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PubMed2001

Signs of sexual behaviour are not increased after subchronic treatment with LHRH in young men.

Apart from its action as gonadotropin releasing factor, luteinizing hormone-releasing hormone (LHRH) is a potent regulator of sexual behaviour in animals. The present study aimed to assess a similar role of LHRH for sexuality in humans. In a double-blind placebo-controlled and randomized study, effects of human LHRH after acute (400 microg) and subchronic (800 microg/day over 2 weeks) intranasal administration were evaluated in 20 young and healthy men. Sexual desire and activity was assessed by a diary, ratings of women's attractiveness, a modified version of the Stroop colour naming task and a short term memory task. Effects on sexuality were contrasted with those on eating motivation and general neurocognitive functioning, the latter being assessed in addition by tasks of divergent thinking and a motor perseveration test. None of the measures of sexual desire and activity indicated any effect of LHRH, neither after acute nor after subchronic treatment. Unexpectedly, the diary indicated a significant increase in 'food intake' towards the end of the 14-day LHRH treatment. Enhanced colour naming performance on the Stroop task (independently of whether sex, food or neutral stimuli were used) in conjunction with an increased motor perseveration after LHRH points to a general effect on cognitive function towards stronger focussing of cortical processing. While overall the data show discrete central nervous changes after LHRH, a particular influence on sexuality after acute or subchronic intranasal administration in healthy men was not detected.

Administration, Intranasal↗

PubMed2001

Total dose and frequency of administration critically affect success of nasal mucosal tolerance induction.

AIMS: Nasal tolerance induction with autoantigens can effectively protect against a variety of experimental models of autoimmune disease. The aims of this study were to characterise the dosage and kinetics of inhibition of experimental autoimmune uveoretinitis (EAU) via intranasal administration of the uveitogenic antigen interphotoreceptor retinal binding protein (IRBP) in the murine model of IRBP induced EAU. METHODS: B10RIII mice were tolerised by intranasal administration of IRBP either with a long term multiple low dose or a short term/high dosing regimen before subcutaneous immunisation with IRBP in complete Freund's adjuvant (CFA). On day 15 post-immunisation, mice were killed and eyes were removed for histological examination and quantification of inflammatory cell infiltration and degree of target organ (rod outer segment, ROS) destruction. RESULTS: Nasal administration of multiple low doses of IRBP (1 microg or 3 microg IRBP per mouse per day for 10 days) significantly protected mice from IRBP induced EAU. Short term/high dose regimens were only effective when given either as a single or, at most, as two consecutive doses (40 microg per dose). Multiple doses in the range of 45-120 microg over 3 days afforded no protection. CONCLUSIONS: These results indicate that both dose and frequency of intranasal antigen administration are pivotal to tolerance induction and subsequent suppression of T cell mediated autoimmune disease.

Administration, Intranasal↗

PubMedDate not supplied

Effects of intranasal insulin in non-obese type II diabetics.

The comparative effects of intranasal and subcutaneous insulin on blood glucose and insulin levels are described in non-obese type II diabetics, in the fasting state and following a standard meal. In the fasting studies, intranasal insulin (30 units) produced a single early insulin peak. Elevated insulin levels and their hypoglycaemic effect persisted for less than 2 h whereas with subcutaneous insulin (8 units) elevated insulin levels and evidence of hypoglycaemic action were still present at 4 h. By contrast, in the meal studies both forms of insulin had similar effects on serum insulin levels and blood glucose. Moreover elevated insulin levels and evidence of reduction in post-prandial hyperglycaemia were now present at 4 h with both intranasal and subcutaneous insulin administration. Intranasal insulin in combination with a test meal now produced a biphasic insulin profile more closely resembling the normal insulin response to a meal, and reflecting the combined effects of endogenous and exogenous insulin.

Administration, Intranasal↗

PubMed2000

Genital antibody responses in mice after intranasal infection with an attenuated candidate vector strain of Bordetella pertussis.

Intranasal administration of live attenuated Bordetella pertussis, from which the pertussis toxin gene has been deleted, has previously been shown to give rise to high levels of serum immunoglobulin G (IgG) antibodies against both the protective antigen filamentous hemagglutinin (FHA) and heterologous antigens genetically fused to FHA. Here, we extend these results by demonstrating that anti-FHA IgA and IgG antibodies are also produced in the genital tract of mice, both in the vagina and in the uterus, after a single intranasal administration of B. pertussis. By comparing the immune responses induced after infection with wild-type virulent B. pertussis with that induced by infection with an attenuated pertussis toxin-deficient strain, we conclude that pertussis toxin produced by the virulent bacteria does not modify antibody production to FHA in the genital tract of B. pertussis-infected mice. The intranasal infection with either the attenuated or the virulent B. pertussis strain also led to the development of immunologic memory that could be efficiently boosted with purified FHA administered either intranasally or intravaginally to give rise to a significant increase in the levels of specific IgA and IgG produced locally in the genital tract, as well as of specific antibodies in the serum. These observations suggest that attenuated B. pertussis could be a promising vector for intranasal administration to induce antibody responses against antigens from sexually transmitted pathogens fused to FHA.

Adhesins, Bacterial↗

PubMedDate not supplied

Disposition of rifampicin following intranasal and oral administration.

Leprosy is transmitted by dissemination of M.leprae which are lodged in the nose of the patients suffering from multibacillary (MB) type of the disease. Rifampicin, a potent bactericidal antileprotic drug is given orally to the patients with a view to make the infective cases non-infective. Earlier work by us has shown that intranasal administration of rifampicin helps in reducing the M.leprae load in the nose much faster than after conventional oral administration. In the present study, rifampicin concentrations in plasma/urine/nasal wash of healthy volunteers following oral and intranasal administration were determined. Following intranasal administration, rifampicin was not detectable in plasma and high concentrations were measured in the nasal wash. Following oral administration, rifampicin was not detectable in the nasal wash indicating that enough antibiotic levels are not available for clearing M.leprae from nose.

Administration, Intranasal↗

PubMed1986

Comparison of levocabastine, a new selective H1-receptor antagonist, and disodium cromoglycate, in a nasal provocation test with allergen.

The effect of intranasal administration of levocabastine, a new selective H1-receptor antagonist, was investigated in a nasal provocation test (NPT) performed with allergens. The NPT allowed a quantitative estimation of the nasal allergic threshold (concentration of allergen necessary to trigger the reaction). In addition, the intensity of the three major rhinitis symptoms (obstruction, rhinorrhea and sneezing) was determined. Twelve adult patients, allergic to grass pollen, underwent a first NPT without pretreatment ('initial NPT'); the NPT was then repeated after the single intranasal administration of either placebo, 8 mg disodium cromoglycate (DSCG) or 0.2 mg levocabastine in a double-blind random order. The NPTs gave reproducible results since both the threshold and symptom intensities were similar in the initial NPT and in the NPT performed after placebo. The reaction threshold increased in 8/12 patients after DSCG (0.05 less than P less than 0.1) and in 9/12 patients after levocabastine (P less than 0.05). Levocabastine clearly inhibited rhinorrhea (P less than 0.001) and sneezing (P less than 0.02) but did not influence the nasal obstruction. DSCG inhibited rhinorrhea only (P less than 0.01). The intranasal administration of levocabastine might be useful in the treatment of allergic rhinitis.

Administration, Inhalation↗

PubMed1987

Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility.

A comparison was made of intranasal administration of 300 micrograms desmopressin (DDAVP) by spray, with intravenous administration of 0.2, 0.3 and 0.4 microgram DDAVP/kg in 10 healthy volunteers. The effect of DDAVP was measured on F VIII/vWF complex and on plasminogen activator release. In addition, plasma levels of DDAVP were determined using a specific and sensitive radioimmunoassay. Moreover, the reproducibility of the spray effect in 10 healthy volunteers was tested after administration of 300 micrograms DDAVP intranasally by spray on 5 different occasions. Plasma levels of DDAVP showed a clear dose-response with the maximum levels at 0.4 microgram/kg i.v. The effect of the spray approximated the 0.2 microgram/kg response. However, the maximum response in both F VIII/vWF complex and plasminogen activator release was obtained after 0.3 microgram/kg i.v. The response to 0.4 microgram/kg i.v. was not significantly different from the response to 0.3 microgram/kg indicating that maximum stimulation was reached with 0.3 micrograms/kg. There was no correlation between plasma levels of F VIII/vWF and DDAVP indicating that the biological response to DDAVP is subjected to saturation kinetics. The reproducibility of the effect of the spray dose on VIII:C was 21% (c.v.) and 27% for the intra-individual and inter-individual variation, respectively, and compared favorably with intravenous administration. Intranasal DDAVP (300 micrograms) is as effective as 0.2 micrograms/kg intravenously and provides an accurate, reproducible and convenient alternative to parenteral administration.

Administration, Intranasal↗

PubMed2006

Unique uptake of acid-prepared mesoporous spheres by lung epithelial and mesothelioma cells.

Lung cancers, malignant mesotheliomas (MM), and fibrosis are devastating diseases with limited treatment strategies, in part due to poorly-effective drug delivery to affected areas of lung. We hypothesized that acid-prepared mesoporous spheres (APMS) (1-2 microm diameter, 40 A pore size) might be effective vehicles for pulmonary chemotherapeutic drug delivery. To assess this, APMS, chemically modified with different surface molecules (lipid, a linker having a terminal amine group, a thiol group, or tetraethylene glycol [TEG]), were evaluated for uptake and possible cytotoxic effects after in vitro administration to murine alveolar epithelial Type II (C10) and human mesothelioma (MM) cells and after intrapleural or intranasal administration to C57Bl/6 mice. APMS coated with TEG (APMS-TEG) were most efficiently taken up by C10 and MM cells. The mechanism of cell uptake was rapid, actin-dependent, and did not involve clathrin- or caveolae-mediated mechanisms nor fusion of membrane-bound APMS with lysosomes. When injected intrapleurally in mice, APMS-TEG were taken up by both CD45-positive and -negative cells of the diaphragm, lung, and spleen, whereas APMS administered by the intranasal route were predominantly in lung epithelial cells and alveolar macrophages. After intrapleural or intranasal administration, APMS were nonimmunogenic and nontoxic as evaluated by differential cell counts and lactate dehydrogenase levels in bronchoalveolar and pleural lavage fluids. In the treatment of lung and pleural diseases, APMS-TEG may be useful tools to deliver chemotherapeutic drugs or molecular constructs.

Administration, Intranasal↗

PubMed2000

Intranasal instillation of aflatoxin B(1) in rats: bioactivation in the nasal mucosa and neuronal transport to the olfactory bulb.

Aflatoxin B(1) (AFB(1)) may be present in moldy dust. Inhalation of contaminated dust particles may result in high local exposure of the nasal mucosa. The present study was designed to assess bioactivation and toxicity of AFB(1) in the nasal mucosa after intranasal administration of the mycotoxin in rats and also to examine if translocation of the mycotoxin occurs from the nasal mucosa to the brain along olfactory neurons. Female Sprague-Dawley rats were given (3)H-AFB(1) (0.2, 1 or 20 microg) intranasally and were sacrificed at various intervals (1 h to 20 d). Tissues were examined autoradiographically or histopathologically. Quantitative data were obtained by beta-spectrometry in rats given (3)H-AFB(1) intranasally or orally (for comparison). The data indicated that intranasal administration of AFB(1) resulted in formation of tissue-bound metabolites in sustentacular cells, in some cells of Bowman's glands, and in a population of neuronal cells in the olfactory mucosa, whereas in the respiratory nasal mucosa, there was selective bioactivation of AFB(1) in mucous cells. Intranasal instillation of 20 microg AFB(1) resulted in disorganized undulating olfactory epithelium, with injured neuronal and sustentacular cells. In the respiratory epithelium, there was selective destruction of mucous cells. beta-Spectrometry and autoradiography with tape-sections of the head of rats given (3)H-AFB(1) intranasally indicated transport of AFB(1) and/or AFB(1) metabolites along the axons of the primary olfactory neurons to their terminations in the glomeruli of the olfactory bulb. The data indicate that the materials transported in the olfactory nerves represent AFB(1) and/or some of its nonreactive metabolites. It is concluded that application of AFB(1) on the nasal mucosa in rats results in high local bioactivation of the mycotoxin in this tissue and translocation of AFB(1) and/or its metabolites to the olfactory bulb.

Administration, Intranasal↗

PubMed1985

Radioimmunoassay of an analog of luteinizing hormone-releasing hormone, [D-Ser(tBu)]6des-Gly-NH2(10) ethylamide (Buserelin).

A sensitive and specific radioimmunoassay is described for plasma and urinary levels of [D-Ser(tBu)]6des-Gly-NH2(10) ethylamide (buserelin). No appreciable cross-reaction (less than 0.05%) was observed with LH-RH and its analogs other than buserelin fragments (1.6-45%). The sensitivity was 3 pg per tube. At buserelin concentrations of 125, 250 and 500 pg/ml, the intra- and inter-assay coefficients of variation were 7.9, 10.0 and 10.0%, and 19.0, 7.8 and 6.8% respectively. Recovery of buserelin added to plasma was quantitative (62.5 pg/ml, 101.6%; 125 pg/ml, 76.8% and 250 pg/ml, 63.4%). A dose of 5 micrograms buserelin injected subcutaneously into 5 normal male adults, reached a peak plasma level in 45 min (mean value 119.3 +/- 47.3 pg/ml) and remained detectable for at least 4 h. The half disappearance time was 118.8 +/- 26.0 min. Between 9 and 16% of the administered dose was excreted in the urine within 24 h. Buserelin could also be detected in the plasma after intranasal administration of doses of 150, 300 and 450 micrograms. There was a significant difference in the area under the curve (AUC) for plasma levels after subcutaneous injection of 5 micrograms and intranasal administration of 150 micrograms, but not between the AUC values after the three intranasal doses. These results indicate that this method for radioimmunoassay of buserelin is suitable for analyzing the pharmacokinetics and bioavailability of buserelin in man.

Administration, Intranasal↗

PubMedDate not supplied

[A trial of the intranasal vaccination of adults against measles: the approaches to an alternative revaccination method].

The safety and efficacy of a measles vaccine from the L-16 strain was studied after its intranasal administration to adult volunteers using an atomizer. The controls were adult volunteers given one dose of the vaccine subcutaneously. The measles vaccine given intranasally was used in the same or double dose. The intranasal administration of the vaccine caused practically no side effects. Within 14-60 days postvaccination, the volunteers in all the groups showed a significant rise in titres of antibodies to measles virus determined by hemagglutination inhibition test. The double dose of intranasally administered vaccine was approximately as effective as a single dose given subcutaneously.

Administration, Intranasal↗

PubMedDate not supplied

Plasma concentrations of heroin and morphine-related metabolites after intranasal and intramuscular administration.

The disposition of heroin and its metabolites was investigated in four healthy male volunteers following intranasal administration of 6 and 12 mg heroin hydrochloride. In addition, two doses of 6 mg heroin hydrochloride were injected intramuscularly for comparison of pharmacokinetic parameters. Serum samples were analyzed for heroin, 6-acetylmorphine, and morphine by solid-phase extraction-gas chromatography-mass spectrometry. The concentration of morphine glucuronides was determined by high-performance liquid chromatography based on the native fluorescence of the conjugates. Major findings were rapidly rising and declining terminal phases for heroin and 6-acetylmorphine and slowly declining phases of morphine and metabolites after both routes of administration. The area under the curve values of morphine-3-glucuronide depended on dose but not on route of administration. The apparent terminal half-lives of morphine-3-glucuronide ranged from 2.2 to 5.2 h for intranasally administered heroin and were 3.0 and 1.7 h for the intramuscularly applied drug. A mean morphine-3-glucuronide-heroin area-under-curve ratio of 93 for the intranasal route as compared with 38 for the intramuscular route demonstrated that circulating amounts of heroin were about half the size after intranasal administration of the same dose.

Administration, Intranasal↗

PubMed2003

Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats.

The aim of this paper was to investigate the levels of methotrexate (MTX) in blood and the cerebrospinal fluid (CSF) in rats to find out whether there is any direct drug transport from nasal cavity to CSF following intranasal administration. Methotrexate was administered to male Sprague-Dawley rats either intranasally or intravenously. Drug concentrations were determined from CSF and plasma samples collected from the cisterna magna and caudal vein, respectively. To collect CSF sample continuously, blank artificial CSF was infused into the lateral ventricle. The plasma levels achieved following intranasal administration were significantly lower than those after intravenous administration (P<0.01) were, while CSF concentrations achieved after intranasal administration were significantly higher than those after intravenous administration (P<0.01). The ratio of the AUC(CSF) value between the intranasal route and the intravenous injection was 13.76, whereas the absolute bioavailability was only 6.3%, the drug targeting index (DTI) of nasal route was 21.7. In conclusion, these results showed that the antineoplastic MTX must be directly transported from the nasal cavity into the CSF in rats.

Administration, Intranasal↗

PubMed2002

New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25.

We have biologically characterized two new members of the IL-17 cytokine family: IL-17F and IL-25. In contrast to conventional in vitro screening approaches, we have characterized the activity of these new molecules by direct in vivo analysis and have compared their function to that of other IL-17 family members. Intranasal administration of adenovirus expressing IL-17, IL-17C, or IL-17F resulted in bronchoalveolar lavage neutrophilia and inflammatory gene expression in the lung. In contrast, intranasal administration of IL-25-expressing adenovirus or IL-25 protein resulted in the production of IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia in the bronchoalveolar lavage and lung tissue. Mice given intranasal IL-25 also developed epithelial cell hyperplasia, increased mucus secretion, and airway hyperreactivity. IL-25 gene expression was detected following Aspergillus and Nippostrongylus infection in the lung and gut, respectively. IL-25-induced eosinophilia required IL-5 and IL-13, but not IL-4 or T cells. Following IL-25 administration, the IL-5(+) staining cells were CD45R/B220(+), Thy-1(+/-), but were NK1.1-, Ly-6G(GR-1)-, CD4-, CD3-, and c-kit-negative. gamma-common knockout mice did not develop eosinophilia in response to IL-25, nor were IL-5(+) cells detected. These findings suggest the existence of a previously unrecognized cell population that may initiate Th2-like responses by responding to IL-25 in vivo. Further, these data demonstrate the heterogeneity of function within the IL-17 cytokine family and suggest that IL-25 may be an important mediator of allergic disease via production of IL-4, IL-5, IL-13, and eotaxin.

Adenoviridae↗

PubMed2000

Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology?

Given the tremendous number of neuropeptides, which are synthesized in the central nervous system, the brain can be viewed as one of the most prominent endocrine organs. Elucidation of the functions of these peptides is hampered by the facts that after intravenous administration access to brain receptors is prevented or impaired by the blood-brain barrier. Here, we provide evidence that intranasal administration can be a way to circumvent the blood-brain barrier. Selected experiments will be reported indicating that peptides after intranasal administration in humans can specifically alter a great variety of brain functions. For vasopressin, we demonstrated improving effects of long-term intranasal treatment on sleep in elderly people. Insulin showed improving effects of short-term memory functions. For adrenocorticotropin/melanocyte stimulating hormone, ACTH/MSH-(4-10), a twofold action was isolated: The melanocortin fragment diminished selective attention and, with subchronic administration, reduced body fat. These results could provide the basis for developing a new, specific, and "soft" neuropharmacology.

Administration, Intranasal↗

PubMed2001

Mucosal antigen primes diabetogenic cytotoxic T-lymphocytes regardless of dose or delivery route.

Administration of antigens via mucosal routes, such as orally or intranasally, can induce specific immunological tolerance and has been used as a rational basis for the treatment of autoimmune diseases, including type 1 diabetes. Recently, however, orally delivered antigens were shown to induce CD8 cytotoxic T-lymphocytes (CTLs) capable of causing autoimmune diabetes. In this report, we have examined several mucosal routes for their ability to induce CTLs and autoimmune diabetes, with the aim of identifying approaches that would maximize tolerance and minimize CTL generation. In normal C57BL/6 mice, ovalbumin (OVA) delivered by either the oral or nasal routes or by aerosol inhalation was able to prime CTL immunity in both high- and low-dose regimens. To address the relevance of these CTLs to autoimmune disease, OVA was given to mice that transgenically expressed this antigen in their pancreatic beta-cells. Irrespective of antigen dose or the route of delivery, mucosal OVA triggered diabetes, particularly after intranasal administration. These findings suggest that CTL immunity is likely to be a consequence of mucosal antigen delivery, regardless of the regimen, and should be considered in the clinical application of mucosal tolerance to autoimmune disease prevention.

Administration, Intranasal↗

PubMed1995

Ability of histamine to increase nasal mucosal permeability to macromolecules in guinea pigs.

The effect of histamine on nasal mucosal permeability against an antigen was investigated by using modified passive cutaneous anaphylaxis (PCA) reactions in normal and actively sensitized guinea pigs. The administration of a dinitrophenyl-coupled Ascaris (DNP-Ascaris) solution as an antigen into the nasal cavity caused PCA reactions in the dorsal skin of normal guinea pigs. The administration of histamine into the nasal cavity before the antigen treatment significantly enhanced the anaphylactic responses. The PCA reactions did not occur when ovalbumin (OA) was administered intranasally in normal guinea pigs. In guinea pigs sensitized against DNP-Ascaris, however, PCA reactions to anti-OA antiserum were elicited by the intranasal administration of OA. The intranasal administration of histamine before the antigen treatment also enhanced anaphylactic responses in sensitized guinea pigs. These results indicate that histamine increases nasal mucosal permeability and that this may be one of the causes of nasal hypersensitivity in nasal allergy.

Allergens↗

PubMed1987

Comparison of the acute effect of the intranasal and intramuscular administration of salmon calcitonin in Paget's disease.

On 7 patients with mild-to-moderately active Paget's disease, 200 IU of salmon calcitonin (SCT) nasal spray (NS), induced a significant decrease of the total urinary hydroxyproline excretion (THP) during the 8-16 hour and the 0-24 hour (P less than 0.05) periods after treatment as compared to control day. However, the administration of 100 IU of SCT intramuscularly (i.m.) caused a significantly greater effect than 200 IU-NS during the second 8 hour period after its administration (P less than 0.01) and on the over-all 24 hour effect (P less than 0.05). On 3 patients with severe Paget's disease, SCT-NS was essentially ineffective whereas the injection of SCT induced a marked diminution of the THP excretion.

Administration, Intranasal↗