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PubMed1995

Human immune responses to influenza virus vaccines administered by systemic or mucosal routes.

Healthy adult volunteers were immunized by parenteral or oral routes with trivalent inactivated influenza vaccine (A/Chile/1/83 (H1N1), A/Mississippi/1/85 (H3N2), and B/Ann Arbor/1/86), or intranasally with live attenuated, cold-adapted influenza type A/Texas/1/85 (H1N1) reassortant virus. In all volunteers, cells spontaneously secreting IgA, IgG or IgM antibodies specific to influenza virus were detected in peripheral blood on days 6-13 after immunization, and specific IgA, IgG and IgM antibodies to influenza vaccine were measured in sera and external secretions (saliva and nasal lavage). Following systemic immunization, a raise in specific antibodies of all isotypes was observed in sera beginning on day 13. Although small variations in IgA and IgM antibodies in saliva and nasal lavages were detected, antigen-specific IgG significantly increased between days 13 and 27. Intranasal administration of attenuated virus induced IgA and IgG antibodies in serum as well as in secretions. Serum antibodies were not substantially influenced by oral immunization, only a small increase in all isotypes was observed in volunteers' sera 21 days after ingestion of vaccine. However, in secretions, antigen-specific IgA and IgG responses were detected one week after immunization and reached a peak response on day 20. These studies show that different routes of immunization can be effective for the induction of specific antibodies, and support the concept of the common mucosal immune system in humans by demonstrating that the oral or intranasal administration of antigen-induced specific antibodies of IgA isotype in external secretions, preceded by the transient appearance in peripheral blood of specific antibody-producing cells.

Administration, Intranasal↗

PubMed2004

Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes.

OBJECTIVE: Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate beta-cell destruction, and could induce immune effects consistent with mucosal tolerance. RESEARCH DESIGN AND METHODS: A total of 38 individuals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was beta-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly; the secondary outcome was immunity to islet antigens, measured monthly for 12 months. RESULTS: No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible beta-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as beta-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin. CONCLUSIONS: Results from this pilot study suggest that intranasal insulin does not accelerate loss of beta-cell function in individuals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes.

Administration, Intranasal↗

PubMed1991

Intranasal activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in conscious dogs.

This series of experiments was conducted to evaluate the growth hormone (GH) releasing activity of intranasally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in conscious dogs. Intranasal administration of GHRP-6 increased plasma growth hormone levels in the conscious dog in a dose-related manner. Doses of 0.25 and 0.5 mg/kg produced GH levels of 11.3 +/- 4.8 ng/ml and 28.6 +/- 8.0 ng/ml, respectively. Peak levels were observed 15 minutes after dosing and GH levels were elevated for up to 105 minutes after intranasal dosing. Intranasal administration of isotonic saline did not produce any change in basal (negligable) GH levels. When GHRP-6 was given by the intravenous route, a maximal dose of 0.5 mg/kg, produced a peak plasma GH concentration of 60.8 +/- 10.5 ng/ml. Saline had no effect on GH levels when given intravenously. Using the intravenous and intranasal GH response data (i.e., area under the time-response curves), the intranasal bioavailability of GHRP-6 was estimated to be 34.4 to 44.9%. The results of these studies suggest that significant activity and excellent bioavailability can be achieved when GHRP-6 is administered by the intranasal route to conscious dogs. Based on these results, the intranasal activity of GHRP-6 should be evaluated in man. The successful intranasal administration of this peptide in man should provide GH therapy with reduced patient discomfort and better patient compliance when compared to presently available parenterally administered remedies.

Administration, Intranasal↗

PubMed2002

Stimulatory and inhibitory epitopes in the T cell responses of mice to Der p 1.

BACKGROUND: The responses of mice to the mite allergen Der p 1 have been used to study the mechanisms of allergic sensitization and the development of new types of immunotherapy. Many of the studies require a knowledge of the T cell epitopes, and because Der p 1 is polymorphic, the effect of natural amino acid substitution in the allergen. The intranasal administration of peptides containing T cell epitopes can induce a mucosal tolerance but it is not known if the major activity is limited to stimulatory peptides and if, as found for autoimmunity, some epitopes are not inhibitory. OBJECTIVE: To determine and compare the sequences of Der p 1 which contain stimulatory epitopes for the high responding H-2(b) and H-2(q) mice and the sequences which induce tolerance by intranasal administration of peptides. METHODS: T cell responses of mice immunized with Der p 1 were measured by in vitro T cell stimulation assays so an extensive study of epitope recognition and intranasal tolerance could be made. Synthetic peptides were used to examine the stimulatory and inhibitory ability of all Der p 1 sequences and to map the major H-2(b) epitope in detail. This included the effect of the common polymorphic amino acid 124 substitution found within this epitope. RESULTS: Three and two regions, respectively, were found to contain stimulatory T cell epitopes for H-2(b) and H-2(q) mice. The peptides in these regions were also the most active at inducing intranasal tolerance for the responding haplotype. The correspondence between inhibitory and stimulatory peptides was maintained for the fine mapping of the major H-2(b) epitope. This was found about a core region of 118-126 which was overlapping but separate to a consensus sequence for the binding of endogeneous peptides. Peptides with alanine at the naturally polymorphic residue 124 stimulated and inhibited responses to Der p 1 more effectively, while peptides with the valine 124 variant were immunogenic but poorly cross-reactive. CONCLUSIONS: The intranasal administration of peptides representing each of five epitopes recognized by two strains of mice were able to induce mucosal tolerance and the major tolerizing activity was limited to these epitopes. The position of the core major epitope for C57 mice, which differs from a previously predicted epitope, and its specificity for the natural alanine 124 variant is described.

Administration, Intranasal↗

PubMed1989

The systemic availability of buprenorphine administered by nasal spray.

The kinetics and systemic bioavailability of intranasally administered buprenorphine have been investigated in 9 healthy volunteers in an intranasal/intravenous cross-over study. Each subject received a nominal 0.3 mg dose of buprenorphine intranasally followed one week later by a matched dose intravenously. For the intranasal administration mean tmax and mean Cmax were 30.6 min and 1.77 ng mL-1, respectively. Mean intranasal bioavailability was 48.2 +/- 8.35% (mean +/- s.e.m.) of the intravenous value. Intranasal administration may represent a valuable new delivery route for buprenorphine.

Administration, Intranasal↗

PubMed2003

Zolmitriptan nasal spray: advances in migraine treatment.

Zolmitriptan nasal spray was developed specifically to achieve fast, high effectiveness and to overcome many of the limitations associated with oral and sc migraine therapies. Pharmacokinetic studies have demonstrated a very rapid appearance of zolmitriptan in plasma as early as 5 minutes after intranasal dosing, with about 40% of peak plasma concentration (C(max)) being achieved within 10 to 15 minutes of dosing. Comparison of plasma concentration-time profiles of zolmitriptan and its active metabolite after oral and intranasal administration, together with PET scanning, clearly indicate direct absorption of zolmitriptan across the nasal mucosa after intranasal administration. The remainder of the dose is then swallowed and is absorbed through the gastrointestinal tract. In one blinded, randomized, placebo-controlled, multiple-attack study of zolmitriptan nasal spray, headache response was superior to placebo as early as 15 minutes after dosing (p < 0.05). In the zolmitriptan 5 mg treatment group, the primary end point of 2-hour headache response was achieved in 70% (300/427) of attacks versus 31% of attacks (119/389 attacks) in the placebo group (p < 0.001). Patients achieved a 2-hour headache response, had no recurrence, and used no additional or escape medications for up to 24 hours in 49% of attacks versus 14% of attacks in the placebo group (p < 0.001). Zolmitriptan 5 mg nasal spray was well tolerated. These data and those from other similar studies demonstrate that zolmitriptan nasal spray combines early, sustained efficacy and good tolerability, making it an optimal acute treatment for migraine.

Absorption↗

PubMed2001

Intranasal immunisation with influenza-ISCOM induces strong mucosal as well as systemic antibody and cytotoxic T-lymphocyte responses.

Intranasal administration of vaccines is preferred for induction of mucosal immune responses. In this study, mice were immunised intranasally and subcutaneously with influenza-immuno stimulating complexes (influenza-ISCOM). The intranasal dose was 15-times the subcutaneous dose. All mice dosed with influenza-ISCOMs survived challenge with live virus and comparable serum antibody and splenic cytotoxic T-lymphocyte responses were detected in both groups. Induction of mucosal IgA was significantly higher with intranasal immunisation and was comparable to responses induced with the heat labile enterotoxin of Escherichia coli as adjuvant. These findings demonstrate that intranasal administration of high dose influenza-ISCOM results in potent systemic and mucosal immune responses.

Adjuvants, Immunologic↗

PubMed1992

Evaluation of the degradation of desamino1,D-arginine8-vasopressin by nasal mucosa.

The nasal route is a convenient and simple way to administer peptides to humans. Absorption of the drug, however, requires passage of the substance through the nasal mucosa. This is a possible site of enzymatic degradation of the peptide. It is shown that rabbit nasal mucosa homogenates rapidly degrade the synthetic anti-diuretic hormone analogue desamino1,D-arginine8-vasopressin in vitro. The metabolite formed has been identified as des-(amino,arginine8,glycineamide9)- vasopressin, which is stable under the prevalent in vitro incubation conditions. It is proposed that this process is catalyzed by intracellular post-proline cleavage enzyme. Reversed phase chromatography in combination with immunological detection has been used to study the possible presence of this metabolite in the circulation after intranasal administration to humans. The metabolite des-(amino,arginine8,glycineamide9)-vasopressin could not be detected in plasma following intranasal administration, possibly indicating a paracellular absorption of desamino1,D-arginine8-vasopressin or absence of this enzymatic activity in humans.

Administration, Intranasal↗

PubMed2006

Modified pulmonary surfactant is a potent adjuvant that stimulates the mucosal IgA production in response to the influenza virus antigen.

The intranasal administration of influenza hemagglutinin (HA) vaccine with Surfacten, a modified pulmonary surfactant free of antigenic c-type lectins, as a mucosal adjuvant induced the highest protective mucosal immunity in the airway. The intranasal immunization of mice with HA vaccine (0.2 microg)-Surfacten (0.2 microg) selectively induced the neutralizing anti-HA IgA, but not IgG, and conferred nearly maximal protection in the airway, without inducing a systemic response. In contrast, intranasal inoculation of vaccine with 0.2 microg of the potent mucosal adjuvant cholera toxin B* (CT-B*), prepared by adding 0.2% native CT to the B subunit of CT, induced both anti-HA IgA and IgG in the airway and in the serum. The intranasal administration of HA vaccine alone induced a limited amount of mucosal IgA against influenza virus. Although the s.c. administration of HA vaccine prominently induced serum IgG and IgA, Surfacten and CT-B* did not enhance their induction, and the concentrations of Abs leaking into the airways were insufficient to prevent viral multiplication. The intranasal administration of HA-Surfacten stimulated the expression of MHC class II, CD40, and CD86 molecules in the CD11c-positive cells isolated from the nasal mucosa, but not the expression of cells from the lungs or spleens. Lymphocytes isolated from the airway mucosa after intranasal HA-Surfacten immunization prominently induced TGF-beta1 which, compared with inoculation without Surfacten, promoted an Ag-specific mucosal IgA response. Surfacten alone, however, did not induce TGF-beta1. Our observations suggest that Surfacten, by mimicking the natural surfactant, is an effective mucosal adjuvant in the process of airway immunization.

Administration, Intranasal↗

PubMedDate not supplied

[Interferon-inducing and protective action of polyguacyl in an experimental influenza infection].

A comparative study of the interferon-inducing and anti-influenza activity of polyguacyl, an interferon inducer, given to human volunteers intranasally and as an aerosol, was carried out. The induction of endogenous interferon in the blood to 100-127 units/ml was observed only after intranasal administration of 5 mg polyguacyl. By both routes of administration the inducer did not diminish the implantation of the virus and development of postvaccination reactions in volunteers to intranasal administration of live influenza A (H1N1) vaccine.

Administration, Intranasal↗

PubMed1993

Renal concentrating capacity test by desmopressin in children: intranasal or intravenous route?

Intranasal administration of desmopressin (dDAVP) is frequently used to test renal concentrating capacity in children. However, the bioavailability of intranasal dDAVP is about 10% and may be modified by nasal congestion. The study aimed to compare the efficacy of intranasal dDAVP with an equivalent dose of intravenous dDAVP for a renal concentrating capacity test in children. We studied 18 children aged 12.6 +/- 3.8 years weighing more than 20 kg in whom a dDAVP test was indicated as part of global renal function evaluation. Spray applicator (Minirin Spray) was used for intranasal administration (20-40 micrograms according to BW); the dose of intravenous dDAVP (Minirin IV) was reduced to 10% (2-4 micrograms according to BW). A randomized sequence was used for the first intranasal or intravenous dDAVP test; the second alternate test was repeated in the same children in a time interval ranging from 1 to 3 weeks. Osmolality of the urine (Uosm, mosm/kg) was determined before (T0), then 2 (T2) and 4 (T4) h after dDAVP administration. There was no significant difference in Uosm at T0 (intranasal = 480 +/- 212, intravenous = 443 +/- 168 mosm/kg), T2 (604 +/- 226 and 542 +/- 173 mosm/kg, respectively), and T4 (657 +/- 206 and 629 +/- 190 mosm/kg, respectively). There was an obvious correlation between intranasal and intravenous Uosm at T4 (r2 = 0.826; p = 0.001). Even if intravenous dDAVP is of theoretical interest, intranasal administration of dDAVP using a spray applicator can be considered as first-choice method for a renal concentrating capacity test in children weighing more than 20 kg.

Administration, Intranasal↗

PubMed2002

IgE cross-linking or lipopolysaccharide treatment induces recruitment of Th2 cells to the lung in the absence of specific antigen.

We previously showed that Th1 cells can increase recruitment of Th2 cells to the lungs even in the absence of the Th2-specific Ag. The fact that Th2 recruitment is independent from the Th2 cell Ag suggested that Th1 cells may support Th2 cell recruitment using their Ag-nonspecific proinflammatory functions. To investigate the potential for inflammatory stimuli that are distinct from Ag-specific signals to affect the recruitment of T cells, we tested whether cross-linking of IgE or treatment with LPS modulated influx of Th2 cells into the airways in the presence or absence of inhaled Ag. When naive mice that had been treated with OVA-specific Th2 cells and passively sensitized with anti-DNP IgE were challenged by intranasal administration of either DNP-haptenated OVA or DNP-BSA, increased numbers of Th2 cells were recruited to the lung compared with mice challenged intranasally with OVA alone. Intranasal administration of LPS also increased recruitment of Th2 cells to the airways. These two distinct inflammatory stimuli increased the numbers of recruited Th2 cells equally with or without concurrent challenge using the cognate Th2 Ag. This Ag-independent recruitment of Th2 cells to the lung was not associated with localization of these cells to the regional lymph nodes and was independent of Th2 cell activation. Interestingly, P- or E-selectin contributed to Th2 cell recruitment to the lung. These data suggest that Th2 cells of the adaptive immune response are similar to cells of the innate immune response in their lack of requirement for protein Ag to initiate cell recruitment. They demonstrate further that recruitment can occur independently of Ag-dependent activation.

Adjuvants, Immunologic↗

PubMed1996

Study on specific mucosal immunity by intranasal immunization of outer membrane protein P6 of Haemophilus influenzae with cholera toxin B subunit.

Effective induction of the specific mucosal immunity against the outer membrane protein P6 of Haemophilus influenzae was investigated. Twenty-four BALB/c mice were intranasally immunized with P6, twice, with 2 weeks in between, with or without intranasal cytokine treatment. The intranasal immunization evoked both anti-P6 specific mucosal IgA immunity and systemic IgG immunity. In addition, intranasal administration of rIL-2 and rIL-5 enhanced anti-P6 specific immune response was maintained for 3 weeks after the final immunization with the intranasal cytokine treatment. These suggest the possibility of intranasal immunization and the advantage of intranasal administration of cytokines for eliciting both mucosal and systemic immunity.

Administration, Intranasal↗

PubMed2004

Intranasal insulin reduces body fat in men but not in women.

Insulin acts in the central nervous system to reduce food intake and body weight and is considered a major adiposity signal. After intranasal administration, insulin enters the cerebrospinal fluid compartment and alters brain functions in the absence of substantial absorption into the blood stream. Here we report the effects of 8 weeks of intranasal administration of insulin (4 x 40 IU/day) or placebo to two groups of healthy human subjects (12 men and 8 women in each group). The insulin-treated men lost 1.28 kg body wt and 1.38 kg of body fat, and their waist circumference decreased by 1.63 cm. Plasma leptin levels dropped by an average of 27%. In contrast, the insulin-treated women did not lose body fat and gained 1.04 kg body wt due to a rise in extracellular water. Our results provide a strong, first confirmation in humans that insulin acts as a negative feedback signal in the regulation of adiposity and point to a differential sensitivity to the catabolic effects of insulin based on sex.

Adipose Tissue↗

PubMed2006

Preparation of bupleurum nasal spray and evaluation on its safety and efficacy.

Radix Bupleuri is widely used in traditional medicine for the treatment of fever, pain, and inflammation associated with influenza or the common cold. The essential oil extracted from the herb is generally claimed to play the major role in the efficacious treatment of fever. The purpose of the present study was to formulate an intranasal delivery system for the essential oil in an aqueous solution used in the form of nasal spray. From 450 g Radix Bupleuri was extracted the essential oil in the amount of about 0.2 ml, which was slightly water-soluble and viscous with low-fluidity. In order to dissolve the essential oil evenly in the aqueous solution, tween-80 (TW-80, used in 10% (w/v) solution), propylene glycol (PG) and diethylene glycol monoethyl ether (TC) were selected as the favorable solubilizing agents, whose amount was respectively determined by L16(4(5)) orthogonal design. An aqueous solution with clarity and no ciliotoxicity was prepared when TW-80 8% (v/v), PG 14.4% (v/v) and TC 14.4% (v/v) were added. Employed to evaluate the acute toxicity, the rats grew well and were kept active and healthy within 14 d after an intranasal administration of this preparation at the dose of oil from 10 g Bupleuri/kg (50-fold higher than the clinical dose), indicating that there would be no serious toxicity at the normal dose. Intranasal administration of this preparation to 2 kg rabbits with fever induced by subcutaneous injection of turpentine decreased body temperature markedly (0.5, 0.8 and 1.0 degrees C respectively at the dose of oil from 1, 2 and 4 g Bupleuri/body). In addition, the administration significantly reduced fever in 200 g rats induced by intramuscular injection of colicine suspension (0.6 degrees C at the dose of oil from 0.8 g Bupleuri/body). The results suggest that the formulation of nasal spray for the essential oil from Radix Bupleuri can be potentially effective in the treatment of fever.

Administration, Intranasal↗

PubMed2002

Kinetics and mode of peptide delivery via the respiratory mucosa determine the outcome of activation versus TH2 immunity in allergic inflammation of the airways.

BACKGROUND: Specific immunotherapy involving systemic injection of allergen, though highly effective, can cause severe side effects due to IgE-mediated activation of effector cells. Allergen-derived peptides might provide a safer alternative. We have investigated the use of mucosally delivered peptide to induce CD4(+) T(H)2 cell tolerance and thus protect against allergen-induced airway inflammation. OBJECTIVE: The purpose of this study was to investigate whether intranasal administration of an allergen-derived peptide, either alone or adsorbed to chitosan, can prevent the induction of T(H)2-mediated pulmonary inflammation after sensitization and challenge of the airways with allergen. METHODS: Mice were given (intranasally) a peptide containing an immunodominant epitope of the Dermatophagoides pteronyssinus (Der p) 1 allergen, either as soluble antigen or adsorbed to chitosan, before sensitization and allergen challenge. Pulmonary inflammation, antigen-specific CD4(+) T-cell responses, and antibody levels in sera were then determined. RESULTS: Mice given peptide adsorbed to chitosan had significant reductions in airway eosinophilia, which correlated with reduced levels of IL-4 and IL-5 in the bronchoalveolar lavage fluid. There was decreased recruitment of activated CD4(+) T cells into the airways after allergen challenge, which correlated with a loss of Der p 1-specific T-cell cytokine responses in the periphery and the localized production of IL-10 by antigen-specific T cells in bronchial lymph nodes. Induction of peripheral T-cell tolerance was preceded by transient T-cell activation and IFN-gamma production. CONCLUSION: Our data demonstrate that suppression of airway inflammation by intranasal administration of peptide antigen adsorbed to chitosan is initiated by transient T-cell activation and maintained by the production of IL-10 by antigen-specific T cells in the draining lymph nodes.

Administration, Intranasal↗

PubMed1994

Nasal mast cells in experimentally induced allergic rhinitis in guinea-pigs.

The kinetics of mast cell accumulation in the nasal mucosa during allergen exposure were investigated in the animal model of experimentally induced allergic rhinitis. Guinea-pigs were divided into an unsensitized control group and five sensitized groups each containing five animals. Five sensitized groups were immunized intraperitoneally with ovalbumin, followed by intranasal administration of ovalbumin in each of four groups for 1, 2, 3 and 4 weeks, respectively. There were significant increases in the number of mast cells in the epithelium after 2 and 3 weeks in the groups receiving intranasal ovalbumin. No significant changes were detected in the lamina propria and the total number of mast cells. In the lamina propria, the distance between a mast cell and the basement membrane was significantly decreased in the groups after 2, 3 and 4 weeks of intranasal administration. These findings suggest that an infiltration of mast cells from the lamina propria to the epithelium occurred after 2 weeks of intranasal administration of allergen. An electron microscopic study showed no mast cells at the luminal surface of the epithelium and the majority of mast cells lying around the basal cells. This finding suggests that the allergen must penetrate into the epithelium in order to interact with mast cells in guinea-pig nose.

Animals↗

PubMed1998

Microparticle resins as a potential nasal drug delivery system for insulin.

The application of various resins for the nasal delivery of insulin was examined in rabbits. Intranasal administration of human insulin (28 U, 1 mg) mixed with fractionated sodium polystyrene sulfonate powder (an anionic resin with a particle size of 20-45 microns) caused a rapid increase of the plasma insulin level 413.0 +/- 71.7 microU/ml (mean +/- S.D.) after 15 min, while intranasal administration of insulin alone caused little increase. The blood glucose level decreased from 118.8 +/- 18.5 mg/dl to 65.8 +/- 13.8 mg/dl at 45 min after administration. These results were superior to those obtained with the unfractionated resin. Styrene-divinylbenzene copolymer (a nonionic resin; 20-45 microns fraction) showed similar enhancement of nasal insulin absorption. In contrast, polyacrylester (a nonionic resin; 20-45 microns fraction) and cholestyramine (a cationic resin) did not promote insulin absorption. These results suggest that some resins may be useful for nasal delivery of insulin.

Administration, Intranasal↗