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1.
J Immunol Res ; 2020: 9465398, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33134398

RESUMO

This new decade has started with a global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), precipitating a worldwide health crisis and economic downturn. Scientists and clinicians have been racing against time to find therapies for COVID-19. Repurposing approved drugs, developing vaccines and employing passive immunization are three major therapeutic approaches to fighting COVID-19. Chicken immunoglobulin Y (IgY) has the potential to be used as neutralizing antibody against respiratory infections, and its advantages include high avidity, low risk of adverse immune responses, and easy local delivery by intranasal administration. In this study, we raised antibody against the spike (S) protein of SARS-CoV-2 in chickens and extracted IgY (called IgY-S) from egg yolk. IgY-S exhibited high immunoreactivity against SARS-CoV-2 S, and by epitope mapping, we found five linear epitopes of IgY-S in SARS-CoV-2 S, two of which are cross-reactive with SARS-CoV S. Notably, epitope SIIAYTMSL, one of the identified epitopes, partially overlaps the S1/S2 cleavage region in SARS-CoV-2 S and is located on the surface of S trimer in 3D structure, close to the S1/S2 cleavage site. Thus, antibody binding at this location could physically block the access of proteolytic enzymes to S1/S2 cleavage site and thereby impede S1/S2 proteolytic cleavage, which is crucial to subsequent virus-cell membrane fusion and viral cell entry. Therefore, the feasibility of using IgY-S or epitope SIIAYTMS-specific IgY as neutralizing antibody for preventing or treating SARS-CoV-2 infection is worth exploring.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Mapeamento de Epitopos , Imunoglobulinas/isolamento & purificação , Pneumonia Viral/terapia , Administração Intranasal , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/isolamento & purificação , Galinhas , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Reações Cruzadas , Estudos de Viabilidade , Humanos , Imunização Passiva/métodos , Imunoglobulinas/administração & dosagem , Imunoglobulinas/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/imunologia
3.
Clin Exp Pharmacol Physiol ; 47(11): 1874-1878, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32881059

RESUMO

A novel concept in DNA vaccine design is the creation of an inhaled DNA plasmid construct containing a portion of the coronavirus spike protein for treatment and vaccination. The secretion of a spike protein portion will function as a competitive antagonist by interfering with the binding of coronavirus to the angiotensin-converting enzyme 2 (ACE2) receptor. The secreted protein binding to the ACE2 receptor provides a unique mechanism of action for treatment to all strains of coronavirus in naïve patients, by blocking the ACE2 receptor site. An inhaled plasmid DNA vaccine replicates the route of lung infection taken by coronavirus with transfected cells secreting spike protein portions to induce immunity. Unlike most DNA vaccines with intracellular antigen presentation through MHC I, the current vaccine relies on the secreted proteins presentation through MHC II as well as MHC I to induce immunity. Lung specific production of vaccine particles by inhaled plasmid DNA is appealing since it may have limited systemic side effects, and may induce both humoral and cytotoxic immunity. Finally, the ease and ability to rapidly produce this plasmid construct makes this an ideal solution for managing the emerging threat of coronavirus.


Assuntos
Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/uso terapêutico , Vacinas Virais/administração & dosagem , Vacinas Virais/uso terapêutico , Administração Intranasal , Betacoronavirus/genética , Betacoronavirus/imunologia , Quitosana , Infecções por Coronavirus/prevenção & controle , Humanos , Pandemias , Pneumonia Viral , Vacinação/métodos , Vacinas de DNA/química
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 240-244, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981279

RESUMO

Objective: To investigate the inflammatory mechanism of nasal instillation of fine particulate matter (PM2.5)on hippocampal tissue injury in mice.Methods: Thirty C57BL/6J mice were randomly divided into 3 groups(n=10):control group, low-dose group, high-dose group. The nasal instillation doses of PM2.5 in the low-dose group and the high-dose group were 1.5 mg/kg BW and 7.5 mg/kg BW, respectively, and the control group was given saline with an equal volume. Saline was sprayed once every other time for 12 times. The serum levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were determined by ELISA method. HE staining and electron microscopy were used to observe the pathological changes and ultrastructure of lung tissue and hippocampus. The inflammatory cytokine levels in hippocampus were detected by antibody chip technique. Results: There was no significant effect of PM2.5 nasal instillation on serum TNF-α, IL-1ß and IL-6 levels (P>0.05), and there was no obvious pathological changes in lung tissue structure. In hippocampus, low-dose and high-dose PM2.5 exposure could lead to disordered neuronal arrangement in the hippocampal CA3 region, and there were neurological changes around the neuron cells and ultrastructural changes such as edema around small blood vessels. Compared with the control group, the levels of inflammatory cytokines such as CX3CL1, CSF2 and TECK in the low-dose group were increased significantly (P <0.05), while sTNFR1 was decreased significantly (P<0.05); the inflammatory factors CX3CL1, CSF2, and TCA-3 were significantly increased in the high-dose group (P<0.05), while leptin, MIG, and FASLG were significantly decreased (P<0.05). Conclusion: Nasal instillation of PM2.5 can induce tissue damage in the hippocampus of mice, and its mechanism of action may be the olfactory brain pathway. The increasing of TNF-α and IL-6 and the decreasing of sTNFR1 and FASLG may be involved in inflammatory mechanisms.


Assuntos
Lesões Encefálicas , Hipocampo , Material Particulado , Administração Intranasal , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/fisiopatologia , Citocinas/sangue , Hipocampo/efeitos dos fármacos , Hipocampo/lesões , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Material Particulado/toxicidade
5.
Cell ; 183(1): 169-184.e13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931734

RESUMO

The coronavirus disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a prefusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal immunoglobulin A (IgA) and T cell responses, and almost entirely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission and curtailing pandemic spread.


Assuntos
Infecções por Coronavirus/imunologia , Imunogenicidade da Vacina , Pneumonia Viral/imunologia , Vacinas Virais/imunologia , Adenoviridae/genética , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Humanos , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , Pneumonia Viral/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero , Vacinas Virais/administração & dosagem
6.
Cochrane Database Syst Rev ; 9: CD013628, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936947

RESUMO

BACKGROUND: COVID-19 infection poses a serious risk to patients and - due to its contagious nature - to those healthcare workers (HCWs) treating them. The risks of transmission of infection are greater when a patient is undergoing an aerosol-generating procedure (AGP). Not all those with COVID-19 infection are symptomatic, or suspected of harbouring the infection. If a patient who is not known to have or suspected of having COVID-19 infection is to undergo an AGP, it would nonetheless be sensible to minimise the risk to those HCWs treating them. If the mouth and nose of an individual undergoing an AGP are irrigated with antimicrobial solutions, this may be a simple and safe method of reducing the risk of any covert infection being passed to HCWs through droplet transmission or direct contact. Alternatively, the use of antimicrobial solutions by the HCW may decrease the chance of them acquiring COVID-19 infection. However, the use of such antimicrobial solutions may be associated with harms related to the toxicity of the solutions themselves or alterations in the natural microbial flora of the mouth or nose. OBJECTIVES: To assess the benefits and harms of antimicrobial mouthwashes and nasal sprays administered to HCWs and/or patients when undertaking AGPs on patients without suspected or confirmed COVID-19 infection. SEARCH METHODS: Information Specialists from Cochrane ENT and Cochrane Oral Health searched the Central Register of Controlled Trials (CENTRAL 2020, Issue 6); Ovid MEDLINE; Ovid Embase and additional sources for published and unpublished trials. The date of the search was 1 June 2020.  SELECTION CRITERIA: This is a question that urgently requires evidence, however at the present time we did not anticipate finding many completed RCTs. We therefore planned to include the following types of studies: randomised controlled trials (RCTs); quasi-RCTs; non-randomised controlled trials; prospective cohort studies; retrospective cohort studies; cross-sectional studies; controlled before-and-after studies. We set no minimum duration for the studies.   We sought studies comparing any antimicrobial mouthwash and/or nasal spray (alone or in combination) at any concentration, delivered to the patient or HCW before and/or after an AGP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were: 1) incidence of symptomatic or test-positive COVID-19 infection in HCWs or patients; 2) significant adverse event: anosmia (or disturbance in sense of smell). Our secondary outcomes were: 3) COVID-19 viral content of aerosol (when present); 4) change in COVID-19 viral load at site(s) of irrigation; 5) other adverse events: changes in microbiome in oral cavity, nasal cavity, oro- or nasopharynx; 6) other adverse events: allergy, irritation/burning of nasal, oral or oropharyngeal mucosa (e.g. erosions, ulcers, bleeding), long-term staining of mucous membranes or teeth, accidental ingestion. We planned to use GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We found no completed studies to include in this review.   AUTHORS' CONCLUSIONS: We identified no studies for inclusion in this review, nor any ongoing studies. The absence of completed studies is not surprising given the relatively recent emergence of COVID-19 infection. However, we are disappointed that this important clinical question is not being addressed by ongoing studies.


Assuntos
Anti-Infecciosos/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/transmissão , Pessoal de Saúde , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Antissépticos Bucais/administração & dosagem , Sprays Nasais , Pneumonia Viral/transmissão , Administração Intranasal , Microbiologia do Ar , Anti-Infecciosos/efeitos adversos , Infecções Assintomáticas/terapia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Humanos , Boca/virologia , Antissépticos Bucais/efeitos adversos , Nariz/virologia , Doenças Profissionais/etiologia , Doenças Profissionais/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia
7.
Vestn Otorinolaringol ; 85(4): 46-50, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32885637

RESUMO

OBJECTIVE: To evaluate the efficacy of the drug Frinozol (nasal spray phenylephrinein 0.25% + cetirizine 0.25%) comparison with Rinostop Extra (nasal spray oxymetazoline 0.05%) in relation to nasal symptoms of rhinosinusitis, evaluated on rating scales, when using these drugs intranasally for 7 days in patients with acute viral and post-viral rhinosinusitis of mild (VAS 0-3) and moderate (VAS 3-7). PATIENTS AND METHODS: The randomized open-label study included 60 ambulatory patients (men and women aged 18 to 60 years) with a verified diagnosis of acute rhinosinusitis (ARS) lasting no more than 120 hours. 1 group of patients took Frinozol (nasal spray phenylephrinein 0.25% + cetirizine 0.25%) for 2 sprays per each nostril 3 times a day for 7 days; 2 group - Rinostop Extra (nasal spray oxymetazoline 0.05%) at the same dose and the therapy regimen. We evaluated 3 visits (day 1, day 3, and day 7) with an ENT examination on each of them; questionnaires on the 1st and 3rd visits of nasal symptoms (nasal obstruction, rhinorrhea, hyposmia) on the visual analog scale (VAS) and Clinical Global Impression Scale-CGI. Active anterior rhinomanometry (AAR) was performed on the 1st, 2nd and 3rd visits using the PTS-14P-01 rhinomanometer Rinolan before and 20 minutes after the use of the drugs Frinozol and oxymetazoline 0.05%.


Assuntos
Obstrução Nasal/tratamento farmacológico , Rinite/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Descongestionantes Nasais/uso terapêutico , Oximetazolina/uso terapêutico , Adulto Jovem
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(6): 864-868, 2020 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895199

RESUMO

OBJECTIVE: To compare the median effective dose (ED50) 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 ED95 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 ED50 value of intranasal dexmedetomidine for sedation was 1.84 µg/kg (95% CI: 1.68-2.00 µg/kg) in children with congenital heart disease before cardiac surgery, and 3.38 µg/kg (95% CI: 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 ED50 of intranasal dexmedetomidine for TTE sedation increases to 3.38 µg/ kg after cardiac surgery from the preoperative value of 1.84 µg/kg.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Administração Intranasal , Criança , Dexmedetomidina , Cardiopatias Congênitas/cirurgia , Humanos , Hipnóticos e Sedativos
10.
Anesth Analg ; 131(4): 1102-1110, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32925331

RESUMO

BACKGROUND: High-flow nasal oxygen (HFNO) is increasingly being used in intensive care units for management of hypoxemia and respiratory failure. However, the effectiveness of HFNO for preventing hypoxemia in the intraoperative period is unclear. The purpose of this systematic review was to compare patient oxygenation and end-tidal CO2 (EtCO2), between HFNO and conventional oxygenation, during the intraoperative period in surgical patients. METHODS: Standard databases were searched from inception to February 2020. Studies involving intraoperative use of HFNO with 1 of the 4 outcomes: (1) oxygen (O2) desaturation, (2) minimum O2 saturation, (3) safe apnea time, or (4) EtCO2 were included. Intraoperative period was divided into 2 phases: at induction with general anesthesia and during surgical procedure under sedation without tracheal intubation. RESULTS: Eight randomized controlled trials (RCTs; 4 induction, 4 procedure, 2314 patients) were included for systematic review and meta-analyses. We found the risk of intraoperative O2 desaturation was lower in HFNO versus conventional oxygenation control group; at induction with an odds ratio (OR; 95% confidence interval [CI]) of 0.06 (0.01-0.59, P = .02), and during procedure, OR (95% CI) of 0.09 (0.05-0.18; P < .001). The minimum O2 saturation was higher in HFNO versus conventional oxygenation; at induction by a mean difference (MD) (95% CI) of 5.1% (3.3-6.9; P < .001), and during procedure, by a MD (95% CI) of 4.0% (1.8-6.2; P < .001). Safe apnea time at induction was longer in HFNO versus conventional oxygenation by a MD (95% CI) of 33.4 seconds (16.8-50.1; P < .001). EtCO2 at induction was not significantly different between HFNO and conventional oxygenation groups. CONCLUSIONS: This systematic review and meta-analysis show that, in the intraoperative setting, HFNO compared to conventional oxygenation reduces the risk of O2 desaturation, increases minimum O2 saturation, and safe apnea time. HFNO should be considered for anesthesia induction and during surgical procedures under sedation without tracheal intubation in patients at higher risk of hypoxemia.


Assuntos
Cuidados Intraoperatórios/métodos , Oxigenoterapia/métodos , Administração Intranasal , Humanos , Resultado do Tratamento
11.
Cell Rep ; 32(6): 108016, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32755598

RESUMO

The influenza virus hemagglutinin (HA) and coronavirus spike (S) protein mediate virus entry. HA and S proteins are heavily glycosylated, making them potential targets for carbohydrate binding agents such as lectins. Here, we show that the lectin FRIL, isolated from hyacinth beans (Lablab purpureus), has anti-influenza and anti-SARS-CoV-2 activity. FRIL can neutralize 11 representative human and avian influenza strains at low nanomolar concentrations, and intranasal administration of FRIL is protective against lethal H1N1 infection in mice. FRIL binds preferentially to complex-type N-glycans and neutralizes viruses that possess complex-type N-glycans on their envelopes. As a homotetramer, FRIL is capable of aggregating influenza particles through multivalent binding and trapping influenza virions in cytoplasmic late endosomes, preventing their nuclear entry. Remarkably, FRIL also effectively neutralizes SARS-CoV-2, preventing viral protein production and cytopathic effect in host cells. These findings suggest a potential application of FRIL for the prevention and/or treatment of influenza and COVID-19.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fabaceae/química , Infecções por Orthomyxoviridae/tratamento farmacológico , Lectinas de Plantas/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Células A549 , Administração Intranasal , Animais , Antivirais/administração & dosagem , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Embrião de Galinha , Chlorocebus aethiops , Cães , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , Lectinas de Plantas/administração & dosagem , Lectinas de Plantas/farmacologia , Ligação Proteica , Células Vero , Proteínas do Envelope Viral/metabolismo
12.
Int J Nanomedicine ; 15: 5253-5264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801690

RESUMO

Background and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X 1), liquid lipid % (LL%, X 2), and sonication time (ST, X 3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.


Assuntos
Benzimidazóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/administração & dosagem , Administração Intranasal , Animais , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Lipídeos/administração & dosagem , Lipídeos/química , Masculino , Nanoestruturas/química , Tamanho da Partícula , Polissacarídeos Bacterianos/química , Ratos Wistar , Solubilidade
13.
Science ; 369(6511): 1603-1607, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32732280

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Modelos Animais de Doenças , Camundongos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Administração Intranasal , Animais , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunogenicidade da Vacina , Pulmão/virologia , Doenças Pulmonares Intersticiais/virologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Mutação , Peptidil Dipeptidase A/genética , Glicoproteína da Espícula de Coronavírus/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Virais/administração & dosagem , Virulência/genética
16.
Eur J Drug Metab Pharmacokinet ; 45(6): 785-799, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32813265

RESUMO

BACKGROUND AND OBJECTIVES: An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling microemulsion which gels instantaneously on contact with minute quantities of water to form a mucoadhesive gel. The objective of the study was to develop ATIS diazepam (ATIS-diazepam) as an alternative to the injection for epileptic emergencies and evaluate its brain uptake and nose-to-brain targeting efficiency in rats. METHODS: ATIS-diazepam (1 mg/100 µL) was prepared and characterized for in vitro formulation characteristics. An LC-MS/MS method was developed and validated for the bioanalysis of diazepam. In vivo studies for pharmacokinetics, brain uptake and nasal irritation of intranasal ATIS-diazepam were conducted in rats. Brain uptake was investigated with brain microdialysis, a highly sensitive technique enabling quantification of free drug, which correlates to efficacy. RESULTS: ATIS-diazepam exhibited globule size < 200 nm, low viscosity, negative zeta potential and good stability. A significant increase in mucoadhesion was exhibited by ATIS-diazepam following the addition of a small quantity of water. ATIS-diazepam showed burst release in pH 6.4 with 50% diazepam release in ~ 10 min, which was sustained over 1 h. The absolute bioavailability was ~ 50% with both intranasal free-diazepam and ATIS-diazepam. Intranasal administration of ATIS-diazepam revealed immediate absorption with rapid and high brain extracellular fluid concentration compared to intravenous free-diazepam solution. The estimated direct transport potential and drug targeting efficiency of intranasal ATIS-diazepam was significantly higher (2-fold) than intranasal free-diazepam solution, which was attributed to the mucoadhesive and microemulsion properties of ATIS-diazepam. The nasal irritation study revealed the safety of ATIS-diazepam compared to free-diazepam solution. CONCLUSION: Intranasal ATIS-diazepam showed promise of higher direct nose-to-brain targeting, better safety and hence has an immense implication in the treatment of epileptic emergencies.


Assuntos
Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Encéfalo/metabolismo , Diazepam/administração & dosagem , Diazepam/farmacocinética , Adesividade , Administração Intranasal , Animais , Anticonvulsivantes/efeitos adversos , Diazepam/efeitos adversos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Emulsões , Líquido Extracelular/metabolismo , Géis , Irritantes , Masculino , Microdiálise , Mucosa Nasal , Ratos
17.
Int J Nanomedicine ; 15: 5113-5129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764940

RESUMO

Background: Low bioavailability and poor permeability of the blood-brain barrier are problematic when delivering therapeutic agents and particularly anti-human immunodeficiency virus therapy to the central nervous system. The intranasal route offers an alternative for central nervous system delivery. Cubosomes have been reported as helpful vehicles for intranasal delivery of therapeutics to enable brain targeting. Objective: In this study, we aimed to develop the intranasal cubosomal thermogelling dispersion of saquinavir mesylate for central nervous system delivery. Methods: The Box-Behnken design was applied to study the effect of monoolein, Poloxamer 407, and polyvinyl alcohol as independent factors and the particle size, entrapment efficiency, gelation temperature, and stability index as responses. The optimized cubosomes were evaluated using transmission electron microscopy, ex vivo permeation, and in vivo pharmacokinetics. Results: The optimized formula consisting of monoolein (8.96%), Poloxamer 407 (17.45%), and polyvinyl alcohol (7.5%) was prepared and evaluated. Higher values for the steady-state flux, permeability coefficient, and enhancement factor were observed for the cubosomal thermogelling dispersion of saquinavir during ex vivo permeation in comparison with an aqueous suspension of saquinavir. From the pharmacokinetic profile, the relative bioavailability for the intranasal optimized formula was approximately 12-fold higher when compared with oral aqueous suspension and 2.5-fold greater when compared to the intranasal aqueous suspension of saquinavir. Conclusion: Overall, the saquinavir-loaded cubosomal thermogelling formulation is promising for central nervous system delivery by intranasal administration.


Assuntos
Portadores de Fármacos/química , Cristais Líquidos/química , Nanoestruturas/química , Saquinavir/farmacologia , Temperatura , Administração Intranasal , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Géis , Glicerídeos/química , Masculino , Tamanho da Partícula , Permeabilidade , Poloxâmero/química , Álcool de Polivinil/química , Saquinavir/administração & dosagem , Saquinavir/metabolismo
18.
Life Sci ; 259: 118159, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763288

RESUMO

AIMS: Parkinson's disease dementia (PDD) is one of the most common non-motor symptoms of advanced Parkinson's disease (PD). This study aimed to determine whether intranasal insulin has protective effects on cognition in the rat PD model induced by 6-hydroxylase dopamine (6-OHDA) through the insulin signaling pathway. MATERIALS AND METHODS: The rats were given intranasal insulin administration for six weeks after unilateral medial forebrain bundle (MFB) injection of 6-OHDA. Then a series of cognitive-behavioral tests, immunofluorescence, and immunoblotting was performed on the rats. KEY FINDINGS: The results demonstrated that the injection of 6-OHDA in the unilateral MFB damaged working memory and long-term habituation of rats in the T-maze rewarded alternation test and hole-board test. Besides, rats with unilateral 6-OHDA injury performed poorly in terms of escape latency and average speed during the hidden platform training phase rather than in the probe trial of the Morris Water Maze (MWM) test. Immunofluorescence results showed that unilateral 6-OHDA injury in MFB led to the massive death of ipsilateral-substantia nigra (SN) tyrosine hydroxylase (TH)-positive neurons. Western blot results further indicated that 6-OHDA-induced necrosis of ipsilateral-SN dopaminergic neurons reduced the levels of p-Akt (Ser473) and p-GSK3ß (Ser9) in the ipsilateral-hippocampus. SIGNIFICANCE: These findings provide a solid evidence base for the relationship between PD cognitive impairment and insulin signaling pathways.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Proteína Oncogênica v-akt/efeitos dos fármacos , Doença de Parkinson/complicações , Transdução de Sinais/efeitos dos fármacos , Administração Intranasal , Animais , Encéfalo/patologia , Disfunção Cognitiva/psicologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Doença de Parkinson/psicologia , Ratos , Ratos Wistar
19.
PLoS One ; 15(8): e0236063, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756567

RESUMO

The primary objective of this research was to extract the essential information needed for setting atomization break up models, specifically, the Linear Instability Sheet Atomization (LISA) breakup model, and alternative hollow cone models. A secondary objective was to gain visualization and insight into the atomization break up mechanism caused by the effects of viscosity and surface tension on primary break-up, sheet disintegration, ligament and droplet formation. High speed imaging was used to capture the near-nozzle characteristics for water and drug formulations. This demonstrated more rapid atomization for lower viscosities. Image processing was used to analyze the near-nozzle spray characteristics during the primary break-up of the liquid sheet into ligament formation. Edges of the liquid sheet, spray break-up length, break-up radius, cone angle and dispersion angle were obtained. Spray characteristics pertinent for primary breakup modelling were determined from high speed imaging of multiple spray actuations. The results have established input data for computational modelling involving parametrical analysis of nasal drug delivery.


Assuntos
Sprays Nasais , Nebulizadores e Vaporizadores , Administração Intranasal , Aerossóis/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/instrumentação , Desenho de Equipamento , Humanos , Tamanho da Partícula , Tensão Superficial , Viscosidade , Água/química
20.
Am J Emerg Med ; 38(9): 1860-1866, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32739857

RESUMO

STUDY OBJECTIVE: To assess the efficacy and safety of intranasal analgesic-dose ketamine as compared to intranasal fentanyl for pediatric acute pain. METHODS: A systematic review and meta-analysis was performed following the PRISMA guidelines. We searched PubMed, Embase, and Scopus databases for randomized controlled trials from inception to December 2019. We conducted meta-analysis with random-effects models to evaluate pain reduction, rescue analgesia, adverse events and sedation between intranasal ketamine and intranasal fentanyl. Random-effects models were used to estimate weighted mean differences (WMD) and pooled relative risks (RR). RESULTS: A total of 546 studies were screened and 4 trials were included. In the meta-analysis of 4 studies including 276 patients, ketamine had similar reductions in pain scores from baseline to all post-intervention times (10 to 15 min: WMD -1.42, 95% CI -9.95 to 7.10; 30 min: WMD 0.40, 95% CI -6.29 to 7.10; 60 min: WMD -0.64, 95% CI -6.76 to 5.47). Ketamine was associated with similar rates of rescue analgesia (RR 0.74, 95% CI 0.44 to 1.25). Ketamine had a higher risk of non-serious adverse events (RR 2.00, 95% CI 1.43 to 2.79), and no patients receiving ketamine had a serious adverse event. There was one serious adverse event (hypotension) with fentanyl that self-resolved. No patients receiving either IN fentanyl or ketamine had significant sedation. CONCLUSION: Intranasal analgesic-dose ketamine may be considered as an alternative to opioids for acute pain management in children. Its accepted use will depend on the tolerability of non-serious adverse events and the desire to avoid opioids.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/uso terapêutico , Ketamina/uso terapêutico , Manejo da Dor/métodos , Administração Intranasal , Analgésicos/administração & dosagem , Criança , Fentanila/administração & dosagem , Fentanila/uso terapêutico , Humanos , Ketamina/administração & dosagem
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