflammatory disease. In the field of otolaryngology, organ-specific diagnostic criteria have been established for the occurrence of this condition in the salivary glands, but not in the sinonasal cavity. Here we report a case involving a 70-year-old man with IgG4-related disease in the sinonasal cavity. The patient, with the chief complaint of nasal bleeding, first visited a physician. However, the patient experienced recurrent bleeding with intranasal structure loss and was subsequently referred to our hospital. His IgG4 level was elevated, and histopathological examination of a tissue sample obtained from the edematous sphenoid sinus showed increased IgG4-positive plasma cells and storiform fibrosclerosis. A definitive diagnosis of IgG4-related rhinosinusitis was made on the basis of comprehensive criteria for IgG4-related disease. The disease showed a progressively destructive course that was clearly different from that of chronic sinusitis and represented a very rare case of IgG4-related rhinosinusitis. IgG4-related disease originating in the sinonasal cavity is rare, and, to the best of our knowledge, this is the first primary case of IgG4-related disease that originated in one side of the sinonasal cavity and showed progressive destruction. PMID:26104224

  15. Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

    PubMed Central

    Ionescu, Irina A; Dine, Julien; Yen, Yi-Chun; Buell, Dominik R; Herrmann, Leonie; Holsboer, Florian; Eder, Matthias; Landgraf, Rainer; Schmidt, Ulrike

    2012-01-01

    Experiments in rodents revealed neuropeptide S (NPS) to constitute a potential novel treatment option for anxiety diseases such as panic and post-traumatic stress disorder. However, both its cerebral target sites and the molecular underpinnings of NPS-mediated effects still remain elusive. By administration of fluorophore-conjugated NPS, we pinpointed NPS target neurons in distinct regions throughout the entire brain. We demonstrated their functional relevance in the hippocampus. In the CA1 region, NPS modulates synaptic transmission and plasticity. NPS is taken up into NPS receptor-expressing neurons by internalization of the receptor–ligand complex as we confirmed by subsequent cell culture studies. Furthermore, we tracked internalization of intranasally applied NPS at the single-neuron level and additionally demonstrate that it is delivered into the mouse brain without losing its anxiolytic properties. Finally, we show that NPS differentially modulates the expression of proteins of the glutamatergic system involved inter alia in synaptic plasticity. These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans. PMID:22278093

  16. Intranasal exposure of the Richardson's ground squirrel to Western equine encephalomyelitis virus.

    PubMed Central

    Leung, M K; McLintock, J; Iversen, J

    1978-01-01

    Adult Richardson's ground squirrels were infected with western equine encephalomyelitis virus by intranasal instillation. Mortality followed the instillation of a minimum threshold of 4.7 logs of virus while infection was produced by a dosage of 2.3 logs. The incubation period was from four to seven days, being preceded by a viremic phase. Signs were depression, ataxia and paralysis of the limbs. Highest titres of virus were recovered from the brain and histopathological changes involving the central nervous system included meningitis, vasculitis, perivascular cuffing, gliosis, neuronophagia and neuronal degeneration. The virus was also found in a variety of extraneural tissues. Lesions in extraneural tissues included necrosis of brown fat and an apparent increase in number of Kupffer's cells in the liver. The lymphoid tissue was involved indicating a possible source for viremia. The duration and magnitude of viremia were ample enough to provide virus source for arthropods. The potential for transmission of the virus independent of arthropods was discussed in view of the pathogenesis demonstrated in the experimental infections. PMID:667706

  17. Comparison of traditional intranasal and aerosol inhalation inoculation of mice with influenza A viruses.

    PubMed

    Belser, Jessica A; Gustin, Kortney M; Katz, Jacqueline M; Maines, Taronna R; Tumpey, Terrence M

    2015-07-01

    Intranasal instillation of virus in a liquid suspension (IN) is the most frequently employed method to inoculate small mammalian models with influenza virus, but does not reflect a natural route of exposure. In contrast, inoculation via aerosol inhalation (AR) more closely resembles human exposure to influenza virus. Studies in mice have yielded conflicting results regarding virulence induced by virus inoculated by these routes, and have not controlled for potential strain-specific differences, or examined contemporary influenza viruses and avian viruses with pandemic potential. We used a whole-body AR inoculation method to compare infectivity and disease progression of a highly pathogenic H5N1, a low pathogenic H7N9, and a 2009 H1N1 virus with traditional IN inoculation in the mouse model. Generally comparable levels of morbidity and mortality were observed with all viruses examined using either inoculation route, indicating that both IN and AR delivery are appropriate for murine studies investigating influenza virus pathogenicity. PMID:25771498

  18. Telomerase inhibitors for the treatment of brain tumors and the potential of intranasal delivery.

    PubMed

    Hashizume, Rintaro; Gupta, Nalin

    2010-04-01

    A fundamental limitation in the treatment of brain tumors is that < 1% of most therapeutic agents administered systemically are able to cross the blood-brain barrier (BBB). The development of new strategies that circumvent the BBB should increase the likelihood of tumor response to selected therapeutic agents. Intranasal delivery (IND) is a practical, noninvasive method of bypassing the BBB to deliver therapeutic agents to the brain. This technique has demonstrated promising results in the treatment of neurological disorders. Telomerase is a reverse transcriptase that is expressed in the vast majority of malignant gliomas, although not in the healthy brain. Telomerase inhibition can therefore be used as a therapeutic strategy for selectively targeting malignant gliomas. The first successful IND of a telomerase inhibitor as a therapy for brain tumors was GRN-163, an oligonucleotide N3'-->5' thiophosphoramidate telomerase inhibitor, which was successfully administered into intracerebral tumors in rats with no apparent toxicity. GRN-163 exhibited favorable tumor uptake and inhibited tumor growth, leading to prolonged lifespan in treated animals. The IND of telomerase inhibitors represents a new therapeutic approach that appears to selectively kill tumor cells, without inducing toxic effects in