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2.
Int J Nanomedicine ; 18: 1577-1595, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37007986

RESUMO

Purpose: The research objective is to design intranasal brain targeted CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) aiming to improve central systemic CLZ bioavailability. Methods: In our study, intranasal CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) were formulated using soya phosphatidyl choline (SPC) and sodium deoxycholate (SDC) with different CLZ:SPC:SDC ratios via thin film hydration technique aiming to enhance drug solubility, bioavailability and nose to brain targeting efficiency. Optimization of the prepared CLZ-LbPM using Design-Expert® software was achieved showing that M6 which composed of (CLZ:SPC: SDC) in respective ratios of 1:3:10 was selected as the optimized formula. The optimized formula was subjected to further evaluation tests as, Differential Scanning Calorimetry (DSC), TEM, in vitro release profile, ex vivo intranasal permeation and in vivo biodistribution. Results: The optimized formula with the highest desirability exhibiting (0.845), small particle size (12.23±4.76 nm), Zeta potential of (-38 mV), percent entrapment efficiency of > 90% and percent drug loading of 6.47%. Ex vivo permeation test showed flux value of 27 µg/cm².h and the enhancement ratio was about 3 when compared to the drug suspension, without any histological alteration. The radioiodinated clozapine ([131I] iodo-CLZ) and radioiodinated optimized formula ([131I] iodo-CLZ-LbPM) were formulated in an excellent radioiodination yield more than 95%. In vivo biodistribution studies of [131I] iodo-CLZ-LbPM showed higher brain uptake (7.8%± 0.1%ID/g) for intranasal administration with rapid onset of action (at 0.25 h) than the intravenous formula. Its pharmacokinetic behavior showed relative bioavailability, direct transport percentage from nose to brain and drug targeting efficiency of 170.59%, 83.42% and 117% respectively. Conclusion: The intranasal self-assembling lecithin based mixed polymeric micelles could be an encouraging way for CLZ brain targeting.


Assuntos
Clozapina , Micelas , Radioisótopos do Iodo , Clozapina/metabolismo , Lecitinas , Distribuição Tecidual , Sistemas de Liberação de Medicamentos/métodos , Administração Intranasal , Encéfalo , Mucosa Nasal/metabolismo , Polímeros/química , Tamanho da Partícula , Portadores de Fármacos/química
3.
Biomed Pharmacother ; 160: 114363, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36746096

RESUMO

Allergic rhinitis (AR) is globally prevalent and its pathogenesis remains unclear. Alternative activation of macrophages is suggested in AR and thought to be involved in natural immunoregulatory processes in AR. Aberrant activation of Nod-like receptor protein 3 (NLRP3) inflammasome is linked with AR. Human placenta extract (HPE) is widely used in clinics due to its multiple therapeutic potential carried by diverse bioactive molecules in it. We aim to investigate the effect of HPE on AR and the possible underlying mechanism. Ovalbumin (OVA)-induced AR rat model was set up and treated by HPE or cetirizine. General manifestation of AR was evaluated along with the histological and biochemical analysis performed on rat nasal mucosa. A proteomic analysis was performed on AR rat mucosa. Mouse alveolar macrophages (MH-S cells) were cultured under OVA stimulation to investigate the regulation of macrophages polarization. The morphological changes and the expression of NLRP3 inflammasome and immunity-related GTPase M (IRGM) in nasal mucosa as well as in MH-S cells were evaluated respectively. The results of our study showed the general manifestation of AR along with the histological changes in nasal mucosa of AR rats were improved by HPE. HPE suppresses NLRP3 inflammasome and the decline of IRGM in AR rats and MH-S cells. HPE regulates macrophage polarization through IRGM/NLRP3. We demonstrated that HPE had protection for AR and the protection is achieved partly through suppressing M1 while promoting M2, the process which is mediated by IRGM via inhibiting NLRP3 inflammasome in AR.


Assuntos
Extratos Placentários , Rinite Alérgica , Humanos , Feminino , Ratos , Camundongos , Animais , Gravidez , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Extratos Placentários/metabolismo , Extratos Placentários/uso terapêutico , Proteômica , Placenta/metabolismo , Rinite Alérgica/tratamento farmacológico , Rinite Alérgica/metabolismo , Mucosa Nasal/metabolismo , Macrófagos/metabolismo , Modelos Animais de Doenças , Ovalbumina , Citocinas/metabolismo , Proteínas de Ligação ao GTP/metabolismo
4.
Am J Rhinol Allergy ; 36(1): 33-40, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33910378

RESUMO

BACKGROUND: Currently, no consensus exists on the appropriate control specimen site to utilize in studies evaluating for biomarkers in chronic rhinosinusitis (CRS). Studies thus far have utilized tissue from various anatomic sites despite regional heterogeneity. OBJECTIVE: We set out to quantify the differences in biomarker levels present in inferior turbinate versus sphenoid sinus mucosa in paired healthy control patients. We hypothesize that statistically significant differences in cytokine/chemokine expression exist between these two distinct sites. METHODS: A 38-plex commercially available cytokine/chemokine Luminex Assay was performed on 54 specimens encompassing paired inferior turbinate and sphenoid sinus mucosa samples from 27 patients undergoing endoscopic anterior skull base surgery. Patients with a history of CRS were excluded. Paired sample t-tests and Fisher's exact tests were performed. RESULTS: Twenty-seven patients were included in the study, including 10 male and 17 female patients with an average age of 48 years. The following 8 biomarkers had statistically significant concentration differences between inferior turbinate mucosa and sphenoid mucosa sites: Flt-3L, Fractalkine, IL-12p40, IL-1Ra, IP-10, MCP-1, MIP-1ß, and VEGF, with all P-values <0.01. CONCLUSION: No consensus exists regarding the optimal choice of control specimen for CRS research. We present statistically significant quantitative differences in biomarker levels between paired inferior turbinate and sphenoid mucosa samples. This confirms the presence of heterogeneity between different subsites of sinonasal mucosa and highlights the need for standardization in future CRS research.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Biomarcadores , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Rinite/diagnóstico , Rinite/patologia , Sinusite/diagnóstico , Sinusite/patologia , Conchas Nasais/patologia , Conchas Nasais/cirurgia
5.
Kathmandu Univ Med J (KUMJ) ; 19(73): 62-68, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34812160

RESUMO

Background Recently there has been an increased preference for intranasal delivery of drugs due to highly vascular nasal mucosa, bypassing first pass metabolism and the blood brain barrier (BBB) lead in quick drug absorption to the systemic circulation and direct access to brain from olfactory region. For pediatric patients this route offers significant benefits over injections or oral routes, like increased compliance, easy administration, and minimal side effects. Objective Assessment of prescription pattern of drugs and safety profile of drugs used by intranasal route in paediatric age group. Method Our study was a prospective observational study paediatric age group of patients conducted in the departments of Pharmacology, Paediatrics and Otorhinolaryngology of Burdwan Medical College and Hospital, Burdwan. Data were collected in CRF and frequency distribution of collected data done. Microsoft Excel 2010 was used for analysis. Result Common age group was infants. Males were more in number. Most common indication was epistaxis. Intranasal drugs per prescription were 1.05. Most commonly prescribed intranasal drug was nasal saline. Nasal decongestant was the most common prescribed medication. Nasal drops were the most common dose formulation. Conclusion Intranasal drug prescribing in our study was mainly aimed for treating local problems, very few being for systemic action. Some prescribing indicators like prescribing by generic name and prescribing from national essential drug lists were acceptable with scope for improvement. Average number of drugs per prescription and antibiotic use was high. Adverse events after intranasal drug use were primarily local and nose related.


Assuntos
Pediatria , Preparações Farmacêuticas , Administração Intranasal , Criança , Humanos , Lactente , Masculino , Mucosa Nasal , Centros de Atenção Terciária
6.
Eur J Pharm Biopharm ; 165: 113-126, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34004335

RESUMO

Intranasal immunization with surfactants as vaccine adjuvants enhances protective immunity against invasive mucosal pathogens. However, the effects of surfactants and their adjuvanticity on mucosal immune responses remain unclear. Comparison of the mucosal adjuvanticity of 20 water-soluble surfactants from the four classes based upon the polarity composition of the hydrophilic headgroup revealed that the order of mucosal adjuvanticity was as follows: amphoteric > nonionic > cationic > anionic. Within the same class, each surfactant displayed different adjuvanticity values. Analysis of the diameter and ζ-potential of amphoteric surfactant-OVA complexes and their surface physicochemical properties revealed that the diameter was approximately 100 nm, which is considered suitable for immune induction, and that the ζ-potential of the anionic surfactant-OVA complexes was exceedingly negative. The increase in the number of carbon atoms in the hydrophobic tailgroups of the amphoteric surfactant resulted in an increase in the OVA-specific Ab titers. Our findings demonstrate that amphoteric surfactants exhibit potent mucosal adjuvanticity and highlight the importance of the number of carbon atoms in the tailgroups and the diameter and ζ-potential of the complexes when designing mucosal adjuvants.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imunidade nas Mucosas/efeitos dos fármacos , Mucosa Nasal/imunologia , Tensoativos/administração & dosagem , Vacinação/métodos , Adjuvantes Imunológicos/química , Administração Intranasal , Animais , Feminino , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Modelos Animais , Mucosa Nasal/efeitos dos fármacos , Propriedades de Superfície , Tensoativos/química
7.
Ear Nose Throat J ; 100(5_suppl): 618S-623S, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31914815

RESUMO

OBJECTIVE: This study describes a surgical approach wherein a lobulated pedicled nasal mucosa flap technique was employed for endoscopic dacryocystorhinostomy (EDCR) as a means of treating nasolacrimal duct obstructions. This study also assessed the long-term outcomes of this EDCR approach when implemented without stenting. METHODS: This was a retrospective study of a total of 63 patients (67 eyes) treated for nasolacrimal duct obstructions between January 2011 and November 2016. All patients had undergone ophthalmic diagnosis followed by EDCR treatment using a lobulated pedicled nasal mucosa flap without stenting. Patients were then monitored for both anatomical patency and sustained symptom relief during the follow-up period in order to assess objective and subjective study outcomes. RESULTS: Patients were followed for a mean of 25.3 ± 1.2 months (range: 24-28 months), with a 100% anatomical patency success rate (67/67) and a 94.03% symptomatic cure rate (63/67). There were no instances of complications. CONCLUSIONS: The use of a lobulated pedicled nasal mucosa flap technique for EDCR without stenting is a straightforward, effective, and safe approach that keeps bone exposure to a minimum while offering a high rate of satisfactory outcomes, making it a procedure worthy of consideration as a means of treating patients suffering from nasolacrimal duct obstructions.


Assuntos
Dacriocistorinostomia/métodos , Obstrução dos Ductos Lacrimais/terapia , Mucosa Nasal/transplante , Ducto Nasolacrimal/cirurgia , Retalhos Cirúrgicos , Adulto , Dacriocistorinostomia/instrumentação , Endoscopia/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
8.
Neuroscientist ; 27(6): 582-603, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-32914699

RESUMO

In recent months it has emerged that the novel coronavirus-responsible for the COVID-19 pandemic-causes reduction of smell and taste in a large fraction of patients. The chemosensory deficits are often the earliest, and sometimes the only signs in otherwise asymptomatic carriers of the SARS-CoV-2 virus. The reasons for the surprisingly early and specific chemosensory dysfunction in COVID-19 are now beginning to be elucidated. In this hypothesis review, we discuss implications of the recent finding that the prevalence of smell and taste dysfunction in COVID-19 patients differs between populations, possibly because of differences in the spike protein of different virus strains or because of differences in the host proteins that enable virus entry, thus modifying infectivity. We review recent progress in defining underlying cellular and molecular mechanisms of the virus-induced anosmia, with a focus on the emerging crucial role of sustentacular cells in the olfactory epithelium. We critically examine the current evidence whether and how the SARS-CoV-2 virus can follow a route from the olfactory epithelium in the nose to the brain to achieve brain infection, and we discuss the prospects for using the smell and taste dysfunctions seen in COVID-19 as an early and rapid diagnostic screening tool.


Assuntos
Anosmia/complicações , Anosmia/virologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/virologia , Mucosa Nasal/virologia , Percepção Olfatória , Animais , Anosmia/diagnóstico , Anosmia/fisiopatologia , Encéfalo/fisiopatologia , COVID-19/diagnóstico , COVID-19/fisiopatologia , Humanos , Olfato
9.
Eur Arch Otorhinolaryngol ; 278(6): 1863-1868, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33185743

RESUMO

PURPOSE: We assessed the effects of COVID-19 infection on nasal mucociliary activity. METHODS: The study was conducted in the pandemic wards of Adiyaman University Training and Research Hospital during April and May 2020. All patients admitted to the COVID-19 pandemic wards during the study period were invited to participate in the study. The study included 40 adults who agreed to participate and underwent a mucociliary clearance test successfully. The primary outcome was mucociliary clearance time and the secondary variables of interest were age, sex, and sino-nasal outcome test-22 scores. The control group included 40 concomitant healthy patients who visited the outpatient ear, nose and throat clinic with non-nasal symptoms. RESULTS: The study included 40 COVID-19-positive patients and 40 healthy controls. The mean mucociliary clearance times of the study (15.53 ± 5.57 min) and control (9.50 ± 3.70 min) groups were significantly different (Z = 4.675, p < 0.001). However, the mucociliary clearance time was not significantly different between males and females (t = 0.590, p = 0.558). CONCLUSIONS: Nasal mucociliary clearance time was prolonged in COVID-19 patients compared to healthy controls. Thus, we conclude that smell and taste are crucial symptoms that should not be overlooked in patients suspected of COVID-19 disease.


Assuntos
COVID-19 , Depuração Mucociliar , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Mucosa Nasal , Pandemias , SARS-CoV-2
10.
Aust J Gen Pract ; 49(11): 728-732, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33123703

RESUMO

BACKGROUND: General practitioners (GPs) have some of the highest rates of mortality from COVID-19 among healthcare workers. SARS-CoV-2 has unique properties that place GPs at particular risk. OBJECTIVE: The aim of this article is to discuss the nose-related features of SARS-CoV-2 that place GPs at risk, and to make recommendations pertinent to the safety and protection of primary healthcare physicians. DISCUSSION: The highest viral load of SARS-CoV-2 is in the nose and nasopharynx. It is often highest early in the illness, before the development of symptoms. Further, SARS-CoV-2 replicates and continues to shed in the nasopharynx long after the virus is no longer detectable in the lower respiratory tract. This places any physician performing examinations on, or procedures involving, the upper respiratory tract at risk for contracting COVID-19. New-onset hyposmia and dysgeusia are indicators for COVID-19 and should be included in screening protocols.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Clínicos Gerais/estatística & dados numéricos , Controle de Infecções , Cavidade Nasal/virologia , Nasofaringe/virologia , Transtornos do Olfato/virologia , Pandemias , Pneumonia Viral , Austrália , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Transmissão de Doença Infecciosa/prevenção & controle , Humanos , Controle de Infecções/instrumentação , Controle de Infecções/métodos , Controle de Infecções/normas , Mucosa Nasal/metabolismo , Exposição Ocupacional/prevenção & controle , Exposição Ocupacional/estatística & dados numéricos , Pandemias/prevenção & controle , Equipamento de Proteção Individual/provisão & distribuição , Pneumonia Viral/mortalidade , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Guias de Prática Clínica como Assunto , Atenção Primária à Saúde/normas , Gestão de Riscos , SARS-CoV-2 , Carga Viral
11.
PLoS Genet ; 16(10): e1009100, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33085659

RESUMO

Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Fibrose Cística/terapia , Splicing de RNA/genética , Processamento Alternativo/genética , Substituição de Aminoácidos/genética , Cloretos/metabolismo , Fibrose Cística/patologia , Eletromiografia , Éxons/genética , Variação Genética/genética , Células HEK293 , Humanos , Íntrons/genética , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Nucleotídeos/genética , Medicina de Precisão/métodos , Cultura Primária de Células , RNA Mensageiro/genética
12.
Clin Exp Allergy ; 50(10): 1148-1158, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32865840

RESUMO

BACKGROUND: After the Second World War, the population living in the Karelian region was strictly divided by the "iron curtain" between Finland and Russia. This resulted in different lifestyle, standard of living, and exposure to the environment. Allergic manifestations and sensitization to common allergens have been much more common on the Finnish compared to the Russian side. OBJECTIVE: The remarkable allergy disparity in the Finnish and Russian Karelia calls for immunological explanations. METHODS: Young people, aged 15-20 years, in the Finnish (n = 69) and Russian (n = 75) Karelia were studied. The impact of genetic variation on the phenotype was studied by a genome-wide association analysis. Differences in gene expression (transcriptome) were explored from the blood mononuclear cells (PBMC) and related to skin and nasal epithelium microbiota and sensitization. RESULTS: The genotype differences between the Finnish and Russian populations did not explain the allergy gap. The network of gene expression and skin and nasal microbiota was richer and more diverse in the Russian subjects. When the function of 261 differentially expressed genes was explored, innate immunity pathways were suppressed among Russians compared to Finns. Differences in the gene expression paralleled the microbiota disparity. High Acinetobacter abundance in Russians correlated with suppression of innate immune response. High-total IgE was associated with enhanced anti-viral response in the Finnish but not in the Russian subjects. CONCLUSIONS AND CLINICAL RELEVANCE: Young populations living in the Finnish and Russian Karelia show marked differences in genome-wide gene expression and host contrasting skin and nasal epithelium microbiota. The rich gene-microbe network in Russians seems to result in a better-balanced innate immunity and associates with low allergy prevalence.


Assuntos
Disparidades nos Níveis de Saúde , Hipersensibilidade/epidemiologia , Imunidade Inata , Microbiota/imunologia , Adolescente , Fatores Etários , Feminino , Finlândia/epidemiologia , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Interações entre Hospedeiro e Microrganismos , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/microbiologia , Hipersensibilidade/virologia , Imunidade Inata/genética , Imunoglobulina E/sangue , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Leucócitos Mononucleares/virologia , Masculino , Mucosa Nasal/imunologia , Mucosa Nasal/microbiologia , Mucosa Nasal/virologia , Polimorfismo de Nucleotídeo Único , Prevalência , Federação Russa/epidemiologia , Pele/imunologia , Pele/microbiologia , Pele/virologia , Transcriptoma , Adulto Jovem
13.
Sci Rep ; 10(1): 14974, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917953

RESUMO

Extra-vascular molecular clearance routes from the brain and cerebrospinal fluid (CSF) remain insufficiently characterized in humans. Animal studies consistently suggest that the cribriform plate and nasal lymphatic vessels are crucial for molecular clearance from CSF. In this study, we aimed to examine human in vivo transport of a CSF tracer from CSF to nasal mucosa. We hypothesised a CSF tracer would enrich in nasal mucosa provided that nasal lymphatic drainage has a significant role in CSF molecular clearance. Consecutive magnetic resonance imaging during 48 h after intrathecal administration of a tracer (gadobutrol) was performed in 24 patients. Despite a strong enrichment of CSF tracer in CSF spaces nearby the cribriform plate, there was no significant enrichment of CSF tracer in nasal mucosa, as measured in superior, medial and inferior turbinates, or in the nasal septum. Therefore, this in vivo study questions the importance of CSF drainage to the human nasal mucosa and emphasizes the need of further human studies.


Assuntos
Encéfalo , Líquido Cefalorraquidiano/metabolismo , Imageamento por Ressonância Magnética , Mucosa Nasal , Compostos Organometálicos/administração & dosagem , Adulto , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/diagnóstico por imagem , Mucosa Nasal/metabolismo , Estudos Prospectivos
15.
Toxicol In Vitro ; 67: 104913, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32526344

RESUMO

Chronic inhalation of naphthalene causes nasal olfactory epithelial tumors in rats and benign lung adenomas in mice. The available human data do not establish an association between naphthalene and increased respiratory cancer risk. Therefore, cancer risk assessment of naphthalene in humans depends predominantly on experimental evidence from rodents. The United States Environmental Protection Agency's (US EPA) Toxicity Forecaster (ToxCast™) database contains data from 710 in vitro assays for naphthalene, the majority of which were conducted in human cells. Of these assays, only 18 were active for naphthalene, and all were in human liver cells. No assays were active in human bronchial epithelial cells. In our analysis, all of the active naphthalene ToxCast assay data were reviewed and used to: 1) determine naphthalene human inhalation concentrations corresponding to relevant activity concentrations for all active naphthalene assays, using a physiologically based pharmacokinetic (PBPK) model; and 2) evaluate the transcriptional responses for active assays in the context of consistency with the larger naphthalene data set and proposed modes of action (MoAs) for naphthalene toxicity and carcinogenicity. The transcriptional responses in liver cells largely reflect cellular activities related to oxidative stress and chronic inflammation. Overall, the results from our analysis of the active ToxCast assays for naphthalene are consistent with conclusions from our earlier weight-of-evidence evaluation for naphthalene carcinogenesis.


Assuntos
Carcinógenos/toxicidade , Naftalenos/toxicidade , Animais , Bioensaio , Carcinógenos/farmacocinética , Bases de Dados Factuais , Humanos , Exposição por Inalação , Fígado/metabolismo , Pulmão/metabolismo , Camundongos , Modelos Biológicos , Naftalenos/farmacocinética , Mucosa Nasal/metabolismo , Exposição Ocupacional , Ratos , Medição de Risco , Testes de Toxicidade
16.
Am J Trop Med Hyg ; 102(6): 1323-1327, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32228793

RESUMO

Multiple polymerase chain reaction (PCR)-based approaches have been developed for Leishmania detection in clinical and laboratory samples, and this diversity limits inter-study comparisons, meta-analyses, and generalization of findings. Towards harmonization of a molecular tool for detection of Leishmania (Viannia) for research purposes, we evaluated the concordance of 18SrDNA quantitative polymerase chain reaction (qPCR) and minicircle kinetoplastid DNA (mkDNA) PCR followed by Southern blot (PCR-SB) in in vitro infection systems and in lesion and mucosal swab samples from Colombian patients with cutaneous leishmaniasis caused by L. (Viannia). The lower limit of parasite detection of 18SrDNA qPCR and mkDNA PCR-SB was 10-1 promastigotes and one intracellular amastigote per reaction. From cutaneous lesions (n = 63), an almost perfect concordance was found between the methods (κ = 0.92, 95% CI: 0.82-1.00). Despite equal limits of detection, mkDNA PCR-SB was more efficient for parasite detection in mucosal samples than 18SrDNA qPCR or 18SrDNA digital droplet PCR. The high concordance, sensitivity, scaling potential, and feasibility of implementation of the 18SrDNA qPCR, support its selection as the L. (Viannia) in research laboratories, as a first step towards harmonization of research protocols in the region.


Assuntos
DNA de Protozoário/genética , Leishmania/isolamento & purificação , Leishmaniose/diagnóstico , Leishmaniose/parasitologia , Técnicas de Amplificação de Ácido Nucleico , Linhagem Celular , Túnica Conjuntiva/parasitologia , Feminino , Humanos , Limite de Detecção , Masculino , Monócitos/parasitologia , Mucosa Nasal/parasitologia , Tonsila Palatina/parasitologia , Especificidade da Espécie
17.
Pharm Res ; 37(4): 74, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32215749

RESUMO

PURPOSE: Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson's disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations. METHODS: In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. RESULTS: Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection. CONCLUSIONS: This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.


Assuntos
Administração Intranasal , Encéfalo/metabolismo , Zonisamida/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Humanos , Rim/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Mucosa Nasal/metabolismo , Zonisamida/administração & dosagem
18.
Trials ; 20(1): 754, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856900

RESUMO

BACKGROUND: Current international guidelines recommend the use of a daily topical exit-site antimicrobial to prevent peritoneal dialysis (PD)-related infections. Although nonantibiotic-based therapies are appealing because they may limit antimicrobial resistance, no controlled trials have been conducted to compare topical antimicrobial agents with usual exit-site care for the prevention of PD-related infections among the Thai PD population. We propose a controlled three-arm trial to examine the efficacy and safety of a daily chlorhexidine gluconate-impregnated patch versus mupirocin ointment versus usual exit-site care with normal saline for the prevention of PD-related infections. METHODS/DESIGNS: This study is a randomized, double-blind, multicenter, active-controlled, clinical trial. Adult patients aged 18 years or older who have end-stage kidney disease and are undergoing PD will be enrolled at three PD Centers in Thailand. A total of 354 PD patients will be randomly assigned to either the 2% chlorhexidine gluconate-impregnated patch, mupirocin ointment, or usual exit-site care with normal saline dressing according to a computer-generated random allocation sequence. Participants will be followed until discontinuation of PD or completion of 24 months. The primary study outcomes are time to first PD-related infection (exit-site/tunnel infection or peritonitis) event and the overall difference in PD-related infection rates between study arms. Secondary study outcomes will include (i) the rate of infection-related catheter removal and PD technique failure, (ii) rate of nasal and exit-site Staphylococcus aureus colonization, (iii) healthcare costs, and (iv) skin reactions and adverse events. We plan to conduct a cost-utility analysis alongside the trial from the perspectives of patients and society. A Markov simulation model will be used to estimate the total cost and health outcome in terms of quality-adjusted life years (QALYs) over a 20-year time horizon. An incremental cost-effectiveness ratio in Thai Baht and U.S. dollars per QALYs gained will be illustrated. A series of probabilistic sensitivity analyses will be conducted to assess the robustness of the cost-utility analysis findings. DISCUSSION: The results from this study will provide new clinical and cost-effectiveness evidence to support the best strategy for the prevention of PD-related infections among the Thai PD population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02547103. Registered on September 11, 2015.


Assuntos
Antibacterianos/administração & dosagem , Anti-Infecciosos Locais/administração & dosagem , Infecções Relacionadas a Cateter/epidemiologia , Diálise Peritoneal/efeitos adversos , Peritonite/epidemiologia , Infecções Estafilocócicas/epidemiologia , Administração Tópica , Adulto , Idoso , Antibacterianos/economia , Anti-Infecciosos Locais/economia , Infecções Relacionadas a Cateter/diagnóstico , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/prevenção & controle , Cateteres de Demora/efeitos adversos , Clorexidina/administração & dosagem , Clorexidina/análogos & derivados , Ensaios Clínicos Fase IV como Assunto , Análise Custo-Benefício , Método Duplo-Cego , Custos de Medicamentos , Feminino , Humanos , Incidência , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Mupirocina/administração & dosagem , Mucosa Nasal/microbiologia , Diálise Peritoneal/instrumentação , Peritonite/diagnóstico , Peritonite/microbiologia , Peritonite/prevenção & controle , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto , Solução Salina/administração & dosagem , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/isolamento & purificação , Resultado do Tratamento
19.
Biomed J ; 42(5): 328-334, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31783993

RESUMO

BACKGROUND: Cone-beam computed tomography (CBCT) presurgical assessment on the maxillary sinus can reduce the possibility of Schneiderian membrane perforation. This study examined Schneiderian membrane thickness (SMT) and its relationship with neighboring hard tissues for patients with and without membrane thickening. For patients with sinus infections, we evaluated dimensional changes of the SMT post-extraction relative to pre-extraction SMT and residual bone height (RBH). METHODS: CBCT images from 93 patients needing single-tooth implant reconstruction without (n = 83) and with (n = 14) odontogenic infected maxillary sinuses were assessed. SMT, RBH, and lateral wall thickness (LWT) were measured. Causes of extraction, RBH in the infection site, and retrospective post-extraction record of SMT were recorded for the thickened SMT group. RESULTS: Mean SMT for normal SMT group was 1.13 ± 0.43 mm, RBH was 6.26 ± 2.38 mm; upper and lower LWT was 1.85 ± 0.95 mm, and 3.07 ± 2.26 mm, respectively. RBH and LWT had no significant relationships with SMT. For thickened SMT group, mean values for SMT and RBH prior to extraction were 4.53 ± 2.46 mm and 1.97 ± 1.43 mm, respectively. Pre-extraction SMT had a moderately negative correlation with pre-extraction RBH. SMT resolution in thickened SMT group was observed by 2.80 ± 1.37 months post-extraction; post-extraction SMT was not significantly different from normal SMT group (p = .187). CONCLUSIONS: Within the limitation of the sample size, thickened SMT induced by odontogenic infection subsides about 3 months following tooth extraction, and further sinus lifting implant surgery may be considered.


Assuntos
Tomografia Computadorizada de Feixe Cônico , Infecções/etiologia , Seio Maxilar/diagnóstico por imagem , Mucosa Nasal/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Tomografia Computadorizada de Feixe Cônico/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Dente/diagnóstico por imagem , Dente/cirurgia
20.
Clin Oral Implants Res ; 30(7): 682-690, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059148

RESUMO

OBJECTIVE: We sought to assess the effectiveness of using a microscope and non-invasive camera for assessing sinus membrane perforations during transcrestal sinus floor elevation (TSFE). MATERIALS AND METHODS: Five fresh human cadaver heads corresponding to eight maxillary sinuses (six bilateral and two unilateral) underwent 4 TSFEs per sinus (a total of 32 single site elevations). Each elevation was randomly assigned to receive a three or six mm membrane elevation height (MEH). A microscope and micro-camera were used to assess the sinus membrane perforation. Afterwards, radiological and clinical membrane perforation assessments were performed. The statistical analysis results are expressed using the means, standard deviations, range values of the residual ridge height (RRH), residual ridge width (RRW), sinus membrane thickness (SMT) and incidence of perforation (IoP). Generalized linear methods were used to test for the correlation of RRH and MEH to the microscope and micro-camera perforation assessments and the correlation of microscope and micro-camera assessments with the post-operative CBCT and crestal liquid evaluation. RESULTS: The cumulative percentage of IoP was 40.62%, (23.07% with 3 mm MEH, and 76.92% with 6 mm MEH, p < 0.05). The perforation assessed using either the microscope or micro-camera coincided with the post-operative CBCT and crestal liquid assessment in 87.55% sites. No significant correlation was found between the microscope or micro-camera assessments with RRH or MEH. CONCLUSION: Application of a microscope and micro-camera during transcrestal sinus floor elevation may allow the detection of the integrity of the Schneiderian membrane with greater than 85% accuracy in this ex vivo model.


Assuntos
Levantamento do Assoalho do Seio Maxilar , Cadáver , Humanos , Seio Maxilar , Mucosa Nasal
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