Search

Summary: Background: An increasing number of countries have or are considering legalizing cannabis. One concern is that legalization of cannabis will result in increased cannabis use and in turn a higher prevalence of anxiety disorders. We examined changes in emergency department (ED) visits for anxiety disorders with cannabis involvement in Ontario, over a period that involved medical and non-medical cannabis legalization. Methods: This repeated cross-sectional population-based study identified all ED visits for anxiety disorders from residents of Ontario, Canada aged 10–105 between 2008 and 2022 (n = 15.7 million individuals). We used interrupted time series analyses to examine immediate and gradual changes in cannabis-involvement and alcohol-involvement (control condition) over four policy periods: medical cannabis legalization (January 2008–November 2015), expanded medical access (December 2015–September 2018), non-medical cannabis legalization with restrictions (October 2018–February 2020), and commercialization which overlapped with the COVID-19 pandemic (March 2020–December 2022). Poisson models were used to generate incidence rate ratios with 95% confidence intervals. Findings: Over the 14-year study, there were 438,700 individuals with one or more ED visits for anxiety disorders of which 3880 (0.89%) individuals had cannabis involvement and 6329 (1.45%) individuals had alcohol involvement. During the commercialization/COVID-19 period monthly rates of anxiety disorders with cannabis-involvement were 156% higher (0.11 vs 0.29 per 100,000 individuals) relative to the pre-legalization period, compared to a 27% increase for alcohol-involvement (0.27 vs 0.35 per 1100,000 individuals). Rates of anxiety ED visits with cannabis involvement per 100,000 individuals increased gradually over the study period with no immediate or gradual changes after expanded medical access, legalization with restrictions or commercialization/COVID-19. However, during the commercialization/COVID-19 period there were large declines in total anxiety disorder ED visits and anxiety disorder ED visits with alcohol-involvement. Consequently, during this period there was an immediate 31.4% relative increase in the proportion of anxiety visits with cannabis-involvement (incidence rate ratio [IRR], 1.31; 95% CI 1.05–1.65). Interpretation: We found large relative increases in anxiety disorder ED visits with cannabis involvement over a 14-year period involving medical and non-medical cannabis legalization. These findings may reflect increasing anxiety disorder problems from cannabis use, increasing self-medication of anxiety disorders with cannabis use, or both. The proportion of anxiety ED visits with cannabis involvement increased during the final period of the study but could have been the results of the market commercialization, COVID-19 or both and ongoing monitoring is indicated. Funding: Canadian Institutes of Health Research (grant #452360).

There continues to be no approved drugs for the treatment of Ebola virus disease (EVD). Despite a number of candidate drugs showing limited efficacy in vitro and/or in non-human primate studies, EVD continues to plaque certain areas of Africa without any efficacious treatments yet available. Recently, we have been exploring the potential for anti-malarial drugs to inhibit an in vitro model of Ebola Zaire replication using a transcription-competent virus-like particle (trVLP) assay. We examined the efficacy of chloroquine, amodiaquine and 36 novel anti-parasite quinoline derivatives at inhibiting Ebola virus replication. Drug efficacy was tested by trVLP assay and toxicity by MTT assay. Both chloroquine and amodiaquine were effective for inhibition of Ebola virus replication without significant toxicity. The half-maximal inhibitory concentration (IC50) of chloroquine and amodiaquine to inhibit Ebola virus replication were IC50, Chl = 3.95 µM and IC50, Amo = 1.45 µM, respectively. Additionally, three novel quinoline derivatives were identified as having inhibitory activity and low toxicity for Ebola trVLP replication, with 2NH2Q being the most promising derivative, with an IC50 of 4.66 µM. Quinoline compounds offer many advantages for disease treatment in tropical climates as they are cheap to produce, easy to synthesize and chemically stable. In this report, we have demonstrated the potential of anti-parasite quinolines for further investigation for use in EVD.

Engineering of fragment crystallizable (Fc) domains of therapeutic immunoglobulin (IgG) antibodies to eliminate their immune effector functions while retaining other Fc characteristics has numerous applications, including blocking antigens on Fc gamma (Fcγ) receptor-expressing immune cells. We previously reported on a human IgG2 variant termed IgG2σ with barely detectable activity in antibody-dependent cellular cytotoxicity, phagocytosis, complement activity, and Fcγ receptor binding assays. Here, we extend that work to IgG1 and IgG4 antibodies, alternative subtypes which may offer advantages over IgG2 antibodies. In several in vitro and in vivo assays, the IgG1σ and IgG4σ variants showed equal or even lower Fc-related activities than the corresponding IgG2σ variant. In particular, IgG1σ and IgG4σ variants demonstrate complete lack of effector function as measured by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and in vivo T-cell activation. The IgG1σ and IgG4σ variants showed acceptable solubility and stability, and typical human IgG1 pharmacokinetic profiles in human FcRn-transgenic mice and cynomolgus monkeys. In silico T-cell epitope analyses predict a lack of immunogenicity in humans. Finally, crystal structures and simulations of the IgG1σ and IgG4σ Fc domains can explain the lack of Fc-mediated immune functions. These variants show promise for use in those therapeutic antibodies and Fc fusions for which the Fc domain should be immunologically “silent”.