RESUMO
Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 µm) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (≤ 5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 µm) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Trânsito Gastrointestinal/fisiologia , Absorção Intestinal/fisiologia , Intestino Delgado/metabolismo , Microesferas , Poliestirenos/farmacocinética , Animais , Clorpromazina/farmacologia , Cromatografia em Gel , Citocalasina D/farmacologia , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/ultraestrutura , Masculino , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Poliestirenos/administração & dosagem , Ratos , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
BACKGROUND: Immune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease. METHODS: Thirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication. RESULTS: We observed reduction of serum IL-6 and C-reactive protein in Foralumab alone vs. untreated or Foralumab/Dexa treated patients. More rapid clearance of lung infiltrates as measured by chest CT was observed in Foralumab and Foralumab/Dexa treated subjects vs. those that did not receive Foralumab. Foralumab treatment was well-tolerated with no severe adverse events. CONCLUSIONS: This pilot study suggests that nasal Foralumab is well tolerated and may be of benefit in treatment of immune hyperactivity and lung involvement in COVID-19 disease and that further studies are warranted.
Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/imunologia , COVID-19/prevenção & controle , Pneumonia/terapia , Administração Intranasal , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Biomarcadores , Proteína C-Reativa/análise , COVID-19/fisiopatologia , COVID-19/terapia , Estudos de Coortes , Feminino , Humanos , Imunidade/efeitos dos fármacos , Interleucina-6/sangue , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos , Projetos Piloto , Pneumonia/prevenção & controle , Adulto JovemRESUMO
[This corrects the article DOI: 10.3389/fimmu.2021.709861.].