RESUMO
Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have demonstrated the efficacy of beta-lactams in modulating the expression of glutamate transporter-1 (GLT-1) in different body organs, including the liver. The upregulation of GLT-1 by beta-lactams is associated with the attenuation of hyperglutamatergic state, which is a characteristic feature of opioid use disorders. A novel experimental beta-lactam compound with no antimicrobial properties, MC-100093, has been developed to attenuate dysregulation of glutamate transport, in part by normalizing GLT-1 expression. A previous study showed that MC-100093 modulated hepatic GLT-1 expression with subsequent attenuation of alcohol-increased fat droplet content in the liver. In this study, we investigated the effects of fentanyl overdose on liver metabolites, and determined the effects of MC-100093 and ceftriaxone in the liver of a fentanyl overdose mouse model. Liver samples from control, fentanyl overdose, and fentanyl overdose ceftriaxone- or MC-100093-treated mice were analyzed for metabolomics using gas chromatography-mass spectrometry. Heatmap analysis revealed that both MC-100093 and ceftriaxone attenuated the effects of fentanyl overdose on several metabolites, and MC-100093 showed superior effects. Statistical analysis showed that MC-100093 reversed the effects of fentanyl overdose in some metabolites. Moreover, enrichment analysis revealed that the altered metabolites were strongly linked to the glucose-alanine cycle, the Warburg effect, gluconeogenesis, glutamate metabolism, lactose degradation, and ketone body metabolism. The changes in liver metabolites induced by fentanyl overdose were associated with liver inflammation, an effect attenuated with ceftriaxone pre-treatments. Ceftriaxone normalized fentanyl-overdose-induced changes in liver interleukin-6 and cytochrome CYP3A11 (mouse homolog of human CYP3A4) expression. Our data indicate that fentanyl overdose impaired liver metabolites, and MC-100093 restored certain metabolites.
RESUMO
BACKGROUND: Vaccination is considered the best way to prevent the spread of COVID-19 and to prevent the complications of the disease. Nevertheless, no awareness campaigns were conducted in Saudi Arabia until March 1, 2021, when the Vaxzevria, or ChAdOx1 nCoV-19 (AZD1222), vaccine became available. OBJECTIVES: This study aims to determine the factors that can predict healthcare workers' acceptance of the COVID-19 vaccine. METHODS: A cross-sectional study was conducted from July to September 2021, in our university tertiary hospital (King Saud University Medical City [KSUMC]), Riyadh, Saudi Arabia. The study targeted potential participants among healthcare workers at KSUMC. We assessed healthcare workers' perceptions and beliefs about the COVID-19 vaccine via a questionnaire that was distributed via social media applications such as WhatsApp, Twitter, and Google. Participants were informed about the questionnaire before they filled it out, and they were asked to respond to three screening questions before beginning the main questionnaire. These screening questions ensured that the participants met the inclusion criteria. Included participants were over the age of 18, agreed to answer the questions, and were residents of Saudi Arabia. The participants filled out the self-administered questionnaire. RESULTS: A total of 529 participants completed the questionnaires. All participants were vaccinated, 68% were female, 55% were married, 35% had been working for less than five years, and 65% had a bachelor's degree. More than half of participants had not previously been infected with COVID-19, and most did not interact with COVID-19 patients. More convenient access to the vaccine increased the odds ratio of participant vaccination by 0.39. An increase in the number of vaccinated friends and family members increased the odds ratio of participant vaccination by 0.30. However, COVID- 19 vaccination mandates decreased the odds ratio of participant vaccination by 0.27. The fitted linear regression model explained 32% of the variation observed in the dependent variable, acceptance of the COVID-19 vaccine, and the adjusted R squared was 0.32. The fitted regression model was statistically significant at a 95% confidence interval; the p-value was 0.00001. CONCLUSION: In Saudi Arabia, there is an immense need to increase uptake of the COVID-19 vaccine. This requires encouraging more positive beliefs and attitudes regarding vaccination in general and the COVID-19 vaccine in particular.
