Objective The prevalence of drug-resistant Mycobacterium tuberculosis (Mtb) strains is exacerbating the global burden of tuberculosis (TB), highlighting the urgent need for new treatment strategies for TB. Methods The recombinant adenovirus vaccine expressing cyclic di-adenosine monophosphate (c-di-AMP) phosphodiesterase B (CnpB) (rAd-CnpB), was administered to normal mice via mucosal immunization, either alone or in combination with drug therapy, to treat Mtb respiratory infections in mice.Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of antibodies in serum and bronchoalveolar lavage fluid (BALF). Real-time quantitative PCR was performed to assess the transcription levels of cytokines interferon γ(IFN-γ) and interleukin 10(IL-10) in mouse lungs. Flow cytometry was used to determine the proportions of CD4⁺ and CD8⁺ T cell subsets in the lungs and spleens. ELISA was employed to measure the levels of cytokines IFN-γ, IL-2, IL-10, inflammatory factors IL-6, and tumor necrosis factor α (TNF-α) secreted by spleen cells following antigen stimulation. The bacteria loads in the lungs and spleens of Mtb-infected mice were enumerated by plate counting methods. Resluts Intranasal immunization with rAd-CnpB induced high titers of IgG in mouse serum and the production of IgG and IgA in BALF, along with alterations in T lymphocyte subsets in the lungs and spleens. Administration of rAd-CnpB, either alone or in combination with drugs, to Mtb-infected mice significantly increased serum IgG levels as well as IgA and IgG levels in BALF. rAd-CnpB immunization promoted the secretion of CnpB-specific cytokines and inflammatory factors by splenocytes in Mtb-infected mice. However, rAd-CnpB immunotherapy, either alone or combined with drugs, did not significantly affect the bacterial loads in the lungs and spleens of mice with Mtb respiratory infections. Conclusion Mucosal immunization with rAd-CnpB induced significant mucosal, humoral and cellular immune responses in mice, and significantly enhanced CnpB-specific cellular immune responses in Mtb-infected mice.
Animals ; Adenoviridae/immunology* ; Mycobacterium tuberculosis/genetics* ; Mice ; Female ; Phosphoric Diester Hydrolases/genetics* ; Tuberculosis Vaccines/administration & dosage* ; Tuberculosis/prevention & control* ; Mice, Inbred BALB C ; Cytokines ; Lung/microbiology* ; Immunization ; Bronchoalveolar Lavage Fluid/immunology* ; Immunity, Mucosal

Objective:To investigate the efficacy and assess the safety of transnasal nebulisation of budesonide in children with adenoid hypertrophy. Methods:Children with adenoid hypertrophy who attended the Children's Hospital of Zhejiang University School of Medicine between December 2021 and December 2022 were randomly assigned to budesonide high-dose group（Group A: budesonide 1 mg/dose + saline nasal rinse）, budesonide low-dose group（Group B: budesonide 0.5 mg/dose + saline nasal rinse）, and control group（Group C: saline nasal rinse）, and each group 20 children were collected separately, The efficacy and safety of transnasal nebulisation of budesonide in children with adenoid hypertrophy were assessed by comparing the symptomatic VAS scores, adenoidal nasopharyngeal lateral radiographs A/N values, nocturnal sleep oximetry（SaO2）, and the incidence of adverse events during the treatment period of 8-week in the three groups. Results:The 8-week baseline differences in adenoid A/N values were statistically different between groups A and B（P<0.001） and A and C（P=0.022）, with the reduced amount in adenoid volume being most pronounced in group A, which differed from the other two groups. With the increase of intervention time, SaO2 levels gradually increased（F=154.725, P<0.001） and VAS scores gradually decreased（F=165.616, P<0.001） in all three groups. After 8 weeks of treatment, there was no statistically significant difference in SaO2 level（P=0.085） between groups A and B. There was a statistically significant difference in VAS total scores between Group A and Group B （P < 0.05） . The improvement of SaO2and total VAS score in group A was higher than that in group B. There was a statistically significant difference in the comparison of SaO2 level and total VAS score between groups A and B, and between groups A and C（P<0.01）; after the intervention of the three groups, showing the greatest improvement of total VAS score and SaO2in the group A, followed by Group B. There was no statistically significant difference in the incidence of adverse events among Groups A, B, and C throughout the trial. Conclusion:The treatment of children with adenoid hypertrophy by intranasal nebulisation of budesonide suspension has good efficacy and safety, which is conducive to reducing the size of adenoids, improving the clinical symptoms of children with adenoid hypertrophy, and improving the SaO2of nocturnal sleep, and it has a certain clinical application value.
Humans ; Budesonide/administration & dosage* ; Adenoids ; Child ; Male ; Female ; Hypertrophy ; Nebulizers and Vaporizers ; Treatment Outcome ; Administration, Intranasal ; Child, Preschool

Tripterygium glycosides liposome(TPGL) were prepared by thin film-dispersion method, which were optimized accor-ding to their morphological structures, average particle size and encapsulation rate. The measured particle size was(137.39±2.28) nm, and the encapsulation rate was 88.33%±1.82%. The mouse model of central nervous system inflammation was established by stereotaxic injection of lipopolysaccharide(LPS). TPGL and tripterygium glycosides(TPG) were administered intranasally for 21 days. The effects of intranasal administration of TPG and TPGL on behavioral cognitive impairment of mice due to LPS-induced central ner-vous system inflammation were estimated by animal behavioral tests, hematoxylin-eosin(HE) staining of hippocampus, real-time quantitative polymerase chain reaction(RT-qPCR) and immunofluorescence. Compared with TPG, TPGL caused less damage to the nasal mucosa, olfactory bulb, liver and kidney of mice administered intranasally. The behavioral performance of treated mice was significantly improved in water maze, Y maze and nesting experiment. Neuronal cell damage was reduced, and the expression levels of inflammation and apoptosis related genes [tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), BCL2-associated X(Bax), etc.] and glial activation markers [ionized calcium binding adaptor molecule 1(IBA1) and glial fibrillary acidic protein(GFAP)] were decreased. These results indicated that liposome technique combined with nasal delivery alleviated the toxic side effects of TPG, and also significantly ameliorated the cognitive impairment of mice induced by central nervous system inflammation.
Mice ; Animals ; Tripterygium ; Liposomes ; Glycosides/therapeutic use* ; Administration, Intranasal ; Lipopolysaccharides ; Central Nervous System ; Cognitive Dysfunction/drug therapy* ; Inflammation/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Cardiac Glycosides

Intranasal drug delivery system is a non-invasive drug delivery route with the advantages of no first-pass effect, rapid effect and brain targeting. It is a feasible alternative to drug delivery via injection, and a potential drug delivery route for the central nervous system. However, the nasal physiological environment is complex, and the nasal delivery system requires "integration of medicine and device". Its delivery efficiency is affected by many factors such as the features and formulations of drug, delivery devices and nasal cavity physiology. Some strategies have been designed to improve the solubility, stability, membrane permeability and nasal retention time of drugs. These include the use of prodrugs, adding enzyme inhibitors and absorption enhancers to preparations, and new drug carriers, which can eventually improve the efficiency of intranasal drug delivery. This article reviews recent publications and describes the above mentioned aspects and design strategies for nasal intranasal drug delivery systems to provide insights for the development of intranasal drug delivery systems.
Administration, Intranasal ; Drug Delivery Systems ; Pharmaceutical Preparations ; Drug Carriers ; Brain ; Nasal Cavity/physiology* ; Nasal Mucosa

Objective:To observe the efficacy and safety of the M receptor antagonist Bencycloquidium bromide nasal spray in treatment of seasonal allergic rhinitis with runny nose as the main symptom. Methods:From August 2021 to September 2021, 134 patients with seasonal allergic rhinitis were enrolled in the otolaryngology Outpatient Department of Peking University Third Hospital, First Affiliated Hospital of Harbin Medical University and China-Japanese Friendship Hospital of Jilin University, including 71 males and 63 females, with a median age of 38 years. TNSS score and visual analogue scale（VAS） of total nasal symptoms were observed during 2 weeks of treatment with Bencycloquidium bromide nasal spray. Results:TNSS score decreased from （8.89±3.31） on day 0 to （3.71±2.51） on day 14（P<0.001）, VAS score of nasal symptoms decreased from （24.86±7.40） on day 0 to （6.84±5.94） on day 14（P<0.001）, VAS score of rhinorrhoea decreased from （6.88±2.06） on day 0 to （1.91±1.81） on day 14（P<0.001）. Rhinoconjunctivitis quality of life questionnaire（RQLQ） score decreased from （94.63±33.35） on day 0 to （44.95±32.28） on day 14（P<0.001）. The incidence of adverse reaction was low and no serious adverse events occurred during the whole experiment. Conclusion:Bencycloquidium bromide nasal spray has significant efficacy and good safety in the treatment of seasonal allergic rhinitis.
Male ; Female ; Humans ; Adult ; Rhinitis, Allergic, Seasonal/drug therapy* ; Nasal Sprays ; Quality of Life ; Administration, Intranasal ; Rhinorrhea ; Double-Blind Method ; Treatment Outcome ; Rhinitis, Allergic/drug therapy*

Adaptation, Physiological ; Adenosine Monophosphate ; administration & dosage ; analogs & derivatives ; pharmacology ; therapeutic use ; Administration, Intranasal ; Alanine ; administration & dosage ; analogs & derivatives ; pharmacology ; therapeutic use ; Animals ; Betacoronavirus ; genetics ; physiology ; Chlorocebus aethiops ; Coronavirus Infections ; drug therapy ; virology ; Disease Models, Animal ; Female ; Host Specificity ; genetics ; Lung ; pathology ; virology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mutation, Missense ; Nasal Mucosa ; virology ; Pandemics ; Pneumonia, Viral ; drug therapy ; virology ; RNA, Viral ; administration & dosage ; genetics ; Turbinates ; virology ; Vero Cells ; Viral Load ; Virus Replication

OBJECTIVE: To compare the median effective dose (ED) of intranasal dexmedetomidine for procedural sedation in uncooperative pediatric patients with acyanotic congenital heart disease before and after cardiac surgery. METHODS: We prospectively recruited 47 children (22 in preoperative group and 25 in postoperative group) who needed sedation for transthoracic echocardiography (TTE). A modified up-and-down sequential study design was employed to determine dexmedetomidine dose for each patient with a starting dose of 2 μg/kg in both groups; dexmedetomidine doses for subsequent subjects were determined according to the responses from the previous subject using the up-and-down method at a 0.25 μg/kg interval. The ED was determined using probit regression. The onset time, examination time, wake-up time and adverse effects were measured, and the safety was evaluated in terms of changes in vital signs every 5 min. RESULTS: The ED value of intranasal dexmedetomidine for sedation was 1.84 μg/kg (95% : 1.68-2.00 μg/kg) in children with congenital heart disease before cardiac surgery, and 3.38 μg/kg (95% : 3.21-3.54 μg/kg) after the surgery. No significant difference was found between the two groups in the demographic variables, onset time, examination time, wake-up time, or adverse effects. CONCLUSIONS In children with acyanotic congenital heart disease, the ED of intranasal dexmedetomidine for TTE sedation increases to 3.38 μg/ kg after cardiac surgery from the preoperative value of 1.84 μg/kg.
Administration, Intranasal ; Cardiac Surgical Procedures ; Child ; Dexmedetomidine ; Heart Defects, Congenital ; surgery ; Humans ; Hypnotics and Sedatives

Curcumin( Cur) is a natural active substance extracted from the roots or tubers of traditional Chinese medicinal materials. It has anti-inflammatory and anti-tumor activities on brain diseases. Due to the poor stability,low solubility,poor absorption and low bioavailability of curcumin,N-acetyl-L-cysteine( NAC) was used as an absorption enhancer and mixed with curcumin to improve the absorption of curcumin in the body. In this paper,curcumin was smashed by airflow pulverization,and Cur-NAC mixtures were prepared by being grinded with liquid. Then,the raw material and the product were analyzed by differential scanning calorimetry( DSC),X-ray diffraction( XRD) for structural characterization. The dissolution was determined by high performance liquid chromatography( HPLC) analysis. The characteristic peaks of the samples prepared by grinding method were similar to those of the raw materials,while the melting temperature and the accumulated dissolution degree were not significantly changed. The crystal forms of the products were not changed,and no new crystal form was formed after grinding. After the administration of intranasal powder,blood samples were collected from the orbit,while the whole brain tissues were removed from the skull and dissected into 10 anatomical regions. The concentrations of curcumin in these samples were determined by UPLC-MS/MS. The concentrations of curcumin in plasma and brain were compared at different time points. After intranasal administration of two drugs,it was found that the concentration of curcumin after sniffing up the mixtures in plasma was high,and the concentration of the drug in the olfactory bulb,hippocampus,and pons was increased significantly. Within 0. 083-0. 5 h,the olfactory bulb,piriform lobe and hippocampus remained high concentrations,the endodermis,striatum,hypothalamus and midbrain reached high concentrations within 1-3 h; and the cerebellum,pons and brain extension maintained relatively high concentrations within 3-7 h. The experiment showed that nasal administration of Cur-NAC mixtures can significantly improve the bioavailability of curcumin,and lead to significant differences in brain tissue distribution.
Acetylcysteine ; pharmacology ; Administration, Intranasal ; Animals ; Biological Availability ; Brain ; Brain Chemistry ; Chromatography, Liquid ; Curcumin ; pharmacokinetics ; Rats ; Tandem Mass Spectrometry ; Tissue Distribution

OBJECTIVE: To evaluate the effect of intranasal immunization with CTA1-DD as mucosal adjuvant combined with H3N2 split vaccine. METHODS: Mice were immunized intranasally with PBS (negative control), or H3N2 split vaccine (3 μg/mouse) alone, or CTA1-DD (5 μg/mouse) alone, or H3N2 split vaccine (3 μg/mouse) plus CTA1-DD (5 μg/mouse). Positive control mice were immunized intramuscularly with H3N2 split vaccine (3 μg/mouse) and alum adjuvant. All the mice were immunized twice, two weeks apart. Then sera and mucosal lavages were collected. The specific HI titers, IgM, IgG, IgA, and IgG subtypes were examined by ELISA. IFN-γ and IL-4 were test by ELISpot. In addition, two weeks after the last immunization, surivival after H3N2 virus lethal challenge was measured. RESULTS: H3N2 split vaccine formulated with CTA1-DD could elicit higher IgM, IgG and hemagglutination inhibition titers in sera. Furthermore, using CTA1-DD as adjuvant significantly improved mucosal secretory IgA titers in bronchoalveolar lavages and vaginal lavages. Meanwhile this mucosal adjuvant could enhance Th-1-type responses and induce protective hemagglutination inhibition titers. Notably, the addition of CTA1-DD to split vaccine provided 100% protection against lethal infection by the H3N2 virus. CONCLUSION CTA1-DD could promote mucosal, humoral and cell-mediated immune responses, which supports the further development of CTA1-DD as a mucosal adjuvant for mucosal vaccines.
Adjuvants, Immunologic ; Administration, Intranasal ; Animals ; Cholera Toxin ; Female ; Immunity, Humoral ; Influenza A Virus, H3N2 Subtype ; immunology ; Influenza Vaccines ; Mice, Inbred BALB C ; Nasal Mucosa ; immunology ; Random Allocation ; Recombinant Fusion Proteins

OBJECTIVE: To investigate the value of neoadjuvant chemoradiotherapy (nCRT) combined with total pelvic exenteration (TPE) in the treatment of primary T4b rectal cancer. METHODS: A retrospective cohort study was conducted to analyze the clinicopathological data of 31 patients with primary T4b rectal cancer who underwent TPE from January 2008 to December 2015 at Peking University First Hospital. INCLUSION CRITERIA: preoperative clinical stage (cTNM) was defined as cT4b primary rectal cancer with only front wall Invasion; the lower edge of tumor was within 10 cm from the anal margin; TPE was performed; R0 resection was confirmed by pathology. Patients with recurrent rectal cancer, distant metastasis, and undergoing TPE for non-rectal tumors were excluded. Patients were divided into nCRT group and non-nCRT group according to whether receiving nCRT before surgery. The nCRT group received long course radiotherapy (total dose 50 Gy in 25 daily fractions) with concomitant chemotherapy (Capecitabine), and the surgery was performed 6-8 weeks after the neoadjuvant chemoradiation, while the non-nCRT group received surgery directly. The intraoperative, postoperative and pathological conditions and local recurrence were compared between the two groups. The survival curves were drawn by Kaplan-Meier method and the survival of two groups were compared. RESULTS: A total of 31 patients were enrolled, including 13 patients in the nCRT group and 18 patients in the non-nCRT group. The baseline data, such as age, duration of disease, preoperative basic disease, body mass index, smoking rate, and tumor distance from the anal margin, were not significantly different between the two groups (all P>0.05). In the nCRT group and non-nCRT group respectively, the ratio of anal preservation was 30.8%(4/13) and 38.9%(7/18) (P=0.468), the median intraoperative blood loss was 1 000 ml and 800 ml (P=0.644), the operation time was (531.7±137.2) minutes and (498.0±90.1) minutes (P=0.703), the median hospital stay was 18 days and 14 days (P=0.400), the morbidity of complications within 30 days after surgery was 23.1%(3/13) and 38.9%(7/18)(P=0.452), the incidence of postoperative abdominal abscess was 15.4%(2/13) and 0 (P=0.168), the proportion of secondary surgery was 7.7%(1/13) and 11.1%(2/18)(P=1.000), whose differences were not significantly different. The proportion of postoperative pathological pT4b in whole group was 58.1%(18/31), including 53.8%(7/13) in nCRT group and 61.1%(11/18) in non-nCRT group, which was not significantly different between the two groups (P=0.691). The number of harvested lymph node in nCRT group was 13.5±5.9, which was significantly less than 23.0±11.8 in non-nCRT group (P=0.013). There was no pathological complete remission (ypCR) case in nCRT group, and among 13 patients, tumor regression grade (TRG) of 2, 3, 4, and 5 was in 1 case (7.7%), 6 cases (46.2%), 5 cases(38.5%), and 1 case (7.7%), respectively. The median follow-up time was 33 (2 to 115) months, and the follow-up rate was 93.5%(29/31). One case was lost in both the nCRT group and non-nCRT group. The 3-year disease-free survival rate was 43.5% in pooled data, and was 43.6% and 43.3% in nCRT group and non-CRT group respectively without significant difference (P=0.833). The 3-year overall survival rate was 51.1% in pooled data, and was 45.7% and 54.7% in nCRT group and non-nCRT group respectively without significant difference (P=0.653).The local recurrence rate of nCRT and non-nCRT groups was 8.3%(1/12) and 5.9%(1/17) respectively, and the distant metastasis rate was 50.0%(6/12) and 41.2%(7/17) respectively, whose differences were not statistically significant as well (P=1.000 and P=0.865, respectively). CONCLUSION For primary T4b rectal cancer which can achieve R0 resection through total pelvic exenteration, neoadjuvant chemoradiotherapy has not been demonstrated any advantage in tumor regression, reducing local recurrence, or improving survival, and may increase postoperative complications.
Adenocarcinoma ; pathology ; therapy ; Antineoplastic Agents ; administration & dosage ; Chemoradiotherapy ; Combined Modality Therapy ; Humans ; Neoadjuvant Therapy ; Neoplasm Staging ; Pelvic Exenteration ; Rectal Neoplasms ; pathology ; therapy ; Retrospective Studies ; Treatment Outcome