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Induction of systemic and mucosal antibody responses in mice immunized intranasally with aluminium-non-adsorbed diphtheria toxoid together with recombinant cholera toxin B subunit as an adjuvant.

Nasal mucosal immunization is very attractive for vaccination to prevent various bacterial and viral infectious diseases because of induction of systemic and mucosal immune responses. The aim of the present study was to investigate the possibility of changing the immunization procedure of diphtheria toxoid (DT) from intramuscular or subcutaneous injection to intranasal administration. Intranasal immunization with aluminium-non-adsorbed diphtheria toxoid (nDT) together with recombinant cholera toxin B subunit (rCTB, 10 microg) induced, at a concentration of 5 Lf, high levels of serum DT-specific IgG antibody responses and high or moderate levels of the specific IgA antibody responses in all mice and only a slight level of the specific IgE antibody responses in some mice. Furthermore, sufficiently high diphtheria antitoxin titres more than 0.1 international units (IU) ml(-1) were obtained from mice which showed high levels of serum DT-specific IgG antibody responses. Under the same experimental conditions, induction of significant levels of mucosal DT-specific IgA antibody responses occurred in the nasal cavity, the lung, the saliva and vaginal secretions and the small and large intestines of all mice, although there were different titres between individual mice. Similar results were also obtained with rCTB-specific serum IgG and IgA and mucosal IgA antibody responses; serum rCTB-specific IgE antibody titres were not detected. These results show that intranasal administration of nDT with rCTB must be a very useful means for vaccination against diphtheria.

Adjuvants, Immunologic↗

Human tolerance and histopathologic effects of long-term administration of intranasal interferon-alpha 2.

Fifty-two healthy adults were randomly assigned interferon-alpha 2 (HuIFN-alpha 2), 8.4 X 10(6) U/day, or placebo by intranasal spray for 28 days. Symptoms, nasal examinations, and histologic analysis of nasal biopsy specimens obtained three days before and one day after exposure were evaluated under blind conditions. HuIFN-alpha 2 was associated with signs of mucosal irritation (dry mucous membranes, crusts, and friability) and/or symptoms (blood-tinged mucus) in 23% of recipients. Moderate or marked epithelial acute inflammation with ulceration occurred in 19% of HuIFN-alpha 2 recipients. Pronounced submucosal lymphocytic and mononuclear cell infiltrates developed in 58%. These histopathologic abnormalities resolved within eight weeks of stopping exposure. These results indicate that long-term or indefinite intranasal administration of HuIFN-alpha 2 at the dosages used in this study is not feasible strategy for prophylaxis of respiratory viral infections.

Administration, Intranasal↗

Induction of secretory immunity with bioadhesive poly (D,L-lactide-co-glycolide) microparticles containing Streptococcus sobrinus glucosyltransferase.

The effect of mucosal delivery of Streptococcus sobrinus glucosyltransferase (GTF) in bioadhesive poly (D,L-lactide-co-glycolide) (PLGA) microparticles on induction of salivary IgA and serum IgG antibody responses was measured in Sprague-Dawley rats. Preparations of GTF/PLGA/gelatin microparticles, or PLGA/gelatin microparticles or GTF in alum, were administered four times at weekly intervals by intranasal or intragastric routes. Two subcutaneous injections of GTF in PLGA/gelatin microparticles or in alum were given to separate groups of rats. Significant elevations in salivary IgA antibody levels to S. sobrinus GTF were observed only in the groups immunized intranasally 28 days after immunizations were begun. Five of six rats given the GTF microparticles intranasally had positive salivary IgA antibody responses to GTF, and the mean salivary IgA antibody level of this group was 30-fold higher than any other mucosally or systemically immunized group. Salivary IgA responses in the GTF-microparticle group remained significantly higher than all other mucosally immunized groups for at least 10 weeks after the primary immunization. All rats in this group demonstrated aspects of anamnesis following a more limited secondary course of intranasal administration. Intranasal administration of GTF in microparticles also induced a serum IgG response to GTF in some rats. After secondary intranasal GTF microparticle administration, several rats had sustained serum IgG antibody levels that were within the range of sera from rats subcutaneously injected with GTF in microparticles or in alum. Thus intranasal delivery of GTF-containing bioadhesive microparticles induced the highest and longest lasting salivary immune response of any mucosal or systemic route or vehicle tested and could be expected to be a useful method for induction of mucosal immunity.

Administration, Intranasal↗

Mucosal immunization with virus-like particles of simian immunodeficiency virus conjugated with cholera toxin subunit B.

To enhance the efficiency of antigen uptake at mucosal surfaces, CTB was conjugated to simian immunodeficiency virus (SIV) virus-like particles (VLPs). We characterized the immune responses to the Env and Gag proteins after intranasal administration. Intranasal immunization with a mixture of VLPs and CTB as an adjuvant elicited higher levels of SIV gp160-specific immunoglobulin G (IgG) in sera and IgA in mucosae, including saliva, vaginal-wash samples, lung, and intestine, as well as a higher level of neutralization activities than immunization with VLPs alone. Conjugation of CTB to VLPs also enhanced the SIV VLP-specific antibodies in sera and in mucosae to similar levels. Interestingly, CTB-conjugated VLPs showed higher levels of cytokine (gamma interferon)-producing splenocytes and cytotoxic-T-lymphocyte activities of immune cells than VLPs plus CTB, as well as an increased level of both IgG1 and IgG2a serum antibodies, which indicates enhancement of both Th1- and Th2-type cellular immune responses. These results demonstrate that CTB can be an effective mucosal adjuvant in the context of VLPs to induce enhanced humoral, as well as cellular, immune responses.

Administration, Intranasal↗

[The efficacy of combining antibiotic treatment with topical intranasal steroid administration in the treatment of chronic otitis media with effusion].

OBJECTIVES: We evaluated the efficacy of antibiotic treatment with or without topical administration of intranasal budesonide in chronic otitis media with effusion (OME). PATIENTS AND METHODS: The study included 62 patients (age range 2 to 12 years) with chronic OME. The patients were randomly assigned to three groups, namely, antibiotic treatment (20 patients, ampicillin/sulbactam, 25 mg/kg/daily), antibiotic treatment combined with intranasal budesonide (20 patients, 200 mg/daily), and no treatment (22 patients). All patients and families were questioned regarding the presence of allergy, frequent upper respiratory tract infections, passive smoking, low birth weight, and pre-school nursery attendance. Otoscopic examination findings and the results of tympanograms obtained at the time of diagnosis, and at the end of four and eight weeks of treatment were evaluated. RESULTS: At the end of eight weeks, significant improvement in tympanograms and otoscopic findings was obtained in both groups when compared with the control group (p<0.05). Resolution rates were 24% (9/37 ears), 39% (14/36), and 5% (2/40) with antibiotic, budesonide, and no treatment groups, respectively. Although budesonide treatment was associated with a higher rate of resolution of effusion compared to that of antibiotic alone, this did not reach significance (p>0.05). CONCLUSION: Further studies with larger patient series are required to better evaluate the efficacy of antibiotic treatment and topical intranasal steroid administration in chronic OME.

Acoustic Impedance Tests↗

Uptake of ovalbumin-conjugated starch microparticles by pig respiratory nasal mucosa in vitro.

The uptake of ovalbumin-conjugated starch microparticles (OVA-MP) was studied after application to porcine respiratory nasal mucosa in vitro. Nasal mucosa from freshly slaughtered pigs was mounted in horizontal Ussing chambers, which permit monitoring of the viability of the tissue exposed to microparticles and ensure that the microparticles are deposited on the mucosa. The antigen-conjugated starch microparticles have previously been shown to produce strong mucosal, cellular and systemic immune responses to conjugated model antigens following oral administration. Intranasal administration of vaccines for mucosal immunisation is an interesting alternative to oral administration, since nasal delivery systems generally require lower doses of antigen and the site of application is better suited for protection against air-borne antigens. Most of a nasally administered dose is deposited on the surface of the respiratory area of the nasal mucosa. It is therefore important to examine whether the microparticles are taken up in this area and, if so, by which cell type. Confocal laser scanning microscopy and transmission electron microscopy (TEM) of the nasal tissue both showed intracellular OVA-MP in non-ciliated epithelial cells after 45 min' incubation. The morphology of the cells in the TEM preparations did not support the presence of either M cells (specialised antigen sampling cells) or adjacent lymphocytes. Anticytokeratin-18 (Ac18) was used as a potential M cell marker. However, there was no indication of Ac18 binding to M cells, but it did bind to mucus-producing cells in the respiratory nasal mucosa. In conclusion, OVA-MP were taken up intracellularly by non-ciliated epithelial cells in the nasal respiratory mucosa of pigs, in vitro.

Animals↗

Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers.

AIMS: To evaluate the electroencephalographic (EEG) effects, blood concentrations, vehicle irritation and dose-effect relationships for diazepam administered nasally. METHODS: The study had a cross-over design with eight healthy volunteers (one drop out). It consisted of four legs with four different administrations: intranasal (i.n.) placebo, 4 mg diazepam i.n., 7 mg diazepam i.n. and 5 mg intravenous (i.v.) diazepam. Polyethylene glycol 300 (PEG300) was used as a vehicle in the nasal formulations to solubilize a clinically relevant dose of diazepam. Changes in N100, P200 and P300 brain event-related potentials (ERP) elicited by auditory stimulation and electroencephalographic beta-activity were used to assess effects on neurological activity. RESULTS: The mean [95% confidence intervals] differences between before and after drug administration values of P300-N100 amplitude differences were -0.9 [-6.5, 4.7], -6.4 [-10.1, -2,7], -8.6 [-11.4, -5.8] and -9.6 [-12.1, -7.1] for placebo, 4 mg i.n., 7 mg i.n. and 5 mg i.v. diazepam, respectively, indicating statistically significant drug induced effects. The bioavailabilities of 4 and 7 mg i.n. formulations, were found to be similar, 45% [32, 58] and 42% [22, 62], respectively. CONCLUSION: The present study indicates that it is possible to deliver a clinically effective nasal dose of diazepam for the acute treatment of epilepsy, using PEG300 as a solubilizer.

Administration, Intranasal↗

[Dependence of neuropeptide physiological effects on a route of administration].

Following intranasal administration, the peptides' effects could remain either the same as following an invasive administration (ACTH4-10) which is important for clinical application, or enhanced and prolonged (demorphin and argynilvasopressin analogue), or modified (beta-casomorphin-7). Techniques of improvement of the peptides' regulatory efficacy through protection against the protease action, are discussed. Peptide protection by introducing D-aminoacid's isomers into its molecule or addition of proline-rich sequences were compared. The latter technique seems to be more effective.

Administration, Intranasal↗

The sedative effects of intranasal midazolam administration in the dental treatment of patients with mental disabilities. Part 2: optimal concentration of intranasal midazolam.

In a previous paper, we reported on the effect of a 0.2 mg/kg dose of midazolam, administered intranasally, prior to performing various restorative dental procedures on a group of mentally disabled patients under local anesthesia and nitrous oxide/oxygen analgesia. The purpose of this study was to compare the clinical and possible adverse effect of doses of 0.2 mg/kg and 0.3 mg/kg midazolam, administered intranasally, and to determine the most appropriate concentration for the drug when administered by this route. Patients were assessed by a behavioral test which consisted of a scale from 1-7 with 3 ranges: markedly effective (1-3), effective (4-5) or ineffective (6-7). Forty-three mentally handicapped patients, aged 5 to 20 years, all of whom had previously exhibited highly combative and resistant behavior toward dental treatment under local anesthesia, were stratified by age and randomly assigned in a double blind manner to two groups, receiving either 0.2 mg/kg or 0.3 mg/kg midazolam administered intranasally. Group 1, consisting of 22 patients, average age 11 years 8 months, received 0.2 mg/kg. Group 2 consisted of 21 patients, average age 13 years 8 months, each of whom was administered 0.3 mg/kg intranasal midazolam. Only patients assessed as ASA anesthesia status I or II were admitted to the study. Subsequent to intranasal administration of midazolam, no patient rejected the nasal mask nor refused to inhale nitrous oxide/oxygen. The induction of nitrous oxide/oxygen sedation and oral examination were effected smoothly in every case in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗

Evaluation of transduction properties and vaccine efficacy of a simian adenovirus type 25-based vector.

Although human adenovirus serotype 5 (Ad5) is widely used as a vaccine vector for infectious diseases due to its high transduction efficiency, pre-existing immunity to Ad5 in many people reduces vaccine efficacy. To address this limitation, simian Ad vectors, such as ChAdOx1 and ChAdOx2, have been explored as alternative vaccine platforms. ChAdOx2 is based on simian Ad25 (SAd25), but the fundamental characteristics of gene transduction by SAd25-based vectors have not been fully elucidated. This study aimed to characterize the gene transduction efficiency, tissue distribution, and immunogenicity of an SAd25-based vector in comparison with those of the Ad5 vector following various routes of administration. Compared with intravenous administration of the Ad5 vector, intravenous administration of the SAd25 vector showed distinct biodistribution patterns, including reduced liver accumulation and predominant expression in the lung. Transduction by the SAd25 vector was not inhibited by human serum, whereas transduction by the Ad5 vector was inhibited, indicating that the SAd25 vector, but not the Ad5 vector, can evade pre-existing Ad immunity. Although intramuscular administration of the SAd25 vector induced lower transgene product-specific antibody production than intramuscular administration of the Ad5 vector, gene expression and Ad genome distribution mediated by the SAd25 vector, but not the Ad5 vector, were localized only to the muscle at the administration site. Intranasal administration of the SAd25 vector induced an antigen-specific antibody response in serum more rapidly than intranasal administration of the Ad5 vector. The SAd25 vector induced antigen-specific antibody production in bronchoalveolar lavage fluid (BALF) that was comparable to that induced by the Ad5 vector. These findings provide essential insights into the biological characteristics of the SAd25 vector, supporting its potential as a safe and effective vaccine vector.

Animals↗