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PubMed1985

No improvement in ethanol-induced memory deficits after administration of a vasopressin analog.

Acute ingestion of ethanol impairs memory, an effect which might be related to ethanol-induced inhibition of vasopressin release. This was studied using tests of memory and cognitive function in 26 normal subjects before and after ethanol ingestion. Equal numbers of subjects received randomly, by double-blind intranasal administration, placebo or 1-desamino-8-D-arginine vasopressin prior to ethanol ingestion. Administration of the vasopressin analog did not reverse the ethanol-induced deficits in memory and cognitive function.

Administration, Intranasal↗

PubMed2002

Intranasal immunization with recombinant antigens associated with new cationic particles induces strong mucosal as well as systemic antibody and CTL responses.

New cationic nanoparticles (SMBV) were evaluated for use as a nasal vaccine delivery system for two recombinant proteins: HBsAg and beta-galactosidase. Each protein was formulated with SMBV and intranasally administrated to non-anesthetized mice. In each model, the formulated protein induced high levels of specific serum IgG antibodies and cytotoxic T lymphocyte (CTL) responses. Moreover, specific IgA antibodies were found in nasal as well as in vaginal washes of intranasally immunized mice with the protein associated with SMBV. In contrast, no IgG or IgA antibodies and no CTL were detected in mice immunized with free protein. The detection of a CTL response and an increase in both IgG1 and IgG2a antibodies in serum suggest that SMBV amplifies both Th1 and Th2 responses without modifying the Th1/Th2 profile of the immune response induced by the natural protein. These data demonstrate the high potential of SMBV for use as a nasal delivery system for sub-unit vaccines.

Adjuvants, Immunologic↗

PubMed2006

Pharmacokinetics and pharmacodynamics of intranasal insulin administered to patients with type 1 diabetes: a preliminary study.

BACKGROUND: The pharmacokinetics and pharmacodynamics of a Bentley Pharmaceuticals (Exeter, NH) proprietary insulin formulation designed for intranasal administration were studied in patients with type 1 diabetes, using subcutaneous insulin or placebo as comparator. METHODS: Seven fasting volunteer patients with type 1 diabetes (five men, two women; body mass index 23.54+/-1.32 kg/m2) received up to four doses of medication (placebo, subcutaneous insulin, or intranasal insulin) at least 3 days apart. Serum insulin and plasma glucose were measured in the 5-h period after dosing. RESULTS: The relative bioavailability of intranasal insulin compared with subcutaneous insulin was 16.6-19.8% over 2 h and 14.0-19.8% over 5 h. The formulation was generally well tolerated. At doses of 25 IU and above, a rise in serum insulin levels accompanied by a decrease in plasma glucose was seen. Peak insulin levels were generally attained in 15-20 min and remained elevated for approximately 1 h; the resultant effect upon glucose peaked at 40 min and waned 1.5-2 h post-dosing. The effect was dose related. Mean peak insulin levels increased with dose escalation. As reported in other insulin studies, the inter-individual responsiveness to insulin was variable. CONCLUSIONS: This intranasal formulation was generally well tolerated, and relatively well absorbed as demonstrated by a rapid rise in serum insulin level and concomitant reduction of plasma glucose levels.

Administration, Intranasal↗

PubMed2001

Effect of intranasal challenge with interleukin-6 on upper airway symptomatology and physiology in allergic and nonallergic patients.

BACKGROUND: Interleukin-6 (IL-6) is a potent regulator of airway inflammation and an important component of biologic homeostasis. Previously, a temporal relationship between the local elaboration of IL-6 and the development of upper airway symptoms and pathophysiologic findings was reported for patients experimentally infected with influenza A virus or rhinovirus. OBJECTIVE: The objective of this study was to determine the provocative effects of direct, intranasal administration of IL-6 on those symptoms, signs, and pathophysiologic findings that accompany viral upper respiratory infection. METHODS: In this double-blind, placebo-controlled, crossover trial, 10 symptomatic allergic, 10 asymptomatic allergic, and 10 nonallergic adult patients were pretreated with intranasal histamine and, after 15 minutes, were challenged with repeated doses of placebo (saline) or with increasing doses (0, 0.01, 0.1, and 1 microg/mL) of recombinant IL-6 at 20-minute intervals, during randomized paired sessions. Symptom scores, sneeze and cough counts, nasal secretion weights, nasal conductance (rhinomanometry), middle ear pressure (tympanometry), Eustachian tube function (sonotubometry), and pulmonary function (spirometry) were evaluated before and after the histamine challenge, after each dose of IL-6 or placebo, and then at 90 minutes and 2, 3, 4, 6, and 24 hours. RESULTS: At the doses used, intranasal challenge with IL-6 was well tolerated. At the 90-minute postchallenge endpoint, a significant effect of challenge substance and group assignment was documented for nasal secretion weight. Paired comparisons showed that the effect was greater for the allergic patients when compared with the nonallergic patients. There were no differences between placebo and IL-6 challenge for any of the other measured parameters. CONCLUSIONS: These results show that local IL-6 at relatively low doses can provoke increased nasal secretions in patients with allergic rhinitis.

Acoustic Impedance Tests↗

PubMed2000

Intranasal vaccination of New Zealand white rabbits against pasteurellosis, using alginate-encapsulated Pasteurella multocida toxin and potassium thiocyanate extract.

OBJECTIVE: We evaluated the efficacy of intranasal administration of Pasteurella multocida toxin (PMT) and a potassium thiocyanate extract of P. multocida (CN) encapsulated in alginate microspheres, compared with unencapsulated PMT and CN antigens, in protection of rabbits against pasteurellosis. METHODS: New Zealand male rabbits (n=24) were allotted randomly into four intranasally administered vaccine groups: 1, PMT/CN; 2, microencapsulated PMT/CN with or; 3, without subcutaneous priming; and 4, empty microspheres (control). Blood samples and nasal wash specimens were collected before vaccination and one week after each vaccination (days 7, 21, 35, and 49). Rabbits were primed subcutaneously with either unencapsulated PMT/CN or aluminum hydroxide (control) (day 0), vaccinated intranasally (days 14, 28, and 42), challenged intranasally with live P. multocida (day 56), and necropsied (day 60). RESULTS: Compared with controls, PMT/CN-immunized rabbits had significantly higher concentrations of serum IgG and IgM, nasal IgG, and bronchoalveolar lavage fluid IgA and IgG against CN. Immunized rabbits had 100% survival rate and low numbers of bacteria in liver and lungs; the control group had 50% survival rate and higher numbers of bacteria (> 4x) per gram of tissue in liver and lungs. CONCLUSION: The PMT/CN microspheres stimulated systemic and mucosal immune responses similar in effectiveness (protection) to those in response to unencapsulated PMT/CN administration.

Administration, Intranasal↗

PubMed1992

Postoperative pain management by intranasal demand-adapted fentanyl titration.

The aim of the present study was to investigate whether intranasal administration of fentanyl allows a demand-adapted postoperative opioid titration. Forty-two patients who had undergone surgery for lumbar intervertebral disk protrusion were included in a prospective randomized double-blind study. When complaining about intense pain, 22 patients received six sprays of fentanyl (0.027 mg) intranasally and 6 ml sodium chloride 0.9% intravenously and 20 patients received six sprays of sodium chloride 0.9% intranasally and 6 ml of a diluted fentanyl solution (0.027 mg) intravenously. In both groups, these doses were repeated every 5 min until the patients were free of pain or refused further analgesic. Before the beginning of opioid titration and then every 10 min for at least 1 h, pain was evaluated with the aid of a 101-point numerical rating scale and a verbal rating scale. Blood pressure, heart rate, arterial hemoglobin oxygen saturation, respiratory rate, and side effects were recorded. All patients were satisfied with the pain reduction achieved. The total fentanyl dose was 0.073 mg (range 0.027-0.162) in the intravenous group and 0.11 mg (range 0.027-0.243) in the intranasal group. The onset of action after intranasal application was nearly as fast as after intravenous titration. The pain reduction achieved was comparable in both groups. Only at the (10-), 20- and 30-min measurement points was the pain intensity significantly lower in the intravenous than in the intranasal group. One patient of the intravenous group showed a decrease in arterial hemoglobin oxygen saturation to less than 90%. Other serious side effects were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗

PubMed1999

Systemic availability of budesonide after nasal administration of three different formulations: pressurized aerosol, aqueous pump spray, and powder.

AIMS: The present study was undertaken to determine the absolute systemic availability of budesonide from three different devices for nasal administration: pressurized aerosol, aqueous pump spray, and powder. METHODS: Sixteen healthy, non-smoking, volunteers participated in this open, randomized, and crossover study. All subjects received budesonide as an intravenous dose of 400 microg, and as three, single-dose, intranasal administrations: pressurized aerosol 800 microg, aqueous pump spray 400 microg, and powder 800 microg. Blood was sampled for 10 h after each administration and budesonide was assayed in plasma by liquid chromatography plus mass spectrometry. RESULTS: The mean [95% CI] systemic availability of budesonide with reference to the metered dose was: 13 [10; 15]%, 29 [23; 37]%, and 20 [16; 23]%, and the maximum plasma concentration (Cmax) was attained at (tmax) 2.0, 0.7, and 0.4 h after administration for the pressurized aerosol, aqueous pump spray, and powder, respectively. CONCLUSIONS: The uptake of budesonide was more rapid and more complete, and the systemic availability of the drug was significantly higher from the aqueous pump spray and powder than from the pressurized aerosol.

Administration, Intranasal↗

PubMed1996

Desensitization from long-term intranasal treatment with hexarelin does not interfere with the biological effects of this growth hormone-releasing peptide in short children.

A clinical, prospective experiment was carried out to determine whether long-term intranasal administration of the growth hormone-releasing peptide hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe -Lys-NH2) affects pituitary growth hormone secretion. Hexarelin (60 micrograms/kg t.i.d.) was administered to seven prepubertal constitutionally short children (mean age +/- SD = 7.6 +/- 2.4 years). Serum human growth hormone (hGH) response to an intranasal (20 micrograms/kg) and i.v. (1 mircogram/kg) bolus of hexarelin before, during and after 6-10 months of treatment was measured. The mean ( +/- SD) peak rise of hGH to the intranasal bolus before treatment was 70.6 +/- 28.2 mU/l. After 7 days of hexarelin treatment, mean peak values dropped to 34.1 +/- 15.7 mU/l (p < 0.002) and thereafter remained constant for 6 months of treatment at 37.5 +/- 10.3 mU/l (p < 0.03). The pretreatment peak to th i.v. hexarelin bolus was 84.8 +/- 52.5 mU/l, and at the end of the treatment period it was 19.8 +/- 10.9 mU/l (p < 0.05). Three months after stopping treatment the mean ( +/- SD) hGH response rose to 42.1 +/- 4.7 mU/l (p < 0.005). Growth velocity increased from 5.3 +/- 0.9 cm/year (before treatment) to 7.4 +/- 1.6 cm/year at 6-10 months of treatment (p < 0.005). In conclusion, teh partial suppression of pituitary hGH responsiveness to long-term intranasal hexarelin treatment, probably due to desensitization, does not affect the observed increase in growth velocity.

Administration, Intranasal↗

PubMed2005

Intranasal 17beta-estradiol treatment and Vitamin B12, folate and homocysteine in menopause.

OBJECTIVE: This study assessed the effect of intranasal administration of 17beta-estradiol (Aerodiol) on plasma levels of homocysteine, Vitamin B12 and folate in postmenopausal women. METHODS: In all, 26 symptomatic postmenopausal women who had undergone hysterectomy and oophorectomy at least 12 months previously participated in this 6-month randomized prospective clinical study. Menopause was determined by serum FSH level >30 microIU/ml and serum estradiol concentration <30 pg/ml. Intranasal 17beta-estradiol treatment was given once daily at a standard daily dose of 300 microg to 16 women, and 10 did not receive any treatment. RESULTS: In the group receiving intranasal 17beta-estradiol, mean (+/-S.D.) plasma homocysteine level decreased significantly from pre-treatment values (from 16.68+/-4.33 to 14.15+/-1.18 nmol/ml, p=0.029) and the mean folate level increased (from 4.11+/-0.80 to 5.64+/-1.87 ng/ml, p=0.012). Vitamin B12 levels showed a tendency towards increasing. In the treated group, significant negative correlations were observed between homocysteine and folate values (r=-0.586, p=0.017) and between homocysteine and Vitamin B12 values (r=-0.672, p=0.004). No significant changes were observed in the untreated group. CONCLUSION: The reduction in plasma homocysteine levels observed after 6 months' treatment with intranasal 17beta-estradiol may reflect an alteration in folate and Vitamin B12 homeostasis.

Administration, Intranasal↗

PubMed1998

Interleukin-4 enhances pulmonary clearance of Pseudomonas aeruginosa.

To determine the effects of interleukin-4 (IL-4) on bacterial clearance from the mouse lung, transgenic mice expressing IL-4 in respiratory epithelial cells under the control of the Clara cell secretory protein promoter (CCSP-IL-4 mice) were infected intratracheally with Pseudomonas aeruginosa. Survival of CCSP-IL-4 mice following bacterial administration was markedly improved compared with that of control mice. While bacteria proliferated in lungs of wild-type mice, a rapid reduction in the number of bacteria was observed in the IL-4 mice as early as 6 h postinfection. Similarly, intranasal administration of IL-4 enhanced bacterial clearance from the lungs of wild-type mice. While acute and chronic IL-4 increased the numbers of neutrophils in bronchoalveolar lavage fluid, bacterial infection was associated with acute neutrophilic pulmonary infiltration, and this response was similar in the presence or absence of IL-4. Local administration or expression of IL-4 in the mouse lung enhanced pulmonary clearance of P. aeruginosa in vivo and decreased mortality following infection.

Administration, Intranasal↗

PubMedDate not supplied

[Effect of thyrotropin-releasing hormone and its synthetic analogue digipramine on certain hemostatic indices in vitro and in vivo].

The effect of neuropeptide thyrotropin-releasing hormone (TRH) and its synthetic analogue digipramine on certain indices of the blood coagulation system and fibrinolysis were studied in vitro and in vivo. The peptides added to the pool of normal rat plasma at 10(-10) to 10(-3) M increased the procoagulant activity but had virtually no effect on fibrinolysis. Intravenous administration of TRH and digipramine increased the procoagulant activity of the blood and thrombocyte aggregation but decreased fibrinolysis; digipramine had a more pronounced effect on the coagulation potential of the blood and a less pronounced effect on fibrinolytic indices as compared to TRH. Intranasal administration of the peptides did not change the pattern of their effect on hemostatic indices although the effects became less pronounced.

Administration, Intranasal↗

PubMed2004

A multiple-dose phase I study of intranasal hydromorphone hydrochloride in healthy volunteers.

We evaluated the pharmacokinetics, tolerability, and safety of 1 and 2 mg of intranasal hydromorphone hydrochloride in an open-label, single- and multiple-dose study. This Phase I study was conducted in 24 healthy volunteers (13 men and 11 women). Intranasal doses were delivered as 0.1-mL metered-dose sprays into one or both nostrils for 1- and 2-mg doses, respectively. Venous blood samples were taken serially from 0 to 12 h after the first single dose and the last (seventh) multiple dose. Plasma hydromorphone concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic variables. After 7 intranasal doses of 1 and 2 mg (once every 6 h), mean +/- sd peak plasma concentrations of 2.8 +/- 0.7 ng/mL and 5.3 +/- 2.3 ng/mL, respectively, were observed. The median time to peak concentration was 20 min for both single and multiple doses. Dose proportionality was observed for the 1- and 2-mg doses. Adverse events included somnolence, dizziness, and bad taste after dose administration. Intranasal hydromorphone hydrochloride was well tolerated and demonstrated rapid nasal drug absorption and predictable accumulation. These results support clinical investigation of hydromorphone hydrochloride nasal spray for use as an alternative to oral and IM administration.

Absorption↗

PubMed1997

Pharmacokinetics of allergens after local administration.

The authors review the status of knowledge on absorption and kinetic of allergens administered on nasal mucosa. Intranasal administration is well known in pharmacology, and has been used for a long time for peptide drugs, mainly hormones. The immunological response to intranasally administered antigens have been studied in some experimental models: bovine Rnase, dextran, KLH, tetanus toxoid. These studies showed in atopic people a greater absorption of antigens by nasal mucosa compared to normal individuals, a difference that might be of importance in the pathogenesis of atopic diseases. The absorption rate of peptides through nasal mucosa has been studied biologically by PK-test with Rnase and peanut allergen, and a consistent passage of intact molecules has been observed. Using as tracer 125I-labelled human albumin, transport across the nasal mucosa has been demonstrated in 3/9 normal subjects, 1/9 patients with extrinsic asthma and 9/10 patients with atopic rhinitis. In experimental animals (rabbits) the passage of allergens through the nasal mucosa has been confirmed using 125I-labelled Parietaria allergens that showed a peak in the bloodstream 60 min after administration. It is concluded that peptide molecules such as allergens can be absorbed through the nasal mucosa and reach the bloodstream, and that in atopic patients nasal permeability is enhanced.

Administration, Intranasal↗

PubMed2006

Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria.

Toll-like receptors (TLRs) are key components of the immune system that detect microbial infection and trigger antimicrobial host defense responses. TLR5 is a sensor for monomeric flagellin, which is a component of bacterial flagella known to be a virulence factor. In this study we generated TLR5-deficient mice and investigated the role of TLR5 signaling in the detection of flagellin and antibacterial immune responses to Salmonella typhimurium and Pseudomonas aeruginosa. We found that TLR5 is essential for the recognition of bacterial flagellin both in vivo and ex vivo. TLR5 contribution to antibacterial host response to i.p. infection with S. typhimurium or intranasal administration of P. aeruginosa may be masked by TLR4 or other sensing mechanisms. By using radiation bone marrow chimera, we showed that upon i.p. injection of flagellin immune responses are mediated by lymphoid cells, whereas resident cells are required for the initiation of response upon intranasal flagellin administration. These results suggest that flagellin recognition in different organs is mediated by distinct TLR5-expressing cells and provide insights into the cooperation of the TLR5 and TLR4 signaling pathways used by the innate immune system in the recognition of bacterial pathogens.

Animals↗

PubMed1996

Effects of cocaine on anterior pituitary and gonadal hormones.

Acute and chronic cocaine administration has been reported to change endocrine and neurochemical functions in animals and human drug abusers. This study examined the effects of acute cocaine administration on anterior pituitary and gonadal hormones in male human volunteers without a history of drug abuse. Using a double-blind, randomized study design, luteinizing hormone, follicle-stimulating hormone (FSH), prolactin and testosterone levels were measured in 12 healthy men before and after intranasal administration of 2 mg/kg cocaine or placebo. Each subject was studied twice, serving as his own control. Compared to placebo, both luteinizing hormone, and, to a lesser degree, follicle-stimulating hormone levels increased significantly after cocaine, reaching a peak value 60 min after the administration of the study drug. This pattern is consistent with a possible cocaine induced rise in gonadotropin-releasing hormone and subsequent rise in luteinizing hormone and follicle-stimulating hormone due to stimulation of gonadotroph cells in the pituitary gland. Neither cocaine nor placebo induced a change in testosterone levels. Prolactin levels showed a decrease from base line after both placebo and cocaine administration, with a significantly more pronounced decrease after cocaine. This likely reflects the combination of the physiologic diurnal variation in prolactin secretion and an added inhibitory effect on prolactin due to cocaine. These findings show that the acute administration of cocaine significantly alters anterior pituitary hormonal release patterns.

Administration, Intranasal↗

PubMed2003

Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells.

Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia, can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Consequently, research attention has been directed toward understanding the cytokine networks that may affect fibroblast activation and, hence, the progression of certain IIPs. This led us to investigate whether the specific targeting of resident lung cells responsive to IL-4 and IL-13 exerted a therapeutic effect in an experimental model of IIP, namely the bleomycin-induced model of pulmonary fibrosis. IL-4, IL-13, and their corresponding receptor subunits, IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2, were maximally expressed at the mRNA and protein levels in whole lung samples on day 21 or 28 after an intratracheal bleomycin challenge. The intranasal administration of an IL-13 immunotoxin chimeric molecule (IL13-PE) from days 21-28, but not for 1-wk periods at earlier times, after bleomycin challenge had a significant therapeutic effect on histological and biochemical parameters of bleomycin-induced pulmonary fibrosis compared with the control group. The intranasal IL13-PE therapy significantly reduced the numbers of IL-4 and IL-13 receptor-positive mononuclear cells and macrophages and the levels of profibrotic cytokine and chemokine in the lungs of bleomycin-challenged mice on day 28. Thus, this study demonstrates that IL-4- and/or IL-13-binding cells are required for the maintenance of pulmonary fibrosis induced by bleomycin and highlights the importance of further investigation of antifibrotic therapeutics that target these cells during pulmonary fibrosis.

Administration, Intranasal↗

PubMed1999

Treatment of experimental autoimmune arthritis by nasal administration of a type II collagen-cholera toxoid conjugate vaccine.

OBJECTIVE: To assess the efficacy of intranasal administration of microgram amounts of type II collagen (CII) coupled to cholera toxin B subunit (CTB) with respect to the development of collagen-induced arthritis, even when given after the onset of clinically evident arthropathy. METHODS: DBA/1 mice were immunized with CII to induce arthritis and were subsequently treated with CTB-CII, CTB-conjugated ovalbumin, or CII alone. The incidence and severity of arthritis were assessed clinically and histologically. RESULTS: Treatment with CTB-CII conjugate effectively suppressed leukocyte infiltration into the synovium and prevented bone erosion. Comparable doses of unconjugated CII administered by the same route were relatively ineffective. Protection with nasal CTB-CII vaccine was associated with decreased production of interleukin-4 (IL-4), IL-6, and interferon-gamma and with reduced CII-specific IgG1 and IgG2a antibody responses in regional lymph nodes. CONCLUSION: Nasal treatment with CTB-CII appears to result in decreased peripheral Th1 and Th2 responses to collagen. These results suggest that intranasal vaccination with CTB-CII may offer an effective immunotherapeutic means for the control of chronic polyarthritis.

Administration, Intranasal↗

PubMed1997

Mucosal tolerance is associated with, but independent of, up-regulation Th2 responses.

Intranasal administration of protein antigen is an efficient way to induce mucosal tolerance. Suppressive mechanisms that might be involved in this phenomenon include down-regulation of T-helper type-1 (Th1)-mediated processes by Th2 cells. However, since Th2 responses can also be subjected to mucosal tolerance, we wanted to investigate whether suppression of a typical Th1 response, such as a delayed-type hypersensitivity (DTH) reaction by intranasal tolerance induction, was causally related to up-regulation of Th2 responses. We therefore treated mice either systemically or locally with anti-interleukin-4 (IL-4) or anti-IL-10 antibodies before intranasal tolerance induction or before sensitization for DTH to see whether we could prevent or abrogate tolerance. Although the up-regulation of antigen-specific IgE levels in tolerant mice could be prevented by anti-IL-4 treatment, the extent of tolerance as measured by suppression of DTH was not affected. We therefore conclude that up-regulation of Th2 responses observed after intranasal tolerance induction is an additional or consequential rather than a necessary reaction.

Administration, Intranasal↗