Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19.

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.

Effect of Ammonium Chloride in addition to standard of care in outpatients and hospitalized COVID-19 patients: A randomized clinical trial.

OBJECTIVE: The COVID-19 pandemic has called an urgent need for drug repurposing to improve the outcome of the disease. Quaternary ammonium compounds have been demonstrated to have antiviral effects and may be of use against SARS-CoV-2 infections. DESIGN: In this double-blind, single-center study, we enrolled patients with positive PCR test and/or CT findings for COVID-19. The participants of each group were randomly assigned to Diphenhydramine Compound (Diphenhydramine + Ammonium Chloride) plus standard of care or to Diphenhydramine alone and standard of care groups. The primary outcome was all-cause mortality within 30 days of randomization. Secondary outcomes include viral burden, clinical status, assessed by a 5-point ordinal scale, and length of stay in hospitalized patients. RESULTS: A total of 120 patients were included in the trial, 60 of which were assigned to the Ammonium Chloride group. The primary endpoint was not statistically different between the two groups (HR: 3.02 (95% CI, 0.57-16.06; p = 0.195)). Recovery time and viral burden were significantly lower in the Ammonium Chloride group, corresponding to an odds ratios of 1.8 (95% CI, 1.15-2.83; p = 0.01) and 7.90 (95% CI, 1.62-14.17; p = 0.014), respectively. CONCLUSION: The findings of this study advocate the careful addition of Ammonium Chloride to standard of care for COVID-19 patients.

Drug Sequestration in Lysosomes as One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition.

Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance.

Widely available lysosome targeting agents should be considered as potential therapy for COVID-19.

While the coronavirus disease 2019 (COVID-19) pandemic advances, the scientific community continues to struggle in the search for treatments. Several improvements have been made, including discovery of the clinical efficacy of chloroquine (CQ) in patients with COVID-19, but effective treatment protocols remain elusive. In the search for novel treatment options, many scientists have used the in-silico approach to identify compounds that could interfere with the key molecules involved in entrance, replication or dissemination of severe acute respiratory syndrome coronavirus-2. However, most of the identified molecules are not available as pharmacological agents at present, and assessment of their safety and efficacy could take many months. This review took a different approach based on the proposed pharmacodynamic model of CQ in COVID-19. The main mechanism of action responsible for the favourable outcome of patients with COVID-19 treated with CQ seems to be related to a pH-modulation-mediated effect on endolysosomal trafficking, a characteristic of chemical compounds often called 'lysosomotropic agents' because of the physico-chemical properties that enable them to diffuse passively through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicles. This review discusses lysosomotropic and lysosome targeting drugs that are already in clinical use and are characterized by good safety profiles, low cost and wide availability. Some of these drugs -particularly azithromycin and other macrolides, indomethacin and some other non-steroidal anti-inflammatory drugs, proton pump inhibitors and fluoxetine - could provide additional therapeutic benefits in addition to the potential antiviral effect that is still to be confirmed by well-controlled clinical trials. As some of these drugs have probably been used empirically in the treatment of COVID-19, it is hoped that colleagues worldwide will publish patient data to enable evaluation of the potential efficacy of these agents in the clinical context, and rapid implementation in therapeutic protocols if they are shown to have a beneficial effect on clinical outcome.