RESUMO
Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Antivirais/administração & dosagem , Tratamento Farmacológico da COVID-19 , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Anticorpos Monoclonais/farmacocinética , Antivirais/farmacocinética , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Pulmão/metabolismo , Pulmão/virologia , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , SARS-CoV-2/isolamento & purificação , Distribuição Tecidual , Carga ViralRESUMO
BACKGROUND: Mental imagery is a powerful method of altering brain activity and behavioral outcomes, such as performance of cognition and motor skills. Further, attention and distraction can modulate pain-related neuronal networks and the perception of pain. This exploratory study examined the effects of mental imagery-induced attention on pressure pain threshold and cortical plasticity using transcranial magnetic stimulation (TMS). This blinded, randomized, and parallel-design trial comprised 30 healthy right-handed male subjects. Exploratory statistical analyses were performed using ANOVA and t-tests for pain and TMS assessments. Pearson's correlation was used to analyze the association between changes in pain threshold and cortical excitability. RESULTS: In the analysis of pain outcomes, there was no significant interaction effect on pain between group versus time. In an exploratory analysis, we only observed a significant effect of group for the targeted left hand (ANOVA with pain threshold as the dependent variable and time and group as independent variables). Although there was only a within-group effect of mental imagery on pain, further analyses showed a significant positive correlation of changes in pain threshold and cortical excitability (motor-evoked potentials via TMS). CONCLUSIONS: Mental imagery has a minor effect on pain modulation in healthy subjects. Its effects appear to differ compared with chronic pain, leading to a small decrease in pain threshold. Assessments of cortical excitability confirmed that these effects are related to the modulation of pain-related cortical circuits. These exploratory findings suggest that neuronal plasticity is influenced by pain and that the mental imagery effects on pain depend on the state of central sensitization.