Early use of oral antiviral drugs and the risk of post COVID-19 syndrome: a systematic review and network meta-analysis.

OBJECTIVES: This study aimed to determine the association of early use of oral antiviral drugs (including nirmatrelvir-ritonavir and molnupiravir) with the risk of PCC and compare the possible efficacy of nirmatrelvir-ritonavir and molnupiravir. METHODS: PubMed, Web of Science, Embase, Cochrane, MedRxiv, and Psycinfo were searched from inception until November 1, 2023. We included studies that assessed the effect of oral antiviral drugs on the incidence of PCC. Pairwise and network meta-analyses were conducted using a random-effects model. Risk ratios (RRs) for oral antiviral drugs were calculated with a CI. RESULTS: Nine observational studies containing 866,066 patients were included, in which nirmatrelvir-ritonavir and molnupiravir were evaluated in eight and two studies respectively, with both drugs evaluated in one study. Pair-wise meta-analysis showed that early oral antiviral drugs reduced PCC risk (RR 0.77, 95% CI 0.68-0.88). Network meta-analysis showed that nirmatrelvir-ritonavir may perform better than molnupiravir (surface under the cumulative ranking curve: 95.5% vs. 28.8%) at reducing PCC risk. CONCLUSIONS: Early use of oral antiviral drugs may potentially protect against developing PCC sequelae in non-hospitalized patients with COVID-19. These findings support the standardized administration of oral antiviral drugs in patients during the acute phase of COVID-19 according to the guidelines.

Transformation of chronic disease management: Before and after the COVID-19 outbreak.

Adults with chronic diseases often experience a decline in their quality of life along with frequent exacerbations. These diseases can cause anxiety and impose a significant economic burden. Self-management is a crucial aspect of treatment outside of the hospital and can improve quality of life and reduce the financial burden resulting from unexpected hospitalizations. With the COVID-19 pandemic, telehealth has become a vital tool for both medical professionals and patients; many in-person appointments have been canceled due to the pandemic, leading to increased reliance on online resources. This article aimed to discuss various methods of chronic disease management, both traditional self-management and modern telehealth strategies, comparing before and after the COVID-19 outbreak and highlighting challenges that have emerged.

ATRA improves endothelial dysfunction in atherosclerotic rabbits by decreasing CAV­1 expression and enhancing eNOS activity.

The aim of the present study was to explore the protective effects and possible mechanisms of all­trans­retinoic acid (ATRA) against atherosclerosis (AS). Rabbits were randomly allocated for standard or high­fat diet with or without ATRA. After 12 weeks, the aortic rings of the rabbits were removed. Endothelium­dependent relaxation (EDR) induced by acetylcholine and non­endothelium­dependent relaxation induced by sodium nitroprusside in the thoracic aorta were evaluated. NO level and eNOS activity were measured according to the protocol of NO and eNOS ELISA kits. The permeability and morphology of the arterial walls were identified by immunofluorescence and H&E staining respectively. The expression of caveolin­1 (CAV­1) and occludin was analyzed using western blotting and immunohistochemistry. The EDR function was significantly reduced in the AS rabbits compared with the normal group, however it was elevated following treatment with ATRA. The eNOS activity and NO level were reduced in the AS group, however were notably increased following oral administration of ATRA. There was an enhancement of endothelial permeability in the AS group compared with the normal group, which decreased following ATRA treatment. Western blot analysis and immunohistochemical analysis identified an increase in occludin expression after treatment with ATRA, in contrast to CAV­1 expression under the same conditions. ATRA is able to ameliorate high­fat­induced AS in rabbits, which is mediated through the activation of eNOS and downregulating CAV­1 expression.

Apoptotic events induced by high glucose in human hepatoma HepG2 cells involve endoplasmic reticulum stress and MAPK's activation.

To investigate whether endoplasmic reticulum (ER) stress participates in the induction of apoptosis in HepG2 cells exposed to high glucose and explore its probable mechanism. A series of experiments were performed following HepG2 cells treated with different concentrations of glucose for 48 h. The apoptosis was detected by means of Hoechst staining and flow cytometry. Caspase-3 activity assay was performed by measuring the pNA (p-nitroaniline) to indirectly reveal the catalytic activity of caspase-3. The expression levels of apoptosis-, ER stress-associated proteins and MAPKs were analyzed by western blot. To further characterize the molecular mechanisms, the effects of antioxidant alpha-lipoic acid (ALA) and specific inhibitors for JNK and p38 (SP600125 and SB203580, respectively) were examined by Hoechst staining, immunofluorescence, and western blot. After HepG2 cells were incubated with high glucose for 48 h, both Hoechst staining and flow cytometry analyses unveiled the apoptosis of HepG2 cells. Caspase-3 activity assay revealed that the activity of caspase-3 was enhanced. Western blot showed an enhancement of pro-caspase-9 degradation, a reduction of Bcl-2/Bax ratio, a decrease in GRP78 expression, and increases in CHOP and p47/phox levels. In addition, western blot analysis presented that phosphorylation of p38 and JNK was triggered and that the expression of ASK1 was elevated. In the case of the contributions of oxidative stress and the MAPK signaling pathways, all ALA, SP600125 and SB203580 were able to largely rescue high glucose-induced apoptosis. High glucose induced the apoptosis in HepG2 cells through the activation of ASK1-p38/JNK pathway mediated by ER stress and oxidative stress.

[N-methyl-3H3]AZ10419369 binding to the 5-HT1B receptor: in vitro characterization and in vivo receptor occupancy.

Radiotracers suitable for positron emission tomography studies often serve as preclinical tools for in vivo receptor occupancy. The serotonin 1B receptor (5-HT(1B)) subtype is a pharmacological target used to discover treatments for various psychiatric and neurological disorders. In psychiatry, 5-HT(1B) antagonists may provide novel therapeutics for depression and anxiety. We report on the in vitro and in vivo evaluation of tritiated 5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylicacid (4-morpholin-4-yl-phenyl)-amide ([N-methyl-(3)H(3)]AZ10419369), a potent 5-HT(1B) radiotracer. [N-methyl-(3)H(3)]-AZ10419369 showed saturable single-site high-affinity in vitro binding (guinea pig, K(d) = 0.38 and human, K(d) = 0.37) to guinea pig or human 5-HT(1B) receptors in recombinant membranes and high-affinity (K(d) = 1.9 nM) saturable (B(max) = 0.099 pmol/mg protein) binding in membranes from guinea pig striatum. When [N-methyl-(3)H(3)]AZ10419369 was administered to guinea pigs by intravenous bolus, the measured radioactivity was up to 5-fold higher in brain areas containing the 5-HT(1B) receptor (striatum/globus pallidus, midbrain, hypothalamus, and frontal cortex) compared with the cerebellum, the nonspecific binding region. Specific uptake peaked 30 min after injection with slow dissociation from target regions, as suggested by the in vitro binding kinetic profile. Pretreatment with 6-fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide (AZD1134) and 2-aminotetralin (AR-A000002), 5-HT(1B)-selective ligands, inhibited [N-methyl-(3)H(3)]AZ10419369-specific binding in a dose-dependent manner. In the guinea pig striatum, AZD1134 (ED(50) = 0.017 mg/kg) occupies a greater percentage of the 5-HT(1B) receptors at a lower administered dose than AR-A000002 (ED(50) = 2.5 mg/kg). In vivo receptor occupancy is an essential component to build binding-efficacy-exposure relationships and compare novel compound pharmacology. [N-methyl-(3)H(3)]AZ10419369 is a useful preclinical tool for investigating 5-HT(1B) receptor occupancy for novel compounds targeting this receptor.