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Results for “Administration, Intranasal”

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At least 451 records · Page 25Linked to original sources

PubMed2004

Low molecular weight chitosan nanoparticles as new carriers for nasal vaccine delivery in mice.

High molecular weight (Mw) chitosan (CS) solutions have already been proposed as vehicles for nasal immunization. The aim of the present work was to investigate the potential utility of low Mw CS in the form of nanoparticles as new long-term nasal vaccine delivery vehicles. For this purpose, CS of low Mws (23 and 38 kDa) was obtained previously by a depolymerization process of the commercially available CS (70 kDa). Tetanus toxoid (TT), used as a model antigen, was entrapped within CS nanoparticles by an ionic cross-linking technique. TT-loaded nanoparticles were first characterized for their size, electrical charge, loading efficiency and in vitro release of antigenically active toxoid. The nanoparticles were then administered intranasally to conscious mice in order to study their feasibility as vaccine carriers. CS nanoparticles were also labeled with FITC-BSA and their interaction with the rat nasal mucosa examined by confocal laser scanning microcopy (CLSM). Irrespective of the CS Mw, the nanoparticles were in the 350 nm size range, and exhibited a positive electrical charge (+40 mV) and associated TT quite efficiently (loading efficiency: 50-60%). In vitro release studies showed an initial burst followed by an extended release of antigenically active toxoid. Following intranasal administration, TT-loaded nanoparticles elicited an increasing and long-lasting humoral immune response (IgG concentrations) as compared to the fluid vaccine. Similarly, the mucosal response (IgA levels) at 6 months post-administration of TT-loaded CS nanoparticles was significantly higher than that obtained for the fluid vaccine. The CLSM images indicated that CS nanoparticles can cross the nasal epithelia and, hence, transport the associated antigen. Interestingly, the ability of these nanoparticles to provide improved access to the associated antigen to the immune system was not significantly affected by the CS Mw. Indeed, high and long-lasting responses could be obtained using low Mw CS molecules. Furthermore, the response was not influenced by the CS dose (70-200 microg), achieving a significant response for a very low CS dose. In conclusion, nanoparticles made of low Mw CS are promising carriers for nasal vaccine delivery.

Administration, Intranasal↗

PubMed2005

Polycations enhance emulsion-mediated in vitro and in vivo transfection.

To enhance the in vitro and in vivo transfection activity of the cationic lipid emulsion (LE), three natural polycations, protamine sulfate (PS), poly-L-lysine and spermine, were selected as DNA condensing active agents. Formation of the LE/polycation/DNA ternary complexes was identified by using agarose gel retardation study. The structure of these complexes was characterized by measuring the complex size and the decrease of the DNA fluorescence in the presence of ethidium bromide (EtBr). By adding a polycation, the particle size of the complex decreased, and DNA in the complex became highly condensed and resistant to intercalation of EtBr. Among the polycations, PS yielded the most highly compacted ternary complex. In vitro and in vivo transfection activities of the complexes were determined using various cell lines and Balb/c mouse intravenously and intranasally, respectively. The transfection activity of the ternary complex increases by at least 2.5-5-fold in vitro cell culture system in the presence of 80% serum as well as in vivo mouse system, as compared with LE/DNA binary complexes. More importantly, after intravenous and intranasal administrations, the in vivo transfection efficiency of the LE/PS/DNA complex was ca. 30 and 50 times higher than that of the liposome (LP)/DNA complex in spleen and lung, respectively. On the other hand, cell toxicity of the ternary complex is lower than that of binary complex. Thus, we conclude that the pre-condensation of DNA with polycations can be a promising approach to further increase in vitro and in vivo transfection efficiency of cationic lipid emulsion.

Administration, Intranasal↗

PubMed2006

Rapid-onset intranasal delivery of metoclopramide hydrochloride Part II: Safety of various absorption enhancers and pharmacokinetic evaluation.

In the present study, several nasal absorption enhancers, used in metoclopramide hydrochloride (MCP HCl) nasal solutions, have been screened for their possible damaging effect in the in vitro human erythrocytes lysis experiment. Moreover, the in vivo leaching of biological markers from the rat nasal epithelium was used as a quantitative assessment for possible nasal mucosal irritation whereby the extent of release of total protein and lactate dehydrogenase (LDH) in the nasal lavage fluid was determined. Results showed that insignificant hemolysis from normal saline (P<0.05) occurred with the enhancer protamine sulphate while poly-l-arginine and sodium cholate demonstrated very low (<15%) hemolysis and caused insignificant protein and LDH release from the rat nasal mucosa. Conversely, sodium deoxycholate and chitosan polymers (either of low or high molecular weight) showed high (>60%) hemolysis in vitro and the release of the biological markers in vivo was significantly higher (P<0.05) than the control solution (no enhancer). A significant correlation (P<0.05) existed between the enhancement effect of MCP HCl nasal absorption and the amounts of protein (r=0.85) and LDH (r=0.88). Furthermore, the pharmacokinetics of MCP HCl was determined after intravenous (IV), per-oral and intranasal administration of 10mg drug dose in rabbits. The application of a nasal spray (NS) solution containing 0.5% sodium cholate resulted in a significant improvement (P<0.05) in both the rate and extent of absorption of MCP HCl where the T(max) achieved was 23.3min as compared to 50min in case of the oral solution while the area under the serum concentration-time curve (AUC(0-infinity)) were 506.1, 434.9 and 278.7microg/mlmin for IV, NS and oral solutions, respectively. These values corresponded to absolute bioavailabilities of 87.21 and 55.61% for the NS and oral solutions, respectively. It could thus be concluded that NS of MCP HCl represents a viable approach to achieving rapid and high systemic drug absorption during the emergency treatment of severe emesis.

Absorption↗

PubMed2004

Nasal delivery of human growth hormone: in vitro and in vivo evaluation of a thiomer/glutathione microparticulate delivery system.

It was the aim of this study to develop and evaluate a nasal microparticulate delivery system for human growth hormone (hGH) based on the thiomer polycarbophil-cysteine (PCP-Cys) in combination with the permeation mediator glutathione (GSH). Microparticles were prepared by dissolving PCP-Cys/GSH/hGH (7.5:1:1.5), PCP/hGH (8.5:1.5), and mannitol/hGH (8.5:1.5) in demineralized water, followed by lyophilization and micronization. Particles were evaluated with regard to size distribution and swelling behavior using a laser diffraction particle size analyzer. The release of fluorescence-labelled hGH from microparticles was determined in Franz diffusion chambers. In vivo studies in rats were performed comparing the nasal bioavailability achieved by PCP-Cys/GSH/hGH microparticles with that of unmodified PCP/hGH microparticles and mannitol/hGH powder. PCP-Cys/GSH/hGH and PCP/hGH microparticles showed a comparable size distribution (80% in the range of 4.8-23 microm) and swelled to almost fourfold size in phosphate-buffered saline (PBS). Both formulations exhibited almost identical sustained drug release profiles. The intranasal administration of the PCP-Cys/GSH/hGH microparticulate formulation resulted in a relative bioavailability of 8.11+/-2.15%, which represents a 3-fold and 3.3-fold improvement compared to that of PCP/hGH microparticles and mannitol/hGH powder, respectively. The study suggests that the PCP-Cys/GSH/hGH nasal microparticulate formulation might represent a promising novel tool for the systemic delivery of hGH.

Acrylic Resins↗

PubMed2006

Aminated gelatin microspheres as a nasal delivery system for peptide drugs: evaluation of in vitro release and in vivo insulin absorption in rats.

Aminated gelatin microspheres (AGMS) was investigated as a nasal drug delivery system for peptide drugs. The in vitro drug release from microspheres was evaluated using a fluorescein-labeled insulin (RITC-insulin) and FITC-dextran with a molecular weight of 4.4 kDa (FD-4) as model drugs. RITC-insulin release from AGMS was significantly slower than from native gelatin microspheres (GMS), with a cumulate release of 18.4% and 32.4% within 30 min, and 56.9% and 75.1% within 8 h respectively. However, the release of FD-4 from both AGMS and GMS was quite rapid and no difference was observed for the two microspheres. The electrostatic interactions between the model drugs and the microspheres were supposed to be the main factor that controlled the release behavior. The absorption enhancing effect was estimated by measuring the changes of plasma glucose concentrations of healthy rats following intranasal administration of insulin-incorporated microspheres in both suspension and dry powder forms. AGMS could significantly increase the nasal absorption of insulin in rats when administered in a dry powder formulation, but no significant hypoglycemic effect was observed when given in suspensions. One of the mechanisms for the increased insulin absorption was attributed to the hydrogel nature of the microspheres that could absorb water from the nasal mucosa and thus resulted in a temporarily dehydration of the epithelium membrane and opening of the tight junctions. The positive charge of the AGMS has also evidently contributed to the absorption enhancing effect. In addition, the mucoadhesive properties of AGMS might also have played a role to the total effect. AGMS might be a new candidate carrier for the nasal delivery of peptide drugs.

Absorption↗

PubMed2006

PLGA:poloxamer and PLGA:poloxamine blend nanostructures as carriers for nasal gene delivery.

We have recently reported the formation of a new type of nanoparticles consisting of blends of poly (lactic-co-glycolic acid) (PLGA) and polyethylene oxide (PEO) derivatives, which exhibit the capacity to associate and release plasmid DNA in a controlled manner. In the present work our goal was to investigate the ability of these nanoparticles to overcome cellular and mucosal barriers (i.e. nasal mucosa) and thus, to work as gene delivery carriers. First, we studied the in vitro cellular uptake (HEK 293 cell line) of FITC-labelled plasmid DNA nanoencapsulated in PLGA: Pluronic F68 and PLGA: Tetronic T904 particles by confocal microscopy. Second, we investigated the uptake of rhodamine-labelled nanoparticles by the nasal mucosa following intranasal administration to mice. Third, we monitored the immune response generated by the nanoparticles containing a beta-galactosidase encoding gene, following nasal administration to mice, using the ELISA technique. The results of the in vitro cell culture studies showed the ability of these new nanoparticles to enter the cells and transport the associated DNA molecule across the cell membrane. Moreover, the results obtained following in vivo administration of the fluorescent nanoparticles evidenced their capability to overcome the nasal mucosal barrier. Finally, the results of the immunisation studies showed that DNA-loaded nanoparticles elicit a fast and strong response, significantly more pronounced than that corresponding to the naked plasmid DNA for up to 6 weeks. Overall, these results suggest that these new nanoparticles have a potential as carriers for the delivery of DNA across the nasal mucosa.

Administration, Intranasal↗

PubMed2006

In vivo imaging of functional disruption, recovery and alteration in rat olfactory circuitry after lesion.

Compensatory changes following disruption of neuronal circuitry have been indicated by previous imaging studies of stroke and other brain injury, but evidence of the pathways involved in such dynamic changes has not been shown in vivo. We imaged rats before and after lesion-induced disruption of the lateral olfactory tract to investigate the subsequent recovery and/or reorganization of functional neuronal circuitry. Serial magnetic resonance imaging was performed following intranasal administration of a paramagnetic track tracer Mn(2+). Images were analyzed using statistical mapping techniques in the stereotactic coordinate system. At 1 week post-lesion, Mn(2+) transport caudal to lesion was reduced as expected, and more importantly, increased transport through the anterior commissure was seen. At 4 weeks post-lesion, there was recovery of transport caudal to lesion, and increased transport through the anterior commissure extended to the contralateral olfactory cortex. Correlation analysis of regional Mn(2+) transport indicated that contralateral enhancement was not simply due to septal window spillover. This study demonstrates for the first time in vivo evidence of compensatory changes in functional neuronal activity to a contralateral pathway through the commissure following brain injury.

Administration, Intranasal↗

PubMed2006

In vivo protein transduction to the CNS.

Proteins and peptides are useful research and therapeutic tools, however applications are limited because delivery to the desired location is not easily achievable. There are two hurdles in protein/peptide delivery to the brain: the blood-brain barrier and intracellular penetration. Penetration to both brain and the intracellular space can be achieved by adjusting hydrophilicity, and small molecule pharmacological agents have been successfully developed using this approach. But with proteins and peptides, it is difficult to modify the hydrophilicity without influencing biological functions. Trans-acting factor protein from the human immunodeficiency virus contains a highly conserved cationic peptide sequence necessary for transduction across the cell membrane. While trans-acting factor peptide has been used for in vitro protein transduction, its in vivo application is very limited because it is rapidly degraded by proteolysis. Polyethylenimine is a chemically synthesized small molecule cationization agent; the charge density is greater than a peptide-based cationic cluster such as trans-acting factor, and it is resistant to proteolysis in vivo. We first tested intracellular protein transduction following direct brain injection in mice using polyethylenimine-conjugated green fluorescence protein and beta-galactosidase (molecular weights 29 and 540 kDa, respectively). Polyethylenimine-conjugates penetrated to the intracellular space immediately surrounding the injection site within one hour. We further tested polyethylenimine-mediated protein transduction following intranasal administration, which bypasses the blood-brain barrier. Polyethylenimine-conjugates in pH 7.5 solution did not reach the brain, probably because the polyethylenimine-conjugates penetrated into the intracellular space where first exposed to the tissue, i.e. at the nasal mucosae. We temporarily reduced the electrostatic interaction between cationized polyethylenimine-conjugates and cellular surfaces by adjusting the pH to 4.5; solution rapidly reached the brain and penetrated to the intracellular space. This study suggests that polyethylenimine is a useful protein transduction agent in the brain in vivo, and adjusting cationic charge interaction can determine the extent of brain penetration.

Administration, Intranasal↗

PubMed2004

Effect of dose and long-term storage on the immunogenicity of murine polyomavirus VP1 virus-like particles.

We have analysed the stability and immunogenicity of murine polyomavirus virus-like particles (VLPs) following intranasal administration without adjuvant. No morphological or immunological changes were observed in a preparation of these VLPs stored for 9 weeks at room temperature. Strong humoral and cellular (Th1) responses were obtained after a single 5.55 microg dose immunisation, which are efficiently boosted after a second dose. However, at dose concentrations above 0.22 microg/microl, these VLPs appear to aggregate and, when used for immunisations, they fail to induce a strong cellular response, even though the humoral response is unaffected. These results may reflect the differential processing of VLP aggregates by the immune system or, alternatively, VLP neutralisation by antibodies induced after a primary immunisation.

Administration, Intranasal↗

PubMed2004

Intranasal immunisation with Toxoplasma gondii tachyzoite antigen encapsulated into PLG microspheres induces humoral and cell-mediated immunity in sheep.

Proteins from a crude extract of Toxoplasma gondii tachyzoites were encapsulated into poly(D,L-lactide-co-glycolide) (PLG) micro- and nano-particles with a mean encapsulation efficiency of 80%. An intranasal immunisation and infection experiment using 24 sheep was conducted to compare the immune responses elicited by intranasal administration of soluble and particulate T. gondii antigen (with and without cholera toxin). Sheep immunised with particulate toxoplasma antigen produced enhanced levels of both local and systemic antigen-specific IgA antibody, and showed increased cellular immune responses with a corresponding increase in IFNgamma production. After challenge with toxoplasma oocysts larger quantities of both nasal and systemic IgG were measured more rapidly in all animals immunised with toxoplasma antigen than animals infected with oocysts, suggesting a secondary-type IgG response. A slight modification of the febrile response to toxoplasma infection could be observed in animals immunised with particulate toxoplasma antigen and cholera toxin, although none of the immunised animals were protected against the challenge infection. These studies show that intra-nasal delivery has the potential to be an effective route for mucosal immunisation in sheep.

Adjuvants, Immunologic↗

PubMed2005

Intranasal immunisation with defective adenovirus serotype 5 expressing the Venezuelan equine encephalitis virus E2 glycoprotein protects against airborne challenge with virulent virus.

There is no vaccine licensed for human use to protect laboratory or field workers against infection with Venezuelan equine encephalitis virus (VEEV). Infection of these groups is most likely to occur via the airborne route and there is evidence to suggest that protection against airborne infection may require high antibody levels and the presence of antibody on the mucosal surface of the respiratory tract. Recombinant defective type 5 adenoviruses, expressing the E3E26K structural genes of VEEV were examined for their ability to protect mice against airborne challenge with virulent virus. After intranasal administration, good protection was achieved against the homologous serogroup 1A/B challenge virus (strain Trinidad donkey). There was less protection against enzootic serogroup II and III viruses, indicating that inclusion of more than one E3E26K sequence in a putative vaccine may be necessary. These studies confirm the potential of recombinant adenoviruses as vaccine vectors for VEEV and will inform the development of a live replicating adenovirus-based VEEV vaccine, deliverable by a mucosal route and suitable for use in humans.

Adenoviruses, Human↗

PubMed2005

Genetic stability of live, cold-adapted influenza virus components of the FluMist/CAIV-T vaccine throughout the manufacturing process.

FluMist is a live-attenuated, trivalent influenza vaccine (LAIV) recently approved for intranasal administration. To demonstrate genetic stability during manufacture of the vaccine viruses in LAIV and a similar vaccine in development (CAIV-T), full genome consensus sequences were determined at multiple manufacturing stages for four influenza type A and five type B strains. The critical cold-adapted (ca), temperature-sensitive (ts) and attenuated (att) mutations were preserved in the virus manufacturing intermediates. Moreover, sequence identity was observed for all vaccine intermediates of the same strain. Minor sequence differences were noted in the shared gene segments of the vaccine viruses and their common progenitor master donor virus (MDV) and several of the hemagglutinin (HA) and neuraminidase (NA) genes contained nucleotide differences when compared to the wild-type parent. Nonetheless, all vaccine viruses retained the ca, ts, and att phenotypes. Thus, genetic and phenotypic stability of the vaccine viruses is maintained during the manufacture of LAIV/CAIV-T vaccines.

Adaptation, Physiological↗

PubMed2003

Interleukin-12-independent down-modulation of cockroach antigen-induced asthma in mice by intranasal exposure to bacterial lipopolysaccharide.

Several studies have shown that exposure to bacterial lipopolysaccharide (LPS) can either prevent or inhibit asthma in humans and laboratory rodents. Much emphasis has been placed on the role of cytokines and chemokines in the establishment and maintenance of allergic airway disease. Therefore, it is of interest to study the role of LPS in affecting airway pathology and lung cytokine and chemokine responses in the maintenance phase of asthma. Increasing doses of LPS were administered into the airways of mice presensitized with cockroach allergen (CRAg), then allergic airway disease parameters were assessed after CRAg challenge. Airway hyperresponsiveness after antigen challenge decreased at the highest dose of LPS tested, which was accompanied by a decrease in airway and lung eosinophils. However, a dramatic increase in lung inflammation because of neutrophil influx was observed. Measurement of cytokines in lungs of LPS-treated, CRAg-sensitized mice indicated that interleukin (IL)-12 levels were increased by LPS treatment in a dose-dependent manner, as were levels of several inflammatory chemokines. In contrast, levels of IL-4, IL-13, IL-5, and IL-10 were reduced in whole lung homogenates only of high-dose LPS-treated mice. Intranasal administration of neutralizing anti-IL-12 at the time of high-dose LPS challenge reduced lung IL-12, interferon-gamma, CXCL9, and CXCL10 but did not affect levels of the other chemokines or Th2-type cytokines, and did not restore AHR. These findings suggest that the amelioration of airway hyperresponsiveness observed in LPS-treated, CRAg-sensitized mice is coincident with an immune deviation of the lung inflammatory response, independent of IL-12.

Administration, Intranasal↗

PubMed1977

Assessment of pituitary response to nasal application of synthetic gonadotropin-releasing hormone in men.

An attempt has been made to assess the pituitary response to the nasal application of synthetic gonadotropin-releasing hormone (GnRH) in three oligospermic and two azoospermic men. Intranasal administration of 3 mg of GnRH in aqueous or natural plant gum solution produced a pituitary response pattern similar to that produced by the intramuscular injection of 100 microng, with respect to plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). No technical difficulties or side effects were observed. GnRH in a nasal drop preparation seems to be effective in releasing LH and FSH in men. These findings may have a practical application in those cases where long-term therapy with the hormone is indicated.

Administration, Intranasal↗

PubMed1991

Stimulation of endogenous surge of luteinizing hormone with gonadotropin-releasing hormone analog after ovarian stimulation for in vitro fertilization.

The effect of induction of preovulatory endogenous surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) with intranasal administration of GnRH-analog (GnRH-a) in an in vitro fertilization (IVF) program is reported. The use of GnRH-a resulted in a significantly better percentage of replaceable embryos (91% versus 85%). The pregnancy rate was 51% in comparison with 32% in control cycles in which follicular maturation was achieved by human chorionic gonadotropin administration. There was no significant difference in the postoocyte recovery serum progesterone patterns between the two groups. Our results indicate that the induction of endogenous LH and FSH surge with GnRH-a may be successfully employed for final follicular maturation after ovarian suprastimulation without affecting the outcome of IVF adversely. Apart from being a more physiological approach to oocyte maturation, it also has potential economic and clinical advantages.

Administration, Intranasal↗

PubMed1992

Effect of long-term calcitonin therapy by injection and nasal spray on the incidence of fractures in osteogenesis imperfecta.

The effect of calcitonin therapy by injection or nasal spray on the incidence of bone fractures was studied in patients with osteogenesis imperfecta. In contrast to injection of calcitonin, intranasal administration of calcitonin twice a week for 2 weeks, followed by 2 weeks of no therapy, was simple and seemed beneficial for decreasing bone fractures in patients with osteogenesis imperfecta.

Administration, Intranasal↗

PubMed1986

Intranasal nafarelin: an LH-RH analogue treatment of gonadotropin-dependent precocious puberty.

The agonistic analogues of luteinizing hormone releasing hormone decrease biochemical findings and clinical signs of gonadotropin-dependent precocious puberty. We tested a new analogue, nafarelin acetate, in 15 girls with gonadotropin-dependent precocious puberty. The hydrophobic nature and potency of this compound allow it to be administered by intranasal inhalation. Laboratory assessment of vaginal cytology, estradiol and urinary gonadotropin levels, and growth velocity revealed that nafarelin acetate 800 to 1200 micrograms/day diminished these values during a 6-month treatment period. These results suggest gonadotropin-dependent precocious puberty in girls can be treated with intranasal administration of nafarelin acetate.

Administration, Intranasal↗

PubMed1982

Intranasal DDAVP test in children.

The intranasal DDAVP (1-deamino-8-D-arginine vasopressin) test is a safe and feasible method for the study of renal concentrating ability in children. This study describes a simplification of the test. Sixty randomly selected children were tested for urine osmolality at different hours after intranasal administration of DDAVP. No fluid restriction was prescribed. Optimal concentrating ability was attained after 3 and 5 hours. Without impairing the validity of the DDAVP test, it can be performed in a simpler way than previously recommended.

Administration, Intranasal↗