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PubMedDate not supplied

[Dynamics of distribution of the low molecular weight fraction of cerebral in rat tissues upon intranasal administration].

A homogeneous low-molecular-weight fraction (MW, 350-500 Da) separated from a ready-to-use commercial form of the new neurotropic drug cerebral (for amino acid composition see Arkh. Psikh. 3(18), 138-143 (1998)) increases the survival of experimental rats upon experimental hemorrhagic stroke (HS). The distribution and accumulation of tritium-labeled preparation was studied in various tissues (tractus olfactorius, bulbus olfactorius, damaged neocortex region, hippocampus, hypothalamus, midbrain, pons, medulla oblongata, cerebrum, liver) and in the blood of intact, shame-operated (SO), and HS rats 20 and 120 min after intranasal administration. A significant amount of the labeled drug is accumulated for 20 min in all structures of the brain, liver, and blood. After 120 min, the level of accumulated drug proportionally increases. The amount of labeled preparation accumulated in SO and HS rats is greater than that in intact rats. The character of cerebral accumulation in tractus olfactorius and bulbus olfactorius upon intranasal administration is indicative of the effective drug transport to CNS via these pathways. Therefore, the intranasal administration can offer a promising means of clinical treatment of HS patients.

Administration, Intranasal↗
PubMed2004

Intranasal administration of NAP, a neuroprotective peptide, decreases anxiety-like behavior in aging mice in the elevated plus maze.

NAP, an 8-amino-acid peptide (NAPVSIPQ=Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln), provides neuroprotection at very low doses in a variety of animal models. Previously, acute NAP administration by the intranasal route resulted in improved performance in the Morris water maze of normal and cognitively impaired rats. In these animals, it was observed, but not quantified, that NAP exhibited an anxiolytic effect. Therefore, we have tested here the effects of chronic NAP treatment on anxiety-like behavior in mice in the elevated plus maze. Results showed that 5 months of daily (intranasal) treatment with NAP reduced anxiety, measured as the percentage of time spent in the open arms of the maze (P < 0.01). This effect was maintained after a longer (8 months) exposure to NAP. In addition, after 8 months of NAP treatment, the percentage of open arm entries out of total arms entries was significantly higher in the treated mice ( P < 0.01). Motor function indices indicated no significant differences between the groups. Furthermore, prolonged treatment with NAP (7 months) showed some beneficial effects on Morris water maze performance in the aging mice. It is concluded that NAP offers a unique combination of anxiolytic/cognitive enhancing properties observed after prolonged chronic intranasal treatment.

Administration, Intranasal↗
PubMed2003

Protection against influenza virus infection by intranasal administration of C3d-fused hemagglutinin.

For the induction of mucosal immune responses by intranasal vaccination, cholera toxin B subunits (CTB) and Escherichia coli heat-labile toxin (LT) are often administered as mucosal adjuvants in order to enhance immune responses to mucosally co-administered bystander antigens. However, these toxin also are the causative agents of diarrhea. There is a demand for the establishment of an effective and safer adjuvant or vaccine that elicits mucosal immunity, but does not require the use of CTB or LT adjuvants. In order to induce protective mucosal immune responses in the nasal area against influenza virus infection, we have examined the recombinant protein composed of the complement component, C3d, which is fused to the secreted form of hemagglutinin (sHA-mC3d3) in the influenza-BALB/c mouse model. The fusion protein sHA-mC3d3, the secretory form of hemagglutinin, and the transmembrane form of HA (tmHA) from the influenza virus were intranasally administered to the mice with or without CTB containing a trace amount of holotoxin (CTB*) as an adjuvant. After intranasal administration of these proteins with CTB*, all mice produced nasal IgA and serum IgG antibodies (Abs) against the viral HA. In addition, viral infection was completely inhibited in these mice. In contrast, in the absence of the adjuvant, only sHA-mC3d3-induced locally secreted IgA and serum IgG Abs and provided complete protection against the influenza virus challenge. Thus, C3d fused to the influenza HA antigen is an effective and safe tool for mucosal vaccination.

Adjuvants, Immunologic↗
PubMed1999

Single- and repeated-dose local toxicity in the nasal cavity of rabbits after intranasal administration of different glycols for formulations containing benzodiazepines.

To furnish a systemic effect after intranasal administration, a formulation must contain the therapeutic dose in no more than 150 L, the maximum volume that can be applied as a single administration in one nostril in man. The objectives of these studies were to examine the local toxicity of formulations containing benzodiazepines and to document the effects to support clinical trials in man. After stability, pharmacological and pharmacokinetic studies of several benzodiazepine formulations, we studied nasal toxicity after single and repeated administration to rabbits of poly(ethylene glycol) 200, tetra(ethylene glycol), glycofurolum and mixtures of these vehicles both with and without benzodiazepines. Single-dose studies with examinations 5 or 10min after application were undertaken with poly(ethylene glycol), tetra(ethylene glycol), glycofurolum and tetra(ethylene glycol)-glycofurolum in the ratio 95:5; the reactions were similar to that after physiological saline. A 14-day repeated-dose study was conducted with diazepam, lorazepam and flunitrazepam formulations in poly(ethylene glycol), and flunitrazepam in poly(ethylene glycol)-glycofurolum in the ratio 70:30; the two vehicles without any benzodiazepine were also examined. Microscopic study revealed mild changes only in the treated groups. A final four-week study was conducted with repeated administration of clonazepam formulated in tetra(ethylene glycol)-glycofurolum in the ratio 95:5; microscopy revealed mild changes after three 150-microL doses daily, but no abnormalities after one or three 100-microL doses daily. It was concluded that these three solvents individually or as mixtures resulted in only mild local toxicity and might be acceptable as vehicles in nasal preparations of benzodiazepines and other non-irritating drugs for short-term use in man.

Administration, Intranasal↗
PubMed1998

Intranasal administration of demopressin (DDAVP) for type 1 and type 2A von Willebrand disease.

Desmopressin was administered intranasally to seven patients with von Willebrand disease (type 1: 4 patients, type 2A: 3 patients) to assess the response and safety. von Willebrand factor antigen ranged from 8% to 60% before treatment and increased significantly after intranasal DDAVP administration (the median relative increase: two- to threefold). Factor VIII levels also increased substantially over baseline levels after intranasal administration. Before treatment ristocetin cofactor activity was 32 +/- 12% in patients with type 1 vWD and 9 +/- 5% in patients with type 2A vWD. After intranasal administration, the levels of ristocetin cofactor activity increased to 56 +/- 21% and 29 +/- 9%, respectively. The bleeding time was normalized in 86% of the patients. The abnormality of vWF multimers in type 1 vWD returned more or less to normal after intranasal DDAVP administration whereas that in type 2A vWD did not. The intranasal administration of DDAVP is safe and effective for minor bleeding episodes and is adaptable for home use in patients with type 1 and type 2A vWD.

Administration, Intranasal↗
PubMed2001

Effects of intranasal administration of cholera toxin (or Escherichia coli heat-labile enterotoxin) B subunits supplemented with a trace amount of the holotoxin on the brain.

Effects of intranasal administration of cholera toxin (CT) [or Escherichia coli heat-labile enterotoxin (LT)] B subunits supplemented with a trace amount of the holotoxin, CTB* or LTB*, on the brain were examined in BALB/c mice by comparing with those of the intracerebral injection. Intracerebral injection of CTB* at doses more than 10 microg/mouse caused significant body weight loss and dose-dependent death within 7 days, with localization of conjugates of horseradish peroxidase with CTB (HRP-CTB) in the ventricular system and in the perineural space of olfactory nerves of the nasal mucosa 3 h after injection. Intracerebral injection of CTB* at doses less than 3 microg/mouse (or LTB* at doses less than 22.7 microg/mouse) did not cause any significant body weight loss for 7 days, with localization of HRP-CTB in the brain but not in the nasal mucosa. On the other hand, intranasal administration of 10 microg of CTB* caused localization of HRP-CTB in the nasal mucosa but not in the brain 3 h after administration and caused body weight loss even after 30 administrations. Neither any histological changes of brain tissues nor marked changes in serum biochemical parameters were found in mice after the 30 administrations of CTB* or LTB*. These results suggest that 0.1 microg of CTB* or LTB*, which is known to be close to the minimal effective dose as an adjuvant for nasal influenza vaccine in mice and corresponds to 100 microg per person, can be used as a safe nasal adjuvant without adversely affecting the brain.

Adjuvants, Immunologic↗
PubMed1995

Intranasal administration of the GHRP hexarelin accelerates growth in short children.

OBJECTIVE: Hexarelin is a recently synthesized small growth hormone releasing peptide (GHRP) (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys- NH2). It is active by intravenous, oral and intranasal administration in animals and man. The aim of this study was to find out whether long-term administration of this peptide would promote growth in short children. DESIGN AND PATIENTS: Intranasal hexarelin was administered in a dose of 60 micrograms/kg thrice daily to 8 prepubertal short children aged 4-11.6 years for periods of up to 8 months. RESULTS: Hexarelin treatment stimulated insulin-like growth factor-I (IGF-I) secretion raising the level from 10.4 +/- 3.9 (SD) to 14.1 +/- 4.6 nmol/l (P < 0.004). The rise in IGF-I led to a significant increase in the mean (+/- SD) linear growth velocity from 5.3 +/- 0.8 to 8.3 +/- 1.7 cm/year (P < 0.0001). There was also a significant decrease in skinfold thickness despite increase in body weight and an increase in head circumference. Additional findings were a rise in serum phosphate from 1.5 +/- 0.1 to 1.8 +/- 0.1 mmol/l (P < 0.004) and of alkaline phosphatase from 219 +/- 74 to 261 +/- 75 U/l (P < 0.05). CONCLUSIONS: The long-term GH/IGF-I stimulating, anabolic and growth promoting effects achieved by intranasal administration of this hexapeptide, seemingly without undesirable side-effects, suggests clinical potential for this new class of drugs.

Administration, Intranasal↗
PubMed2005

Effects of intranasal administration of nimodipine on cerebral hemodynamics of dogs.

AIM: To investigate the effect of nimodipine (NM) on cerebral blood flow (CBF) in dogs following intranasal administration. METHODS: NM solution was administered intranasally, intravenously (i.v.), and orally to dogs and the change of CBF was determined by using electromagnetic blood flowmeter. MFLab experimental program was applied to monitor the experimental process and analyze data. RESULTS: CBF markedly increased after iv and intranasal application, while large variance was observed after oral dosing. CBF in dogs after three administrations increased by 26.4%, 28.0% and 8.5%, respectively, compared with that of baseline. Following intranasal administration, the onset of action was slightly slower than that after iv injection [(5 +/- 4) min vs (2.2 +/- 1.2) min], however the duration of improvement was the longest [ (25 +/- 17) min]. CONCLUSION: Intranasal delivery for NM can be a promising alternative to parenteral or oral administration.

Administration, Intranasal↗
PubMed2000

Plasma concentration of flumazenil following intranasal administration in children.

PURPOSE: A pharmacokinetic study in children to determine plasma flumazenil concentrations after the intranasal administration of 40 microg x kg(-1). METHODS: Following institutional approval and informed written consent, 11 ASA physical status I-II patients, aged two to six years, undergoing general anesthesia for dental surgery were recruited. After induction, 40 microg x kg(-1) flumazenil Anexate, Roche, 0.1 mg x mL(-1) (0.4 mL x kg(-1))) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t = 0), and then at 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the on-site laboratory and then stored at -70 degrees C, before batch analysis via high performance liquid chromatography assay. Pharmacokinetic data calculations were performed using WinNonLin software (Scientific Consulting Inc.). RESULTS: Eleven patients were studied, but data for one patient were discarded due to insufficient sampling. The median age was 4.3 yr (range 3 to 6), with a median weight of 18.9 kg (range 14.9 to 22.2). There were seven boys and three girls. Mean Cmax was 67.8 ng x mL(-1) (SD 41.9), with Tmax at two minutes. The calculated half-life was 122 min (SD 99). CONCLUSION: The mean plasma concentrations of flumazenil attained were similar to those reported after intravenous administration, and may be sufficient to antagonize the side-effects of benzodiazepines. This route of administration may be useful when the intravenous route is not readily available.

Administration, Intranasal↗
PubMed1989

[The creation of specific immunity to staphylococcal infection in newborn infants by the intranasal administration of adsorbed staphylococcal anatoxin].

The possibility of enhancing specific immunity in newborn infants by the intranasal administration of adsorbed staphylococcal toxoid to infants with a high risk of staphylococcal infection in doses of 1 drop (0.05 ml) into each nostril during the first 7-9 years of their life. On days 7-9 the level of anti-alpha-toxin in the blood rose to 3.8 +/- 0.14 I. U./ml and remained sufficiently high 3-6 months later. When this method was used for the simultaneous immunization of mothers, their antitoxic titers were not as high as in newborn infants. No side effects were observed. In the control group, the titers of anti-alpha-toxin were low during the whole period of observation. Infants immunized by the proposed method had no staphylococcal infections both during the newborn period and within the first year of their life. In the control group, 8 cases of minor forms of purulent septic infection were registered during the newborn period, and in 2 infants umbilical staphylococcal sepsis was diagnosed.

Administration, Intranasal↗
PubMedDate not supplied

Short term effect of intranasal administration of hexarelin--a synthetic growth hormone-releasing peptide. Preliminary communication.

Twice or three times daily intranasal administration of the hexapeptide hexarelin for 7 days to children with short stature and normal growth hormone (GH) secretion evoked a significant rise in serum levels of insulin-like growth factor-1 (IGF-1) and alkaline phosphatase. There was also a significant, within normal limits, rise of thyroid stimulating hormone (TSH) without evidence of thyroxine suppression.

Administration, Intranasal↗
PubMed1987

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. V. By intranasal administration.

Serum IgE antibody responses were generated in mice by intranasal exposure to grass pollen extract. Primary IgE responses were suppressed by the concomitant intranasal administration of a conjugate of polysarcosine and pollen extract which has been shown to be a potent tolerogen when given parenterally. Partial suppression of boosted IgE responses was observed when the conjugate was applied intranasally with a secondary challenge of unmodified extract. The data suggest that clinical schedules of intranasal application of tolerogenic conjugates can be devised to bring about specific IgE suppression.

Administration, Intranasal↗
PubMed1999

Accidental intranasal administration of phenol.

A 79-y-old man developed erythema and superficial sloughing of the turbinate following accidental intranasal administration of 89.2% phenol solution. Previous documented reports of phenol exposure include exposures via dermal and oral routes, but no reports of nasal phenol administration were found.

Administration, Intranasal↗
PubMed2004

Distribution of nimodipine in brain following intranasal administration in rats.

AIM: To determine whether nasally applied nimodipine (NM) could improve its systemic bioavailability and be transported directly from the nasal cavity to the brain. METHODS: NM was administered nasally, intravenously (iv), and orally to male Sprague-Dawley rats. At different times post dose, blood, cerebrospinal fluid (CSF), and brain tissue samples were collected, and the concentrations of NM in the samples were analyzed by HPLC. RESULTS: Oral systemic bioavailability of NM in rats was 1.17 %, nasal dosing improved bioavailibility to 67.4 %. Following intranasal administration, NM concentrations in olfactory bulb (OB) within 30 min post dose were found significant higher than in the other brain tissues. However, similar NM levels in different brain regions were observed after iv injection. AUC in CSF and OB from the nasal route was 1.26 and 1.39 fold compared with the iv route, respectively. The brain-to-plasma AUC ratios were significantly higher after nasal administration than after iv administration (P<0.01). CONCLUSION: Nasally administered NM could markedly improve the bioavailability and a fraction of the NM dose could be transported into brain via the olfactory pathway in rats.

Administration, Intranasal↗
PubMed1998

Effects of intranasal administration of recombinant murine interferon-gamma on murine acute myocarditis caused by encephalomyocarditis virus.

BACKGROUND: Viral myocarditis has been strongly implicated in the pathogenesis of dilated cardiomyopathy as well as acute myocarditis. Among the antiviral therapies, interferons (IFNs) have been widely studied and become very important in clinical practice. METHODS AND RESULTS: To investigate the possibilities of IFN therapy in viral myocarditis, we analyzed the effects of recombinant murine interferon (mIFN)-gamma and natural mIFN-alpha/beta by the intranasal and intramuscular routes on the development of acute murine myocarditis caused by encephalomyocarditis virus. Both mIFN-gamma and mIFN-alpha/beta treatment by either route significantly increased the survival rate; none of the mIFN-gamma-treated mice died. The effect of mIFN-gamma was significantly greater than that of mIFN-alpha/beta. Furthermore, intranasal administration of mIFN-gamma significantly suppressed virus replication and inflammation in the heart. CONCLUSIONS: Our data demonstrate that IFN therapy, especially intranasal administration of IFN-gamma, dramatically improved the prognosis of acute murine viral myocarditis by suppressing virus replication and raises the possibility of antiviral therapy with IFN-gamma in patients with acute myocarditis.

Administration, Intranasal↗
PubMed1984

[Effect of intranasal administration of an LH-RH analog on basal gonadotropin concentrations and stimulation in patients with hypogonadotropic hypogonadism].

The effect of intranasal administration of the LHRH analogue D-Leu-6-des Gly-10 NH2EA on gonadotropin (Gn) stimulation was studied in 8 juvenile patients with ascertained hypogonadotropic hypogonadism, due to multiple pituitary deficiencies (MPD) in 5 cases and the Prader-Willi syndrome (PWS) in the remaining 3 patients. A bolus LHRH test was performed before and after a treatment period lasting between 2 and 5 weeks. In 2 MPD patients there was a transient rise in basal LH concentrations and a slight improvement in the second LHRH test; hence a hypothalamic lesion is assumed. In the other MPD patients there was no change in Gn stimulation. The sex steroid levels remained low. Gn stimulation was improved in all 3 patients with PWS after LHRH administration and in one 19-year-old boy the onset of puberty was probably induced by this therapy. However, after continuous administration of the analogue the initially increased Gn levels decreased again. In view of this inhibiting action on Gn levels the LHRH analogue does not appear suitable for the long-term treatment of hypogonadotropic hypogonadism.

Administration, Intranasal↗
PubMed1999

Sleep and endocrine changes after intranasal administration of growth hormone-releasing hormone in young and aged humans.

Systemic administration of growth hormone-releasing hormone (GHRH) has been found to improve human sleep in previous studies. Here we examined effects of GHRH on endocrine function and sleep after intranasal administration, a method which based on previous studies appears to enable a direct effect of peptides on brain function. Also, it was hypothesized that elderly humans displaying deficient GH release and sleep, benefit from GHRH administration more than young subjects. A study was performed according to a double-blind cross-over design. Each of 12 young and 11 old healthy men were intranasally administered with 300 micrograms GHRH (vs. placebo) 30 min before bedtime at 23:00 h. Sleep was recorded polysomnographically until 07:00 h and blood was collected in 15 min intervals for determination of cortisol and GH. Apart from the well-known age-related changes of hormonal secretion and sleep, intranasal GHRH reduced cortisol nadir concentrations in the beginning of sleep (P < 0.05), and also reduced the sleep-induced elevation in GH concentrations during early sleep. Moreover, results indicated that after intranasal administration GHRH increased rapid-eye-movement (REM) sleep and slow wave sleep (SWS), with this influence concentrating on the second half of sleep time. Effects of GHRH did not depend on the subject's age. We conclude that there is a coordinate influence of intranasal GHRH on the central nervous regulation of sleep processes and of hypothalamic-hypophysiotropic secretory activity in both young and elderly men. The effects may mimic the dual neuronal and endocrine function of hypothalamic GHRH activity.

Administration, Intranasal↗