A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated Streptococcus pneumoniae Strains Using Human Infection Challenge.

Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).

Dexmedetomidine nasal administration improves perioperative sleep quality and neurocognitive deficits in elderly patients undergoing general anesthesia.

OBJECTIVE: To investigate the improvement of perioperative sleep quality and neurocognitive impairment in elderly patients under general anesthesia by nasal administration of dexmedetomidine. METHODS: One hundred and twenty patients admitted to our hospital for various laparoscopic elective gynecological surgeries lasting more than 1 h under general anesthesia from July 2021 to March 2023 were selected. All subjects were divided into 3 groups according to the random number table method. From 21:00 to 21:30 every night from one day before to 5 days after surgery, group A was given alprazolam 0.4 mg orally; group B was given dexmedetomidine 1.5ug/kg nasal drip; group C was given saline nasal drip. All subjects were observed for general information, sleep quality, postoperative cognitive function, anxiety status, sleep quality, adverse effects and complication occurrence. RESULTS: The difference in general information between the three groups was not statistically significant, P > 0.05; the sleep quality scores of the three groups on admission were not statistically significant, P > 0.05. At the Preoperative 1d, postoperative 1d, 3d and 5d, the RCSQ scores of the subjects in group A and group B were higher than those in groups C, and with the postoperative RCSQ scores of subjects in group B were higher as the time increased; the assessment of anxiety status in the three groups 1d before surgery was not statistically significant, P > 0.05. The cognitive function scores of subjects in the three groups were not statistically significant in the preoperative 1d, P > 0.05. The postoperative 1d (24.63 ± 2.23), 3d (25.83 ± 2.53), and 5d (26.15 ± 2.01) scores of the subjects in group B were higher than those in groups A and C (P < 0.05), and the subjects in group B had better recovery of postoperative cognitive function with increasing time; the occurrence of postoperative delirium (POD) in group B (12.5%) were lower on postoperative 5d than those in groups A (37.5%) and C (32.5%) (P < 0.05). There was no statistical significance in the evaluation of anxiety state of the three groups on the first day before operation (P > 0.05). The scores in group B were lower than those in group C on the postoperative 1d, 3d, 5 d (P < 0.05). The overall incidence of adverse reactions and complications in subjects in group B was 17.5% significantly lower than that in groups A and C (P < 0.05). CONCLUSION: Dexmedetomidine can effectively improve the sleep disorder of elderly general anesthesia patients, reduce the damage to their neurocognitive function and the occurrence of POD, effectively reduce the anxiety of patients and the occurrence of adverse reactions and complications, and has better sedative, improve postoperative cognitive function and anti-anxiety effects, with a high drug safety, worthy of clinical application and promotion.

Liquid nitric oxide donor for adjuvant therapy of acute ischemic stroke via nasal administration.

OBJECTIVES: The aim of this study was to synthesize and characterize a novel NO donor, PEI-PO-NONOate, using propylene oxide and to investigate its biosafety and therapeutic efficacy via nasal administration in vitro and vivo. EXPERIMENTAL PROCEDURES: The PEI-PO-NONOate was synthesized based on polyethylenimine (PEI) with different molecular weights and characterized using Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), and ultraviolet (UV) spectroscopy. Cytotoxicity assays were performed on mouse fibroblast cells L929 and human nasal mucosa epithelial cells (HNEpC), and a rat middle cerebral artery occlusion (MCAO) model was established to evaluate the therapeutic efficacy of PEI-PO-NONOate via nasal administration. RESULTS: The PEI-PO-NONOate was found to be stable under dark, dry, and airproof conditions, and its release was accelerated in an aqueous phase or acidic environment, while it was slowed down in a polyethylene glycol (PEG) mixture system. The NO donor released approximately 0.4, 0.5, and 0.6 µmol of gaseous NO from 1.0 mg of the polymer based on PEI600, PEI1800, and PEI10K, respectively. Cytotoxicity assays showed that the PEI-PO-NONOates had a cryoprotective effect as compared with PEI and PEI-PO. Furthermore, nasal administration of PEI-PO-NONOates resulted in a significant reduction in overall necrotic ratio as compared with the control group (16.4% versus 24.6%, p < 0.05). CONCLUSION: The findings of this study suggest that PEI-PO-NONOates may have potential as an adjuvant therapy for acute ischemic stroke when administered via the nasal route.

Intranasal therapeutic vaccine containing HBsAg and HBcAg for patients with chronic hepatitis B; 18 months follow-up results of phase IIa clinical study.

AIMS: HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device. METHODS: A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18 months, and their HBsAg reduction and anti-HBs induction assessed as endpoints. RESULTS: Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 log10  IU/ml (p < 0.05) and -0.2677 log10  IU/ml (p < 0.05), respectively. Anti-HBs antibody was detected in 40.7% and 58.3% of patients treated with and without NAs, respectively. Six of 71 (9.5%) patients were functionally cured after the CVP-NASVAC treatment. CONCLUSIONS: Anti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB.

Lipid nanocapsules for the nose-to-brain delivery of the anti-inflammatory bioactive lipid PGD2-G.

Here, prostaglandin D2-glycerol ester (PGD2-G) was selected to target neuroinflammation. As PGD2-G is reported to have a short plasmatic half-life, we propose to use lipid nanocapsules (LNC) as vehicle to safely transport PGD2-G to the central nervous system (CNS). PGD2-G-loaded LNC (PGD2-G-LNC) reduced pro-inflammatory cytokine expression in activated microglial cells, even so after crossing a primary olfactory cell monolayer. A single nasal administration of PGD2-G-LNC in lipopolysaccharide (LPS)-treated mice reduced pro-inflammatory cytokine expression in the olfactory bulb. Coating LNC's surface with a cell-penetrating peptide, transactivator of transcription (TAT), increased its accumulation in the brain. Although TAT-coated PGD2-G-LNC modestly exerted its anti-inflammatory effect in a mouse model of multiple sclerosis similar to free PGD2-G after nasal administration, TAT-coated LNC surprisingly reduced the expression of pro-inflammatory chemokines in the CNS. These data propose LNC as an interesting drug delivery tool and TAT-coated PGD2-G-LNC remains a good candidate, in need of further work.

Nasal administration of diacetylmorphine improved the adherence in a patient receiving heroin-assisted treatment.

BACKGROUND: Traditional heroin-assisted treatment in Switzerland consists of oral and injectable diacetylmorphine (pharmaceutical heroin) administration. To date, no suitable treatment option is available for patients who crave rapid onset ("rush") but are either unable to inject or primarily sniff or inhale illicit heroin. We present a patient who successfully switched to intranasal heroin-assisted treatment following several unsuccessful treatment attempts. CASE PRESENTATION: A 29-year-old male with severe opioid use disorder, injection substance use, and concomitant cocaine use, previously prescribed slow-release oral morphine, was started on intravenous diacetylmorphine. Due to complications and harms associated with intravenous injections, nasal diacetylmorphine was prescribed. With this novel route of administration, the patient who had previously been unable to adhere to other OAT options remained in treatment. Health outcomes improved by reduction of injection-related harms, increased adherence to the heroin-assisted treatment regimen, and increased collaboration with the therapeutic staff. CONCLUSIONS: Nasal heroin-assisted treatment can be a feasible therapeutic option for individuals with severe opioid use disorder who crave the fast onset of effect of diacetylmorphine but are unable to inject intravenously.

Preparation, In Vitro and In Vivo Evaluation of Nanoemulsion In Situ Gel for Transnasal Delivery of Traditional Chinese Medicine Volatile Oil from Ligusticum sinense Oliv.cv. Chaxiong.

Ischemic stroke is a difficult-to-treat brain disease that may be attributed to a limited therapeutic time window and lack of effective clinical drugs. Nasal-brain administration is characterized by low systemic toxicity and is a direct and non-invasive brain targeting route. Preliminary studies have shown that the volatile oil of Chaxiong (VOC) has an obvious anti-ischemic stroke effect. In this work, we designed a nanoemulsion thermosensitive in situ gel (VOC-NE-ISG) loaded with volatile oil of Chaxiong for ischemia via intranasal delivery to rat brain treatment of cerebral ischemic stroke. The developed VOC-NE-ISG formulation has a suitable particle size of 21.02 ± 0.25 nm and a zeta potential of -20.4 ± 1.47 mV, with good gelling ability and prolonged release of the five components of VOC. The results of in vivo pharmacokinetic studies and brain targeting studies showed that intranasal administration of VOC-NE-ISG could significantly improve the bioavailability and had excellent brain-targeting efficacy of nasal-to-brain delivery. In addition, the results of pharmacodynamics experiments showed that both VOC-NE and VOC-NE-ISG could reduce the neurological deficit score of model rats, reducing the size of cerebral infarction, with a significant effect on improving ischemic stroke. Overall, VOC-NE-ISG may be a promising intranasal nanomedicine for the effective treatment of ischemic stroke.

Enhanced Influenza Immunity by Nasal Mucosal Administration of the TPGS-Modified Liposomal Vaccine.

Influenza infection is difficult to prevent, control, and treat because of rapid viral mutation, fast disease progression, and high mortality. Vaccination is the main means by which to prevent and control influenza, but effectiveness is limited in that poor cellular uptake and weak immunogenicity of vaccines provides less than optimal host protection. Liposomal influenza vaccines are a promising strategy to overcome these limitations and the use of liposomal immune modulators and intranasal administration of liposomal influenza vaccines may be a means by which to improve influenza protection. The cationic lipids, i.e., dimethyldioctadecylammonium (DDA), 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC), and D-α-tocopherol polyethylene glycol 1000 (TPGS) can form blank liposomes, which can incorporate influenza antigens to produce an influenza vaccine (DDA-DSPC-TPGS). Herein, this vaccine was shown to induce dendritic cell maturation, increase host cellular uptake of the vaccine, and enhance immune responses both in vitro and in vivo. The addition of TPGS, as an amphiphilic immune adjuvant, significantly reduced the toxicity of the DDA liposomal influenza vaccine. Further, the polyethylene glycol component and tocopherol structure of TPGS enhanced the cellular uptake of the vaccine by means of stealth properties and the capacity to inhibit cellular efflux. After nasal mucosal immunization, enhanced cellular uptake rates and abundant immune cells in the nasopharyngeal-associated lymphoid tissue promoted the production of immunoglobulin A, immunoglobulin G1, and interferon-γ, which in turn mediated a more robust immune response against influenza virus. In summary, the DDA-DSPC-TPGS influenza vaccine is a safe and effective means by which to activate the immune system. The results herein provide an effective strategy by which to overcome current difficulties associated with the prevention and treatment of influenza.

[Applying Chitosan-Modified Nanoemulsion in Nasal Vaccine Delivery].

OBJECTIVE: To prepare a chitosan-modified cationic nanoemulsion that could be used to prolong the residence time of nasal vaccines in the nasal cavity and improve the cellular uptake efficiency so as to enhance the immune efficacy of nasal vaccines. METHODS: A nanoemulsion-based vaccine coated with chitosan was prepared, and the particle size, potential, antigen encapsulation efficiency, stability as well as cytotoxicity were examined. The uptake efficiency of vaccine on different cells and the residence time of vaccine in the nasal cavity were measured. Finally, nasal vaccine was administered on mice and the antibody levels in the serum and in the nasal lavage fluids of the immunized mice were examined. RESULTS: The nanoemulsion-based vaccine had an average particle size of (167.2±0.75) nm, a polydispersity index (PDI) of 0.21±0.01, and an average potential of (13.7±0.85) mV. The encapsulation efficiency of antigen was 92.7%. The nanoemulsion-based vaccine had good stability and did not show obvious cytotoxicity in Madin-Darby canine kidney (MDCK) epithelial cells. The vaccine demonstrated relatively high cellular uptake of antigens on DC2.4 and MDCK cells at (49.7±3.45)% and (59.7±2.19)%, respectively. Besides, the cationic nanoemulsion also significantly increased the residence time of the antigen, and a considerable amount of nanoemulsion-based vaccine was found remaining in the nasal cavity 60 minutes after administration. Compared with free antigen and the nanoemulsion without chitosan modification, the chitosan-modified nanoemulsion vaccine induced higher systemic and mucosal antibody levels in mice after nasal immunization ( P<0.01). CONCLUSION: The chitosan-modified nanoemulsion vaccine prepared in the study can enhance the immune efficacy of nasal vaccines, showing great potential to be used as a delivery carrier for nasal vaccines.

[Study on nasal absorption of Cistanche deserticola phenylethanol glycosides nanoemulsion in vivo].

To investigate the transnasal absorption characteristics of Cistanche deserticola phenylethanol glycosides nanoemulsion and its influencing factors. With the use of the classic in vivo nasal circulation perfusion model in rats, the absorption rate constant was used as the index to compare the nasal absorption characteristics of C. deserticola phenylethanol glycosides nanoemulsion and its aqueous solution in different concentrations, and to explore the effects of pH value of the preparation and absorption accelerator Azone on the nasal absorption of C. deserticola phenylethanol glycosides nanoemulsion. The results showed that, as compared with the aqueous solution group, the absorption rate constant was significantly higher in C. deserticola phenylethanol glycosides nanoemulsion with the same concentration(P<0.05), and C. deserticola phenylethanol glycosides nanoemulsion was more easily absorbed by the nasal cavity of rats; with the increase of the concentration of C. deserticola phenylethanol glycosides, the transnasal absorption amount of nanoemulsion was also increased in a dose-dependent manner. When the pH value of nanoemulsion was 6.0 and the ratio of Azone was 2%, the absorption rate constant was highest and the effect of promoting infiltration was the best.

Oxytocin delivered nasally or intraperitoneally reaches the brain and plasma of normal and oxytocin knockout mice.

Intranasal delivery of oxytocin (Oxt) has been identified as a potential therapeutic to target human conditions characterized by social deficits, yet the ability of this administrative route to deliver to the brain is unconfirmed. Oxt knockout (Oxt KO) and wildtype C57BL/6 J male mice received Oxt (12 µg total amount) either by nasal or intraperitoneal administration. Oxt concentrations were monitored for 2 h after administration in circulation via a jugular vein catheter and in the brain by two intracerebral microdialysis probes. Group sizes varied from 4 to 7 mice (n = 22 total). We document for the first time that Oxt applied to the nasal mucosa after nasal administration is delivered to the extracellular fluid in the brain. After nasal application, Oxt concentrations in circulation and in the extracellular fluid of the amygdala and, to an extent, the dorsal hippocampus, rose within the first 30 min and remained elevated for the subsequent hour. These findings were confirmed in an Oxt KO mouse line, establishing that the circulating and brain Oxt elevations derive from the administered dose. Interestingly, the pharmacokinetics of Oxt were slightly biased to the brain after nasal administration and to the periphery following intraperitoneal injection. No change in vasopressin levels was detected. These findings have stimulating implications for the interpretation of various behavioral and physiological effects described in animal and human studies after nasal administration of Oxt and provide the pharmacokinetics necessary to develop this drug delivery route for therapeutic purposes.

HPLC-UV method for temozolomide determination in complex biological matrices: Application for in vitro, ex vivo and in vivo studies.

A high-performance liquid chromatography method for temozolomide (TMZ) determination in complex biological matrices was developed and validated for application in in vitro, ex vivo and in vivo studies of new nanotechnology-based systems for TMZ nasal delivery. The method was able to quantify TMZ in nanoemulsions, following cellular uptake, in the porcine nasal mucosa and in mouse plasma and brain. Analyses were performed on a C18 column at 35°C, under UV detection at 330 nm. The mobile phase was methanol-acetic acid 0.5% (30:70, v/v), eluted at an isocratic flow rate of 1.1 mL/min. The method was found to be specific, precise, accurate, robust and linear (0.05 to 5 µg/mL) for TMZ determination in all matrices. No interference of TMZ degradation products was found under various stress conditions such as acidic, alkaline, oxidative, light and thermal exposure, demonstrating stability. The method was applied for the quantification of TMZ in different matrices, i.e. the efficiency of nanoemulsions in vitro in increasing TMZ cellular uptake, ex vivo TMZ permeation and retention in the porcine nasal mucosa tissue, and for in vivo TMZ quantification in mouse brain following intranasal nanoemulsion administration compared with free TMZ.

A Nasal Temperature and pH Dual-Responsive In Situ Gel Delivery System Based on Microemulsion of Huperzine A: Formulation, Evaluation, and In Vivo Pharmacokinetic Study.

Huperzine A (hup A), extracted from the Chinese medicinal plant Huperzia serrata, is a reversible and highly selective second-generation acetylcholine esterase (AchE) inhibitor for treating Alzheimer's disease (AD), but it suffers from low bioavailability in the brain. This study aimed to develop a nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of hup A (hup A-M-TPISG). The optimal formulation was obtained by central composite design and response surface methodology. The optimized mucoadhesive formulation, hup A-M-TPISG, was composed of pluronic F127 (20.80%), pluronic F68 (2.8%), and chitosan (0.88%) as the gel matrix, which could gelatinize under physiological conditions (29-34°C, pH 6.5) because of its temperature and pH responsiveness. The optimized hup A-M-TPISG formulation was further evaluated by in vitro release and in vivo pharmacokinetic studies via microdialysis. The in vitro release study showed continuous and steady drug release from hup A-M-TPISG, which was in accordance with the first-order model. Moreover, the pharmacokinetic results revealed that the optimized formulation for nasal administration, with convenient administration and improved patient compliance, could achieve similar brain-targeting properties as intravenous administration. In conclusion, the hup A-M-TPISG for intranasal administration, as an effective and safe vehicle, could enhance the absorption of hup A in vivo and would be a promising noninvasive alternative for partially improving brain-targeting therapy.

Nasal Administration of Cationic Nanoemulsions as Nucleic Acids Delivery Systems Aiming at Mucopolysaccharidosis Type I Gene Therapy.

PURPOSE: This study demonstrates the nasal administration (NA) of nanoemulsions complexed with the plasmid encoding for IDUA protein (pIDUA) as an attempt to reach the brain aiming at MPS I gene therapy. METHODS: Formulations composed of DOPE, DOTAP, MCT (NE), and DSPE-PEG (NE-PEG) were prepared by high-pressure homogenization, and assessed in vitro on human fibroblasts from MPS I patients and in vivo on MPS I mice for IDUA production and gene expression. RESULTS: The physicochemical results showed that the presence of DSPE-PEG in the formulations led to smaller and more stable droplets even when submitted to dilution in simulated nasal medium (SNM). In vitro assays showed that pIDUA/NE-PEG complexes were internalized by cells, and led to a 5% significant increase in IDUA activity, besides promoting a two-fold increase in IDUA expression. The NA of pIDUA/NE-PEG complexes to MPS I mice demonstrated the ability to reach the brain, promoting increased IDUA activity and expression in this tissue, as well as in kidney and spleen tissues after treatment. An increase in serum IL-6 was observed after treatment, although with no signs of tissue inflammatory infiltrate according to histopathology and CD68 assessments. CONCLUSIONS: These findings demonstrated that pIDUA/NE-PEG complexes could efficiently increase IDUA activity in vitro and in vivo after NA, and represent a potential treatment for the neurological impairment present in MPS I patients.

Evaluation of brain targeting in rats of Salvianolic acid B nasal delivery by the microdialysis technique.

The purpose of this study was to investigate the biodistribution of Salvianolic acid B in rats blood and brain after intranasal administration and explore its feasibility and evaluate its brain targeting effect. The concentration of Salvianolic acid B in blood and brain following nasal administration (32 mgckg-1) was measured combining with microdialysis sampling and liquid chromatograph-mass spectrometer/MS detection technology. After the microdialysis samples were corrected with in vivo recoveries, the pharmacokinetic parameters were obtained by using non-compartment model and the brain targeting evaluated by the value of drug targeting index (DTI). The Cmax in blood and brain by intravenous injection were higher than intranasal administration, but the intranasal administration of MRT0-∞ significantly prolonged and increased by nearly 2.03 and 1.86 times, respectively. The DTI value of Salvianolic acid B was 5.54 and bioavailability (F) was 43.98%. After nasal administration of Salvianolic acid B, it has a certain brain targeting, which could become a new drug system for the treatment of brain diseases.

Development and Evaluation of pH-Responsive Cyclodextrin-Based in situ Gel of Paliperidone for Intranasal Delivery.

Paliperidone (PLPD) is approved for treatment and management of schizophrenia. The current study demonstrates the potential of in situ gel of PLPD for nasal delivery. The permeation of drug through sheep nasal mucosa was analyzed since the nose-to-brain pathway has been indicated for delivering drugs to the brain. The carbopol 934 (CP)- and hydroxypropyl methyl cellulose K4M (HPMC)-based in situ gels containing 0.2% CP and 0.4% w/v HPMC were optimized using experimental design software. The use of hydroxypropyl-ß-cyclodextrin (HP-ß-CD) in nasal permeation of drug was investigated. Transmucosal permeation of PLPD was examined using sheep nasal mucosa. The in situ gels of PLPD exhibited satisfactory mucoadhesion and showed sustained drug release. The mucocilliary toxicity and histopathological examination confirmed that the nasal mucosa architecture remains unaffected after treatment with PLPD in situ gel. The formulation containing HP-ß-CD complex of PLPD exhibited higher rate of drug permeation through sheep nasal mucosa revealing the role of HP-ß-CD as nasal absorption enhancer. Thus, CP- and HPMC-based pH-triggered in situ gel containing HP-ß-CD-drug inclusion complex demonstrates a novel nasal delivery of PLPD.

Nasal administration of leptin dose-dependently increases dopamine and serotonin outflow in the rat nucleus accumbens.

Leptin is an anorexigenic hormone that acts via its receptor (LepR) to regulate the hypothalamic arcuate nucleus circuitry to mediate energy homeostasis and feeding behavior. Moreover, leptin decreases the reward value of natural and artificial rewards, and low levels of circulating leptin have been implicated in several mood disorders linking leptin to the mesolimbic system. Therefore, the purpose of this study was to assess whether and to what extent an acute intranasal application of leptin is able to modulate monoamine neurotransmitters in the nucleus accumbens (NAc). Microdialysis experiments were carried out in freely moving Wistar rats and in LepR-deficient Zucker rats (LepRfa/fa). Samples were analysed for the levels of dopamine (DA), serotonin (5-HT), and their metabolites using high-performance liquid chromatography with electrochemical detection. We show that in Wistar rats, nasal application of leptin dose-dependently increased extracellular DA and 5-HT levels in the NAc. By contrast, in the LepRfa/fa rats, nasal application of 0.12 mg/kg leptin failed to increase levels of either DA or 5-HT, but their metabolites (DOPAC and HIAA, respectively) were significantly decreased. In addition, leptin interaction with the melanocortin system was tested. Nasal co-administration of leptin and the melanocortin receptor antagonist, SHU9119, completely abolished the leptin-induced increase of both DA and 5-HT outflow in the NAc. These results indicate a marked leptin effect on the basal ganglia-related reward system involving melanocortin receptors.

Nerve growth factor and autophagy: effect of nasal anti-NGF-antibodies administration on Ambra1 and Beclin-1 expression in rat brain.

Nerve growth factor (NGF) exerts protective actions in the healthy and diseased nervous system. Intranasal administration is a suitable and safe strategy to deliver NGF to CNS neurons. We investigated whether nasal anti-NGF-antibody (ANA) administration affects neuronal autophagy, in view of its putative regulatory role in this process. We focused on olfactory bulbs (OB), neocortex (Cx), hippocampus (HF) and septal complex (SC), known to be NGF-responsive and autophagically active. Our combined molecular/morphological results demonstrate that intranasally administered ANA reaches brain NGF-target neurons and lowers the levels of endogenous NGF and its receptors. Treatment also affects - in a brain region-dependent manner - the expression of the autophagic proteins Beclin-1 and Ambra1, as well as that of proteins belonging to the Bcl2 family, namely Bax and Bcl-2, reflecting apoptotic dysregulation. This study provides a nongenetically modified, NGF-defective animal model, representing a suitable tool to investigate novel properties of the neurotrophin, especially in relation to autophagy.

Systemic absorption of nasally administered tobramycin and colistin in patients with cystic fibrosis.

OBJECTIVES: In cystic fibrosis (CF) patients the paranasal sinuses can constitute a niche for bacteria, which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. The objective of this study was to investigate the systemic absorption of nasally administered tobramycin, colistin (administered as colistin sulfomethate sodium; CMS) and a combination of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined. METHODS: Ten adult CF patients performed three different nasal irrigations: 300 mg of tobramycin; 160 mg of CMS; and 300 mg of tobramycin combined with 160 mg of CMS. Serum concentrations of tobramycin and colistin A and B (the main components of colistin) were analysed. Tolerability was measured using a visual analogue scale. Dutch Trial Register: NTR 4008. RESULTS: Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable. All three nasal irrigation solutions were well tolerated with a higher tolerability for CMS compared with tobramycin. CONCLUSIONS: Nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated.

Intranasal dopamine treatment reinstates object-place memory in aged rats.

Following oral or IV administration, dopamine (DA) cannot cross the blood-brain barrier to a significant extent, but can enter the brain when administered via the nasal passages. Intranasal administration of DA was shown to increase extracellular DA in the striatum, to have antidepressant action and to improve attention and working memory in rats. Here we show that aged (22-24 months old) rats are deficient in an object-place learning task, but that this learning/memory is intact and comparable with that of adult rats upon pre-trial administration of 0.3 mg/kg DA gel into the nasal passages. This result raises the possibility of the therapeutic application of intranasal DA treatment for age-related cognitive disorders.