ABSTRACT
Background: ASC10 is an oral double prodrug of the active antiviral ribonucleoside analog, ASC10-A (also known as beta-d-N4-hydroxycytidine), which is a potent inhibitor of SARS-CoV-2. ASC10 is rapidly metabolized into ASC10-A in vivo after oral dosing. Here, we report the results of the first-in-human, phase 1 study to determine the safety, tolerability, and pharmacokinetics (PK) of ASC10 in healthy subjects, and to assess the food effect on the pharmacokinetics. Method(s): This study included 2 parts. Part 1 (multiple-ascending-dose) consisted of 6 cohorts (8 or 12 subjects per cohort). Eligible subjects were randomized in a 3:1 ratio to receive either twice-daily (BID) doses of 50 to 800 mg ASC10 or placebo for 5.5 days, and were then followed for 7 days for safety. In Part 2 (food effect), 12 subjects were randomized in a 1:1 ratio to either 800 mg ASC10 in the fed state followed by 800 mg in the fasted state, or vice versa, with a 7-day washout period between doses. PK blood samples were collected and measured for ASC10-A along with ASC10 and molnupiravir. Safety assessments included monitoring of adverse events (AEs), measurement of vital signs, clinical laboratory tests, and physical examinations. Result(s): ASC10-A was the major circulating metabolite ( >99.94%) in subjects after oral dosing of ASC10. ASC10-A appeared rapidly in plasma, with a median Tmax of 1.00 to 2.00 h, and declined with a geometric t1/2 of approximately 1.10 to 3.04 h. After multiple dosing for 5.5 days, both Cmax and AUC of ASC10-A increased in a dose-proportional manner from doses of 50 to 800 mg BID without accumulation. of ASC10-A in the fed state occurred slightly later, with a median of 3.99 h postdose versus 2.00 h (fasted state). However, Cmax and AUC were very similar or the same between fed and fasted states. Thus, administration of ASC10 with food is unlikely to have an effect on exposure. The incidence of AEs was similar between subjects receiving ASC10 or placebo (both 66.7%) and 95.0% of AEs were mild. There were no serious adverse events as well as no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Conclusion(s): Results of this study showed that ASC10 was well tolerated, and the increase in plasma exposure of ASC10-A was dose proportional across the range of doses tested with no accumulation and no food effect. 800 mg ASC10 BID is selected for further studies in patients infected with SARS-CoV-2.
ABSTRACT
OBJECTIVE: We sought to determine the risk of contracting coronavirus disease (COVID-19) in individuals with alopecia areata (AA) compared to individuals without AA. METHOD(S): We queried the Symphony Health-derived data from the COVID-19 Research Database, and individuals with a diagnosis of AA from 2019 to 2020 were included in the AA cohort. Subjects with no record of AA diagnosis from 2019 to 2020 were randomly placed in the control group in a 4:1 size ratio compared with the AA group. Laboratory-confirmed cases of COVID-19 between January 1, 2020, and September 1, 2021, were identified. RESULT(S): The AA and non-AA cohorts included 73,784 and 280,991 subjects, respectively. The COVID-19 incidence rate ratio (IRR) for adults with AA was 0.72 (95% CI 0.68, 0.76) compared with adults without AA (p<0.001). Within the AA cohort, moderate-severe AA showed a similar decreased risk in COVID-19 infection compared to mild AA. LIMITATIONS: This study is limited by its retrospective nature and the use of ICD-10 codes for the identification of individuals with AA and COVID-19, which may underestimate the true burden of disease. CONCLUSION(S): Individuals with AA have a slightly decreased risk of contracting COVID-19. Notably, it has been demonstrated that interferon-gamma (IFN- gamma) leads to the downregulation of the angiotensin-converting enzyme 2 (ACE2), the SARS-CoV receptor.1 Thus, it is possible that increased levels of IFN- gamma seen in individuals with AA confer some protection against this viral infection.Copyright © 2022 Matrix Medical Communications. All rights reserved.
ABSTRACT
Stimulator of interferon genes, namely STING, an adaptor protein located in the endoplasmic reticulum, has been recognized as a shining target for cancer and infection research. However, STING agonists cyclic dinucleotides (CDNs) have shown almost zero efficacy in phase I clinical trials as a monotherapy, likely due to poor cellular permeability and rapid diffusion despite intratumoral injection. These deficiencies further affect other applications of CDNs, such as pandemic SARS-CoV-2 prevention and therapy. Here, we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene, namely CASTING (CAlixarene-STING), to improve CDN druggability, including degradation stability, cellular permeability, and tissue retention. CASTING efficiently enhances the immunostimulatory potency of CDG(SF) [a chemically modified cyclic di-GMP (CDG)] to generate an immunogenic microenvironment for melanoma regression, anti-PD-1 response rate increase, and durable memory formation against tumor recurrence. More importantly, CASTING displays a superior adjuvant activity on SARS-CoV-2 recombinant spike/receptor binding domain vaccines, inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo. Collectively, the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists. [GRAPHICS] .
ABSTRACT
Amid the current COVID-19 pandemic, there is concern for increased risk of infection while on immunomodulatory therapy. Omalizumab, a monoclonal antibody, is an add-on therapy for the treatment of chronic idiopathic urticaria (CIU) when first line therapy alone fails to achieve appropriate response. Current understanding of the response to COVID-19 infection is largely varied and actively under investigation. In the context of a pandemic, it is important to consider the safety profile of omalizumab as it modulates the immune system. We reviewed data from pivotal Phase III clinical trials investigating omalizumab use in CIU patients with a focus on reported respiratory-related adverse events (AEs) to assess these risks. Results from three phase III trials show that omalizumab adjunct therapy does not significantly increase infection risk and severity.
ABSTRACT
Background: Due to the public health risk associated with SARS-CoV-2 (COVID-19) infection, universal use of face masks has been recommended to protect against viral spread. Adverse facial reactions from the utilization of masks in the general public are poorly characterized in literature. Objective: We aimed to provide a systematic review of studies reporting adverse facial reactions associated with use of face masks during the COVID-19 pandemic. Methods: PubMed and Cochrane databases were searched using the following search terms: "masks" AND "skin reactions, facial dermatosis, rash, acne, atopic dermatitis, rosacea, OR seborrheic dermatitis." Methods: A total of 954 cases of dermatological adverse effects were reported. Over 17 different adverse facial reactions were found, including the top 10 in order: itch (370, 38.8%), indentation/ear pain (102, 10.7%), discomfort (90, 9.4%), erythema (72, 7.5%), dryness (62, 6.5%), rash (60, 6.3%), scarring (42, 4.4%), desquamation (22, 2.3%), pain (19, 2.0%), burning (19, 2.0%), and wheals (7, 0.7%). Face masks can increase acne (n=44), rosacea (n=14), and seborrheic dermatitis (n=9). Limitations: Publication bias of articles, with limited studies available regarding this topic. Conclusion: Wearing face masks to protect from COVID-19 can increase adverse facial dermatoses and exacerbate underlying dermatology conditions;however, several preventative measures may be taken.
ABSTRACT
There is no specific drug against COVID-19, but berberine (BBR) has moderate anti-SARS-CoV-2 pseudovirus activity. Taking BBR as the lead, 18 novel N-cycloberberine derivatives were synthesized and evaluated for their anti-SARS-CoV-2 pseudovirus activities in vitro. Structure-activity relationship analysis revealed that introducing an appropriate heterocyclic group at position 9 might be beneficial for potency. Among the tested compounds, compound 3m showed the most potent activity against SARS-CoV-2, with EC50 value of 1.61 μmol·L-1 and SI value of 22.2, much better than that of BBR. Additional experiment indicated that 3m had inhibitory activity on multiple processes in viral invasion, including adsorption and membrane fusion, suggesting a multi-target synergistic mechanism of action. These results provide a novel family of lead compounds for the discovery of anti-SARS-CoV-2 candidates. © 2021, Chinese Pharmaceutical Association. All rights reserved.