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Intranasal fentanyl is an equivalent analgesic to oral morphine in paediatric burns patients for dressing changes: a randomised double blind crossover study.

INTRODUCTION: The ideal analgesic agent for burns wound dressings in paediatric patients would be one that is easy to administer, well tolerated, and produces rapid onset of analgesia with a short duration of action and minimal side-effects to allow rapid resumption of activities and oral intake. We compared our current treatment of oral morphine to intranasal fentanyl in an attempt to find an agent closer to the ideal. METHODS: A randomised double blind two-treatment crossover study comparing intranasal administration of fentanyl (INF) to orally administered morphine (OM). Children with burn injury aged up to 15 years and weighing 10-75 kg were included. Primary end-point was pain scores. Secondary end-points were time to resumption of age-appropriate activities, time to resumption of fluid intake, sedation and cooperation. Routine observations and vital signs were also recorded. RESULTS: Twenty-four patients were studied with a median age of 4.5 years (interquartile range 1.8-9.0 years) and a median weight of 18.4 kg (interquartile range 12.9-33.2kg). Mean pain difference scores (OM-INF) ranged from -0.500 (95% CI=-1.653 to 0.653) at baseline to -0.625 (05% CI=-1.863 to 0.613) for a retrospective rating of worst pain experienced during the dressing procedure. All measurements were within a pre-defined range of equivalent efficacy. The median time to resumption of fluid intake was 108 min (range 44-175 min) with OM and 140 min (range 60-210 min) with INF. These differences were not statistically significant. Fewer patients experienced mild side-effects with INF compared to OM (n=5 versus n=10). No patients experienced depressed respirations or oxygen saturations. SUMMARY: Intranasal fentanyl was shown to be equivalent to oral morphine in the provision of analgesia for burn wound dressing changes in this cohort of paediatric patients. It was concluded that intranasal fentanyl is a suitable analgesic agent for use in paediatric burns dressing changes either by itself or in combination with oral morphine as a top up titratable agent.

Administration, Intranasal↗

Interacting effects of zinc and cadmium on the cadmium distribution in the mouse.

Effects of zinc (Zn) on cadmium (Cd) distribution in the mouse body were investigated after intranasal administration. The amounts of Cd (2 x 10(-6) M/0.02 ml) reaching respiratory organs increased as the ip dose of pentobarbital increased. Administration of Zn with Cd (2 x 10(-6) M Zn + 2 x 10(-6) M Cd /0.02 ml) further increased the Cd amounts reaching respiratory organs and increased mouse mortality. A single administration of Cd increased Cd levels in blood, liver, kidney and respiratory organs. High levels of Cd were maintained for at least 90 days in these organs after single administrations of Cd. The administration of Cd plus Zn further increased the Cd content in these organs during 0-60 min after administration. However, simultaneous administration of Zn with Cd inhibited prolonged Cd accumulation in kidney and liver. These results suggest that intranasally administered Zn (2 x 10(-6) M) has dual effects on Cd movement. Zn further increases the Cd levels in the lung and mouse mortality increases. On the contrary, Zn inhibits prolonged Cd accumulation in mice and decreases the chronic toxicity in mice that survive the acute phase.

Administration, Intranasal↗

Protective effects of intranasal vaccination with plasmid encoding pseudorabies virus glycoprotein B in mice.

Intranasal administration of plasmid DNA encoding glycoprotein B of pseudorabies virus into mice induced both serum and secretory antibody responses. These mice resisted intranasal challenge with lethal dose of the virus, but did not intraperitoneal challenge. On the other hand, intramuscular injection of the plasmid induced less secretory and higher serum antibody responses than those of intranasally vaccinated mice. None of them was protected from virus challenge. The present results suggest that administration of plasmid DNA encoding glycoprotein B by respiratory mucosal route generates local secretory antibodies which serve to protect animals from pseudorabies virus infection.

Administration, Intranasal↗

Cocaine stimulates the human cardiovascular system via a central mechanism of action.

BACKGROUND: Cocaine is thought to stimulate the cardiovascular system by blocking peripheral norepinephrine reuptake. This study was designed to test the novel hypotheses that cocaine also stimulates the human cardiovascular system by (1) increasing central sympathetic outflow, or (2) decreasing parasympathetic control of heart rate. METHODS AND RESULTS: In 14 healthy cocaine-naive humans, we measured blood pressure, heart rate, and skin sympathetic nerve activity (SNA) with intraneural microelectrodes before, during, and for 90 minutes after intranasal cocaine (2 mg/kg, n=7) or lidocaine (2 mg/kg, n=7). Intranasal cocaine caused an initial but transient 3. 3-fold increase in skin SNA during the period of intranasal administration followed by a sustained 2.4-fold increase lasting for up to 90 minutes after cocaine. Unlike cocaine, intranasal lidocaine caused only a small transient increase in skin SNA due to local nasal irritation. The cocaine-induced increase in SNA was accompanied by decreased skin blood flow, increased skin vascular resistance, and increased heart rate. In 11 additional subjects, we showed that the cocaine-induced increase in heart rate was eliminated by beta-adrenergic receptor blockade (propranolol) but unaffected by muscarinic receptor blockade (atropine), indicating sympathetic mediation. CONCLUSIONS: These studies provide direct microneurographic evidence in humans that intranasal cocaine stimulates central sympathetic outflow. This central sympathetic activation appears to be targeted not only to the cutaneous circulation promoting peripheral vasoconstriction but also to the heart promoting tachycardia.

Administration, Intranasal↗

Mucosal administration of Ag85B-ESAT-6 protects against infection with Mycobacterium tuberculosis and boosts prior bacillus Calmette-Guerin immunity.

We have examined the intranasal administration of a vaccine against Mycobacterium tuberculosis (M.tb) consisting of the mucosal adjuvant LTK63 and the Ag Ag85B-ESAT-6. Vaccination with LTK63/Ag85B-ESAT-6 gave a strong and sustained Th1 response mediated by IFN-gamma-secreting CD4 cells, which led to long-lasting protection against tuberculosis, equivalent to that observed with bacillus Calmette-Guérin (BCG) or Ag85B-ESAT-6 in dimethyldioctadecylammonium bromide/monophosphoryl lipid A. Because a crucial element of novel vaccine strategies is the ability to boost BCG-derived immunity, we also tested whether LTK63/Ag85B-ESAT-6 could act as a BCG booster vaccine in BCG-vaccinated mice. We found that vaccinating with LTK63/Ag85B-ESAT-6 strongly boosted prior BCG-stimulated immunity. Compared with BCG-vaccinated nonboosted mice, we observed that infection with M.tb led to a significant increase in anti-M.tb-specific CD4 T cells in the lungs of LTK63/Ag85B-ESAT-6-boosted animals. This correlated with a significant increase in the protection against M.tb in LTK63/Ag85B-ESAT-6-boosted mice, compared with BCG-vaccinated animals. Thus, LTK63/Ag85B-ESAT-6 represents an efficient preventive vaccine against tuberculosis with a strong ability to boost prior BCG immunity.

Acyltransferases↗

Intranasal midazolam vs rectal diazepam in acute childhood seizures.

One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.

Acute Disease↗

Effect of fluticasone propionate nasal spray on bioavailability of intranasal hydromorphone hydrochloride in patients with allergic rhinitis.

STUDY OBJECTIVE: To investigate the effect of the nasal corticosteroid fluticasone propionate on the bioavailability and pharmacokinetics of single-dose intranasal hydromorphone hydrochloride in patients with allergic rhinitis. DESIGN: Randomized, three-way, crossover pharmacokinetic study. SETTING: University clinical research unit. PATIENTS: Twelve patients with allergic rhinitis. INTERVENTION: Hydromorphone hydrochloride 2.0 mg was administered by intravenous infusion (treatment A), intranasal spray without allergic rhinitis treatment (treatment B), and intranasal spray after 6 days of fluticasone propionate (treatment C). Blood samples were collected serially from 0-16 hours. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were determined by noncompartmental methods. An analysis of variance (ANOVA) model was used for statistical analysis. Mean (% coefficient of variation) absolute bioavailability of intranasal hydromorphone was 51.9% (28.2) and 46.9% (30.3) in patients with allergic rhinitis with and without treatment with fluticasone propionate, respectively. Mean maximum concentration (Cmax) values were 3.02 and 3.56 ng/ml, respectively. No statistical differences in Cmax and area under the concentration versus time curve were detected between intranasal treatments. Bioavailability values for both intranasal treatments were lower than those in healthy volunteers (57%). Median time to Cmax (Tmax) values were significantly different (p=0.02) for treatments B and C (15 and 30 min, respectively) using rank-transformed Tmax for ANOVA. Adverse effects were consistent with known effects of hydromorphone administered by other routes, with the exception of bad taste after intranasal administration. CONCLUSION: Hydromorphone was rapidly absorbed after nasal administration, with maximum concentrations occurring for most subjects within 30 minutes. Allergic rhinitis may affect pain management strategies for intranasal hydromorphone, with a delay in onset of action for patients treated with fluticasone propionate.

Administration, Intranasal↗

Characteristics of immunity induced by viral antigen or conferred by antibody via different administration routes.

The characteristics of the immunity induced by viral antigens or conferred by antiviral antibody via different routes of administration were evaluated comparatively. C57BL/6 mice were immunized via intranasal, intradermal or enteric routes with a live recombinant vaccinia virus expressing the respiratory syncytial virus (RSV) F glycoprotein (F.rVV) or RSV, and then challenged intranasally with RSV. Inhibition of RSV replication was observed in the lungs of all the mice; however, only intranasal immunization hindered virus replication in the nose. Lung inflammation, characterized by infiltration of neutrophils and of mononuclear cells was strongest in the intradermally immunized mice, but was observed in all F.rVV immunized mice to various degrees. Intranasal administration of a potently neutralizing human anti-RSV antibody Fab fragment to infected mice inhibited RSV replication in the nose and, when combined with intraperitoneal administration, protected both the lung and the nose in the absence of deleterious lung pathology. These data suggest that intranasal immunization with F.rVV reduces RSV replication in the respiratory tract, but still induces pathological lung inflammation, even though this is milder than that observed following intradermal immunization. Local neutralizing antibody is indispensable for protection in the nose.

Administration, Cutaneous↗

Intranasal exposure to bacterial superantigens induces airway inflammation in HLA class II transgenic mice.

Staphylococcus aureus is widely prevalent in the nasopharynges of healthy individuals (carriers) but can also cause serious infections. S. aureus can elaborate a variety of superantigen exotoxins in "carrier" or "pathogenic" states. Streptococcus pyogenes can also colonize the nasopharynx and elaborate superantigens. Unlike the acute effects of superantigen exotoxins absorbed through the gut or vaginal mucosa, little is known regarding the pathogenesis of superantigens entering through the intranasal route. In the current study, we evaluated the local and systemic effects of staphylococcal enterotoxin B (SEB) and streptococcal pyrogenic exotoxin A (SPEA) delivered through the intranasal route. Superantigens were administered intranasally on multiple occasions, and experimental animals were sacrificed on day 8 for experimental analyses. SEB-induced airway inflammation was more pronounced for HLA-DR3 transgenic mice than for BALB/c mice, consistent with bacterial superantigens binding more efficiently to human than murine major histocompatibility complex class II. The nature of the airway inflammation in HLA-DR3 mice was determined by the concentration of SEB applied intranasally. Low concentrations (20 ng) induced eosinophilic airway inflammation as well as eosinophil degranulation, whereas intranasal exposure to higher concentrations (2,000 ng) resulted in neutrophilic airway inflammation, permanent airway destruction, toxic shock, and mortality. SEB-induced eosinophilic inflammatory response was enhanced in signal transducer and activator of transcription (STAT)-4-deficient HLA-DQ8 transgenic mice with defective interleukin-12 signaling. Intranasal administration of SPEA induced airway inflammation and systemic immune activation in HLA-DQ8 transgenic mice. In conclusion, repeated chronic intranasal exposure to bacterial superantigens causes airway inflammation and systemic immune activation.

Administration, Intranasal↗

[Anti-influenza effect of bacterial RNAse and the pharmacokinetic basis of its administration in experimental studies].

Anti-influenzal action of bacterial and pancreatic RNAases was studied. It was shown in ovo that the RNAases had distinct virus inhibiting activity with respect to various strains of the grippe A virus and did not practically differ by their activity from remantadin but unlike it had inhibitory action on the grippe B virus. The anti-influenzal activity of bacterial RNAase in contrast to pancreatic one was detected not only in experiments with developing chick embryos but also in albino mice with lethal influenzal infection. The index of the animal protection by the preparation amounted to 54-90 per cent depending on the virus infecting dose and RNAase administration route, the lifespan of the animals being increased by 2.4 to 3.8 days. It was shown that the anti-influenzal effect of bacterial RNAase correlated with high levels of the exogenic enzyme in blood of the animals after the preparation intravenous administration. Elimination of RNAase was observed already within the first 4 hours after the experiment start. Intranasal administration allowed to increase the residence time of RNAase in blood up to 8 hours at the account of its gradual absorption from the administration site and the preparation availability increased more than 2-fold. The results provided the basis for recommending the intranasal route of bacterial RNAase administration for use in further investigation of RNAase antiviral activity.

Actinomyces↗

Assessment of renal concentrating ability in lithium-treated patients. Comparison of long-term dehydration with administration of a vasopressin analogue.

In patients given long-term treatment with lithium maximum urine osmolality was measured after 26 h of dehydration and after intranasal administration of desamino-8-D-arginine vasopressin (DDAVP). A high correlation was found between the results of the two tests suggesting that the DDAVP test is a suitable method of assessing renal concentrating ability in lithium-treated patients.

Administration, Intranasal↗

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers.

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.

Administration, Intranasal↗

Effects of oestrogen replacement therapy on serum C-reactive protein levels in hysterectomised women.

BACKGROUND: It has been hypothesised that oral oestrogen replacement therapy may increase levels of C-reactive protein (CRP), a marker of inflammation associated with increased risk of future cardiovascular events. However, it is possible that intranasal oestrogen replacement therapy have different effects on serum CRP levels. AIM: To investigate the effect of postmenopausal intranasal oestrogen replacement therapy on serum levels of CRP. A prospective comparative study was carried out. METHODS: Twenty-nine healthy hysterectomised, postmenopausal women received 300 micro g/day of intranasal 17beta-oestradiol (E2). The serum levels of CRP after 3 and 6 months after starting treatment were compared with baseline values. RESULTS: There were no significant changes in the values of CRP after 3 and 6 months of treatment (P = 0.305, P = 0.149, respectively). CONCLUSIONS: The data from the present study suggest that intranasal administration of E2 does not affect CRP levels, possibly by avoiding a hepatic first-pass effect. The possible cardiovascular protective role of intranasal oestrogen might be related to its effect of not increasing CRP levels.

Administration, Intranasal↗

Diphtheria toxoid loaded poly-(epsilon-caprolactone) nanoparticles as mucosal vaccine delivery systems.

Poly-(epsilon-caprolactone) (PCL), a poly(lactide-co-glycolide) (PLGA)-PCL blend and co-polymer nanoparticles encapsulating diphtheria toxoid (DT) were investigated for their potential as a mucosal vaccine delivery system. The nanoparticles, prepared using a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation method, demonstrated release profiles which were dependent on the properties of the polymers. An in vitro experiment using Caco-2 cells showed significantly higher uptake of PCL nanoparticles in comparison to polymeric PLGA, the PLGA-PCL blend and co-polymer nanoparticles. The highest uptake mediated by the most hydrophobic nanoparticles using Caco-2 cells was mirrored in the in vivo studies following nasal administration. PCL nanoparticles induced DT serum specific IgG antibody responses significantly higher than PLGA. A significant positive correlation between hydrophobicity of the nanoparticles and the immune response was observed following intramuscular administration. The positive correlation between hydrophobicity of the nanoparticles and serum DT specific IgG antibody response was also observed after intranasal administration of the nanoparticles. The cytokine assays showed that the serum IgG antibody response induced is different according to the route of administration, indicated by the differential levels of IL-6 and IFN-gamma. The nanoparticles eliciting the highest IgG antibody response did not necessarily elicit the highest levels of the cytokines IL-6 and IFN-gamma.

Administration, Intranasal↗

alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor.

alpha-Galactosylceramide (alpha-GalCer) is a ligand of invariant Valpha14+ NKT cells and is presented by CD1d molecule on APC. NKT cells produce a large amount of Th1 and Th2 cytokines in response to alpha-GalCer-presented APC. In this study, we assessed whether alpha-GalCer could act as an effective nasal vaccine adjuvant for mucosal vaccine that would be capable of inducing systemic as well as mucosal immune responses. When alpha-GalCer was administered with OVA via the intranasal route to C57BL/6 and BALB/c mice, significant OVA-specific mucosal secretory IgA, systemic IgG, and CTL responses were induced with mixed Th1 and Th2 cytokine profiles seen in both strains of mice. Interestingly, as BALB/c mice were intranasally immunized with PR8 hemagglutinin Ag isolated from influenza virus A/PR/8/34 together with alpha-GalCer, significant protection was afforded against influenza viral infection. When alpha-GalCer was coimmunized with a replication-deficient live adenovirus to BALB/c mice, it significantly induced both humoral and cellular immune responses. In addition, intranasal administration of OVA with alpha-GalCer showed complete protection against EG7 tumor challenge in C57BL/6. The adjuvant effects induced by intranasal coadministration with alpha-GalCer were blocked in CD1d-/- mice, indicating that the immune responses were exclusively mediated by CD1d molecule on APC. Most interestingly, intranasally coadministered alpha-GalCer activated naive T cells and triggered them to differentiate into functional effector T cells when CFSE-labeled OT-1 cells were adoptively transferred into syngeneic mice. Overall, our results are the first to show that alpha-GalCer can act as a nasal vaccine adjuvant inducing protective immune responses against viral infections and tumors.

Adjuvants, Immunologic↗

Intranasal mite allergen induces allergic asthma-like responses in NC/Nga mice.

Airway responses induced by intranasal administration of mite allergen without adjuvant were studied in NC/Nga mice. A crude extract of Dermatophagoides farinae (Df) was administered for 5 consecutive days and a single intranasal challenge booster dose was given 1 week after the last sensitization. 24 h after the single challenge, the airway hyperresponsiveness (AHR) was measured and the bronchoalveolar lavage fluid (BALF) was analyzed for numbers of eosinophils and neutrophils, and both cytokine and chemokine levels. There were marked increases in number of eosinophils in the BALF, AHR, Th2 cytokines (IL-5 and IL-13), and chemokine (eotaxin-1 and eotaxin-2) levels in the BALF following Df exposure. C57BL/6N, A/J, BALB/c, and CBA/JN mouse strains were also exposed to Df crude extract, but all of the measured responses were strongest in NC/Nga mice. Furthermore, Df-exposed NC/Nga mice showed the goblet cell hyperplasia, pulmonary eosinophilic inflammation, and increases in both total serum IgE and Df-specific IgG1. After intranasal exposure of NC/Nga mice to crude extract of Dermatophagoides pteronyssinus, the BALF eosinophilia and AHR were similar to responses induced by Df. None of the study parameters were increased in response to intranasal exposure to ovalbumin. These data demonstrated that NC/Nga mice developed allergic asthma-like responses after intranasal exposure to mite allergens.

Acetylcholine↗

Small bowel capsule biopsy in children: parents' opinions on children's discomfort.

UNLABELLED: This questionnaire study asked the parents of 62 children undergoing small bowel capsule biopsy for their reactions to the discomfort experienced by their children. The children were randomized to receive sedation with midazolam either intravenously or intranasally. With regard to the biopsy procedure the parents of 94% of the children had no objections. The parents of 3% of the children found the biopsy very unpleasant and another 3% suggested that the biopsy should be performed under general anaesthesia. The proportion of parents with negative reactions to the biopsy procedure did not differ significantly between the intravenously and intranasally sedated children. With regard to the sedation given, the parents of 79% of the children did not think that their children were in any discomfort at all. Ten percent of the children had obvious signs of nasal discomfort using the intranasal administration. In the remaining 11% of the children the parents reported various symptoms. CONCLUSION: The vast majority of parents of children undergoing small bowel capsule biopsy found the procedure satisfactory providing that the sedative medication was given intravenously rather than intranasally.

Administration, Intranasal↗

Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide.

Insulin is a major target of the autoimmune response associated with destruction of pancreatic beta cells in type 1 diabetes. A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes-prone NOD mice. Here we show that proinsulin B24-C36 peptide binds to I-A(g7), the MHC class II molecule of the NOD mouse, and, after intranasal administration, induces regulatory CD4(+) T cells that, in the absence of CD8(+) T cells, block the adoptive transfer of diabetes. Curiously, however, intranasal B24-C36 did not inhibit development of spontaneous diabetes in treated mice. We then determined that B24-C36, and its core sequence B25-C34, bind to K(d), the NOD mouse MHC class I molecule, and elicit CD8(+) CTLs. When the CD8(+) T lymphocyte epitope was truncated at the C34 valine anchor residue for binding to K(d), the residual CD4(+) T cell epitope, B24-C32/33, significantly inhibited diabetes development after a single intranasal dose. This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a "tolerogenic" autoantigen peptide can be compromised by the presence of an integral CTL epitope.

Administration, Intranasal↗