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Results for “Administration, Intranasal”

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PubMed1999

Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: essential role of GM-CSF.

BACKGROUND: Inhaled pollutants were recently shown to be responsible for an increased incidence of airway allergic diseases, including asthma. A common feature of all forms of asthma is airway hyperresponsiveness. OBJECTIVE: Our purpose was to elucidate the effects of diesel exhaust particulate (DEP), one of the most prevalent inhaled pollutants, on airway responsiveness. METHODS: A/J and C57Bl/6 mice were used; the former are genetically predisposed to be hyperresponsive to acetylcholine, whereas the latter are not. DEP was administered intranasally for 2 weeks, after which pulmonary function was analyzed by whole-body plethysmography. RESULTS: Intranasal administration of DEP increased airway responsiveness to acetylcholine in both A/J and C57Bl/6 mice and induced displacement of ciliated epithelial cells by mucus-secreting Clara cells. The effect was mediated by M(3) muscarinic receptors. Acetylcholine-evoked bronchial constriction was reversed by administration of terbutaline, a beta(2)-adrenergic antagonist, which is also characteristic of human asthma. Intranasal administration of antibody raised against GM-CSF abolished DEP-evoked increases in airway responsiveness and Clara cell hyperplasia. The antibody raised against IL-4 also inhibited DEP-evoked increases in airway responsiveness. However, it was to a lesser extent compared with antibody against GM-CSF. In addition, DEP stimulated GM-CSF messenger RNA expression in the lung. CONCLUSION: DEP induces airway hyperresponsiveness by stimulating GM-CSF synthesis.

Acetylcholine↗

PubMed1996

Priming of measles virus-specific CTL responses after immunization with a CTL epitope linked to a fusogenic peptide.

In this study, the potential of the amino-terminal sequence from the F1 polypeptide responsible for the fusion of measles virus (MV) with cell membranes as a carrier system for a CTL epitope from the MV nucleoprotein was examined. The addition of the fusion sequence (FP) at either the amino or the carboxyl terminus of the CTL epitope peptide rendered it immunogenic after intraperitoneal immunization in mice. The CTLs induced were able to lyse target cells pulsed with the peptide or persistently infected with MV. After intranasal administration of a FP-CTL chimera with or without cholera toxin B subunit (CTB) as an adjuvant, CTL responses to the peptide pulsed and to MV-infected target cells were detected. Responses in groups of mice where CTB was used as an adjuvant were stronger. However, intranasal administration of the CTL epitope did not induce a protective response against intracranial challenge with a neuroadapted strain of MV. These findings highlight the potential of fusion sequences as a carrier system for CTL epitopes and the potential of the intranasal route for administration of synthetic peptides representing MV sequences.

Amino Acid Sequence↗

PubMed1993

Immunogenicity of recombinant human adenovirus-human immunodeficiency virus vaccines in chimpanzees.

Recombinant human adenovirus (Ad) type 4-, 5-, and 7-vectored vaccines expressing either the HIV env or gag-protease genes were tested for immunogenicity in three chimpanzees. The first phase of the vaccination protocol consisted of a primary and two booster immunizations with Ad-HIVs by the oral route of administration, followed by a single booster immunization with Gag and/or Env subunit vaccines. The second phase of the vaccination protocol consisted of intranasal administration of Ad-HIVs previously administered by the oral route. Following the first phase adenovirus was shed into stools for only 1-7 days and modest type-specific anti-adenovirus neutralizing antibody titers were induced. Strong anti-Env binding antibody responses were detected in all three animals following the second oral booster immunization. One chimpanzee responded with a low-titered type-specific neutralizing antibody response to HIV. Cell-mediated immune responses to Env were not detected after the primary vaccination, but were detected following all booster immunizations. Administration of the Gag subunit vaccine boosted both humoral and cell-mediated immune responses to Gag antigens. In contrast, the Env subunit vaccine boosted cellular but not humoral immune responses. In the second phase of the vaccination protocol, both virus shedding and anti-adenovirus responses were enhanced. All three chimpanzees responded to the intranasal administration of Ad7-HIVs with boosted anti-HIV serum responses, including low-titered type-specific neutralizing antibodies, elicited anti-HIV antibodies at secretory sites, and stimulated cell-mediated immune responses to both Gag and Env antigens.

AIDS Vaccines↗

PubMed1985

[Intranasal TRH for the stimulation of hypophyseal and thyroid reserves. Preliminary report].

Intranasal, intravenous and oral TRH have been compared in 9 healthy volunteers. Intranasal administration of TRH leads to excellent stimulation of pituitary TSH secretion. Serum TSH levels are significantly higher than after intravenous TRH (p less than 0.005) and lower than after oral TRH (p less than 0.005). As with intravenous TRH, peak TSH response is reached at 20-30 minutes, but the stimulatory effect is prolonged and elevated TSH levels can be measured for up to 3 hours. Stimulation of T3 and free T4 at 3 hours is comparable in all three administration forms of TRH. The practical advantages of the intranasal route are that no intravenous injection is necessary, overnight fasting is not required and the duration of the test is short (30 minutes, in contrast to 3 hours in the oral test).

Administration, Intranasal↗

PubMed1989

Induction of an endogenous tumor necrosis factor in mice by murine recombinant interferon-gamma combined with a lipid A subunit analog (GLA-60) of low toxicity.

We have investigated the endogenous production of a serum cytotoxic factor when recombinant interferon-gamma (rIFN-gamma) is combined with synthetic lipid A subunit analogs of low toxicity (GLA compounds). The cytotoxic activity of the serum was measured by the crystal violet staining method with L929 cells as a target. Intravenous administration of rIFN-gamma followed by intravenous administration of lipopolysaccharide induced the endogenous production of a cytotoxic factor in the serum. The priming effect of rIFN-gamma appeared immediately and persisted for approximately 20 h after the injection. Administration of lipopolysaccharide as a trigger enhanced the production of the cytotoxic factor in the serum maximally 2 h after the injection. The cytotoxic activity in the serum was completely inhibited by anti-(mouse tumor necrosis factor) (TNF) antibody. A synthetic lipid A subunit analog (GLA-60), which is much less toxic in its endotoxin activities than lipopolysaccharide or synthetic lipid A (compound 506), induced the endogenous production of serum TNF in rIFN-gamma-primed mice. GLA-60 entrapped within liposomes induced the production of serum TNF in rIFN-gamma-primed mice more effectively than GLA-60 solubilized in phosphate-buffered saline. Intravenous or intranasal administrations of rIFN-gamma followed by intranasal administration of GLA-60 produced TNF in the lung washing fluid but not in the serum, indicating that TNF production can be induced locally rather than systemically by the alteration of the administration route of the primer and trigger. These results indicate that GLA-60, a lipid A subunit analog of low toxicity, is a beneficial triggering agent in the production of endogenous TNF, as well as having other immunopharmacological properties, and may provide a basis for cancer (metastases) treatment as a result of its ability to induce endogenous TNF.

Animals↗

PubMed1986

Biological effect and plasma concentrations of DDAVP after intranasal and peroral administration to humans.

DDAVP was administered intranasally (20 micrograms) and perorally (100 and 200 micrograms) to 6 hydrated volunteers. Urine was collected and blood was sampled at intervals for the following 6 hr. In all experiments DDAVP induced a marked and long lasting antidiuretic response. Radioimmunoassay of DDAVP in blood samples made it possible to calculate bioavailability of DDAVP after the two forms of administration. Following intranasal application 11.3% of the dose appeared in the blood and the figures for oral administration was 0.7-1.0%. Based on analysis of the amount of DDAVP excreted in the urine the urinary clearance rate was estimated to be 0.10 ml/min/kg body wt.

Administration, Intranasal↗

PubMed2000

Development of anti-influenza drugs: II. Improvement of oral and intranasal absorption and the anti-influenza activity of stachyflin derivatives.

The in-vivo anti-influenza-virus activity of Stachyflin derivatives (III and its phosphate ester, III-Phos), a new class of haemagglutinin fusion inhibitor, and the improvement of their absorption after oral or intranasal administration were studied in mice, rats, and ferrets. The absorption of III in PEG 4000 and III-Phos aqueous solution increased about three and four fold in AUC after oral administration to uninfected mice compared with that of 0.5% HPMC (hydroxypropyl-methylcellulose) suspension. Using a mouse influenza virus infection model, significant anti-influenza-virus activity was observed in infected mice treated orally with these compounds dissolved in PEG 4000 or distilled water, respectively, but not in mice treated with 0.5% HPMC. The in-vivo anti-influenza-virus activity in ferrets, a good model for influenza virus infection in man, was also studied. Although the concentration of III in plasma was above the IC50 against the influenza virus strain used for 6h after the oral administration of III in PEG 400 to uninfected ferrets, no in-vivo anti-influenza-virus activity was observed at the same dosage given 4 times daily for 3 days. The intranasal administration of III-Phos, which was expected to have a more notable in-vivo anti-influenza-virus activity, was examined. III-Phos, whose intranasal absorption had been improved by the modification of III with phosphate ester in rats, inhibited viral replication in the nasal cavity and suppressed influenza-virus-induced fever when administered intranasally to infected ferrets. This study demonstrates that intranasally administered compounds with anti-influenza-virus activity must permeate the nasal membranes to produce their anti-influenza-virus effect.

Absorption↗

PubMed1988

Preliminary experience on treatment of insulin-dependent diabetes mellitus with a long-acting somatostatin analogue (L363,586).

L363,586 is a potent, long-acting, somatostatin derivative. Intravenous and intranasal administration to diabetic subjects was effective in reducing both fasting and postprandial hyperglycemia. Also in patients stabilized on a closed-loop insulin infusion device, the intranasal administration of L363,586 was able to improve the glucose imbalance known as dawn phenomenon. Therefore, this analogue associated to standard insulin replacement could be useful in the control of unstable diabetes.

Blood Glucose↗

PubMed2006

Interleukin-2 concentration in hypothalamic structures of rats receiving peptides during mild stress.

The number of hypothalamic IL-2-containing cells changed in rats receiving Vilon and Epithalon during mild stress (handling). The number of IL-2-positive cells in hypothalamic structures decreased 24 h after intramuscular injection of Epithalon and 2 h after intranasal administration of the test peptides. Adaptation of animals to experimental conditions prevented the decrease in the number of IL-2-positive cells in the supraoptic nucleus after intranasal administration of Epithalon.

Animals↗

PubMed1987

Safety and efficacy of a streptomycin dependent live Pasteurella multocida vaccine in rabbits.

The safety of and protection provided by a streptomycin dependent live Pasteurella multocida (serotype 12:A) vaccine was evaluated in New Zealand white rabbits. The vaccine strain was isolated from two of twelve rabbits 24 hours after intranasal administration. Streptomycin independent P. multocida isolates were not recovered for 4 weeks after vaccination, indicating a lack of reversion to the wild type. Thirty days after a single intranasal administration of vaccine, eight rabbits were challenged with either P. multocida serotype 3:A or serotype 12:A. Eight non-vaccinated rabbits were challenged in the same manner. Vaccinated rabbits challenged with serotype 12:A had nasal infections for only 2 weeks following challenge. Vaccinated rabbits challenged with serotype 3:A developed chronic nasal infections but were protected from severe disease. Immunoglobulin A or G antibodies against P. multocida were not detected after vaccination in nasal lavages or sera using an enzyme-linked immunosorbent assay. However, both antibodies increased following challenge with either serotype 3:A or serotype 12:A. These studies indicated that the streptomycin dependent pasteurella strain colonized rabbits briefly and was genetically stable in vivo. The results in challenged rabbits suggest that the vaccine provided protection against chronic infection by a homologous pasteurella serotype and protection against severe disease by a heterologous pasteurella serotype.

Animals↗

PubMed1998

Systemic and mucosal immune responses of mice to aluminium-adsorbed or aluminium-non-adsorbed tetanus toxoid administered intranasally with recombinant cholera toxin B subunit.

For the purpose of changing the immunization procedure of tetanus toxoid from intramuscular or subcutaneous injection, which has been in practice for a long time, to intranasal administration, we examined systemic and mucosal immune responses of mice to aluminium-adsorbed tetanus toxoid (aTT) and aluminium-non-adsorbed tetanus toxoid (nTT) inoculated intranasally with recombinant cholera toxin B subunit (rCTB). Intranasal immunization with aTT induced, at a concentration of 0.5 Lf, high levels of TT-specific serum IgG antibody titres and moderate levels of TT-specific serum IgA antibody titres in the presence and absence of rCTB. Induction of high or moderate levels of mucosal TT-specific IgA antibody responses was observed with and without rCTB in the lung, the nasal cavity, the small and large intestines and the vagina. Generally speaking, the co-administration of aTT and rCTB showed higher mucosal TT-specific IgA antibody titres when compared with the administration of aTT alone. In case of intranasal administration of nTT, the dose of 5 Lf was necessary and stimulated, only in the presence of rCTB (10 micrograms), high levels of tetanus toxoid (TT)-specific serum IgG antibody responses in all mice examined and moderate or slight levels of TT-specific IgA antibody responses in the nasal, pulmonary and small and large intestinal lavages of a few mice. All mice intranasally immunized with aTT alone or nTT and rCTB escaped onset of tetanus. This is the first report concerned with the mucosal adjuvant activity of an aluminium compound. Judging from these results, intranasal administration of aTT with and without rCTB or nTT with rCTB appears to be a very useful means for a vaccination against tetanus with respect to ease, safety, certainty, low cost and no need for an injection needle.

Administration, Intranasal↗

PubMed2001

Serum amyloid P component inhibits influenza A virus infections: in vitro and in vivo studies.

Serum amyloid P component (SAP) binds in vitro Ca(2+)-dependently to several ligands including oligosaccharides with terminal mannose and galactose. We have earlier reported that SAP binds to human influenza A virus strains, inhibiting hemagglutinin (HA) activity and virus infectivity in vitro. These studies were extended to comprise five mouse-adapted influenza A strains, two swine influenza A strains, a mink influenza A virus, a ferret influenza A reassortant virus, a influenza B virus and a parainfluenza 3 virus. The HA activity of all these viruses was inhibited by SAP. Western blotting showed that SAP bound to HA trimers, monomers and HA1 and HA2 subunits of influenza A virus. Binding studies indicated that galactose, mannose and fucose moieties contributed to the SAP reacting site(s). Intranasal administration of human SAP to mice induced no demonstrable toxic reactions, and circulating antibodies against SAP were not detected. Preincubation of virus (A/Japan/57) with SAP prevented primary infection of mice and development of antiviral antibodies. After a single intranasal administration of SAP (40 microg) 1 h before primary infection with virus (2LD(50)), nine out of 10 mice survived on day 10 and these mice approached normal body weight, whereas control mice (one out of five surviving on day 10) died. The data provide evidence of the potential of intranasally administered SAP for prophylactic treatment of influenza A virus infections in humans.

Animals↗

PubMed1988

Induction of nasal turbinate atrophy in germ-free pigs, using Pasteurella multocida as well as bacterium-free crude and purified dermonecrotic toxin of P multocida.

To establish the role of the dermonecrotic toxin (DNT) of Pasteurella multocida in the cause and pathogenesis of atrophic rhinitis, germ-free pigs were inoculated with several strains of P multocida, crude DNT, or purified DNT. In some experiments, the aforementioned inocula were combined with Bordetella bronchiseptica. All DNT-producing P multocida strains induced severe turbinate atrophy. Histologic examination of the remnants of the nasal turbinates revealed intact, but undulated, ciliated epithelium and numerous osteoclasts. Inflammation was minimal or absent. A DNT-producing B bronchiseptica strain induced only mild turbinate atrophy. The lesions were characterized histologically by loss of cilia and ciliated cells and by an infiltration of predominantly mononuclear cells. Bone formation seemed impaired. Turbinate lesions were most severe in pigs infected with a combination of B bronchiseptica and a DNT-producing P multocida strain. Intranasal administration of sterile DNT-containing culture filtrate of P multocida or purified DNT of P multocida did not result in turbinate atrophy. In contrast, turbinate atrophy developed when these preparations were injected IM or when intranasal administration of DNT was preceded by inoculation of B bronchiseptica.

Animals↗

PubMed2000

The effect of prolil-glycil-proline (PGP) peptide and PGP-rich substances on haemostatic parameters of rat blood.

The effect of intravenous and intranasal administration of proline-containing peptide, especially prolil-glycil-proline (PGP), on the haemostatic system of rats was investigated. Tripeptide PGP after single intravenous (0.2, 1.0 and 1.5 mg/kg) or intranasal (0.5 mg/ kg) administration increased (P < 0.05) total fibrinolytic and fibrin depolymerizating (FDA) activities, and tissue plasminogen activator levels (t-PA), and decreased the plasmin inhibitors (PI) and activated factor XIII (factor XIIIa) levels in blood plasma. Repeated daily intranasal administration (5 days) of PGP produced a significant increase of anticoagulant and fibrinolytic activities (P < 0.05), and a decrease of platelet aggregation, PI and factor XIIIa levels in blood plasma. Fibrinogen concentrations remained practically unchanged. Chronic peroral administration of gelatin (protein particularly rich of PGP, prolil-glycil, glycil-proline) as a food supplement significantly increased t-PA level (by 120%) at day 10 and FDA (by 290%) at day 14 in blood plasma. We also observed potent suppression of thrombus formation (venous thrombosis model) by intranasal PGP administration. Therefore, PGP and some PGP-rich substances can be qualified as potent anticoagulant and antithrombotic agents.

Administration, Intranasal↗

PubMed2005

NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP).

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Peptide activity scanning identified NAP (NAPVSIPQ) as a small active fragment of ADNP that provides neuroprotection at very low concentrations. In cell culture, NAP has demonstrated protection against toxicity associated with the beta-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs, and functional behavioral assays in rats, no adverse side effects were observed with NAP concentrations that were approximately 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer's disease.

Alzheimer Disease↗

PubMed1988

Pharmacokinetics and haematological effects of desmopressin.

The pharmacokinetics and haematological effects of 1-deamino-8-D-arginine vasopressin (desmopressin, DDAVP) after intravenous, subcutaneous and intranasal administration has been studied in man. Using a sensitive, specific radioimmunoassay for DDAVP, the AUC was determined for each route of administration. It was not significantly different for the i.v. and s.c. routes. There was no effect of the route on the plasma half-life of DDAVP which ranged from 2.7 to 4.6 h. Absorption of DDAVP after intranasal (i.n.) administration was poor. Based on AUC data, bioavailability via the two s.c. methods and the i.n. route was 112%, 94% and 2%, respectively. DDAVP has a pronounced effect on coagulation and fibrinolytic parameters, causing a 4.0- (i.v.), 2.9- (s.c.), 3.1- (s.c.; 40 micrograms/ml) and 1.2- (i.n.) fold increase in factor VIII: Ag. The corresponding effect on tissue-type plasminogen activator (t-PA) was 1.9- (i.v.), 1.3- (s.c.), 2.2- (s.c.; 40 micrograms/ml) and 1.0- (i.n.) increase over the basal value. There was also a 1.4- to 1.6-fold increase in leukocyte count 4 h after s.c. and i.v. DDAVP. At plasma DDAVP levels greater than 300 pg/ml no correlation was found between the AUC and the maximum plasma DDAVP and biological response, which indicates a ceiling limit for exogenous stimulation of the coagulation and fibrinolytic systems.

Administration, Intranasal↗

PubMed1995

[The effect of KW-4679, an antiallergic drug, on experimental allergic rhinitis].

Effect of KW-4679, an antiallergic agent, on the experimental allergic rhinitis was studied in guinea pigs. 1) KW-4679 inhibited the sneeze response and the nasal rubbing induced after the intranasal administration of antigen in sensitized guinea pigs. The inhibitions were dose-related and significant at 0.03 mg/kg p.o. for sneeze response and 1 mg/kg p.o. for nasal rubbing, respectively. 2) The nasal vascular permeability was increased after the intranasal administration of antigen in sensitized guinea pigs. KW-4679 significantly reduced the increase of the nasal vascular permeability at 1 mg/kg p.o. or higher. From these results, KW-4679 may have inhibitory effects on sneeze, nasal irritation and rhinorrhea in clinical use.

Animals↗

PubMed2005

The ICOS molecule plays a crucial role in the development of mucosal tolerance.

The ICOS molecule stimulates production of the immunoregulatory cytokine IL-10, suggesting an important role for ICOS in controlling IL-10-producing regulatory T cells and peripheral T cell tolerance. In this study we investigate whether ICOS is required for development of oral, nasal, and high dose i.v. tolerance. Oral administration of encephalitogenic myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to ICOS-deficient (ICOS-/-) mice did not inhibit experimental autoimmune encephalomyelitis (EAE), T cell proliferation, or IFN-gamma production, in striking contrast to wild-type mice. Similarly, intranasal administration of MOG(35-55) before EAE induction suppressed EAE and T cell responses in wild-type, but not in ICOS-/-, mice. In contrast, ICOS-/- mice were as susceptible as wild-type mice to high dose tolerance. These results indicate that ICOS plays an essential and specific role in mucosal tolerance and that distinct costimulatory pathways differentially regulate different forms of peripheral tolerance. Surprisingly, CD4+ cells from MOG-fed wild-type and ICOS-/- mice could transfer suppression to wild-type recipients, indicating that functional regulatory CD4+ cells can develop in the absence of ICOS. However, CD4+ T cells from MOG-fed wild-type mice could not transfer suppression to ICOS-/- recipients, suggesting that ICOS may have a key role in controlling the effector functions of regulatory T cells. These results suggest that stimulating ICOS may provide an effective therapeutic approach for promoting mucosal tolerance.

Administration, Intranasal↗