Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard care for sepsis is predominantly supportive, with few therapeutic options available. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. It was discovered that the ER-resident protein sigma-1 receptor (S1R) is an essential inhibitor of cytokine production in a preclinical model of septic shock.
The antidepressant fluvoxamine can bind sigma-1 and acts as an agonist. Therapeutic treatment of mice in two inflammatory models revealed that fluvoxamine lowered inflammatory cytokine production and improved survival. Only 9% of the mice given fluvoxamine died, compared with 62% of the untreated mice. The results suggest that repurposing fluvoxamine to enhance sigma-1 activity may be beneficial for treating sepsis.
Structure of fluvoxamine
Fluvoxamine is not unknown for the cyclodextrin researchers. Molecular modeling data suggest that fluvoxamine/β-CD inclusion complex has a 1:1 stoichiometry and that the CF3-substituted ring of fluvoxamine is embedded in the cavity of β-CD, indicating a good agreement between molecular modeling calculation and experimental data (NMR results). 
A Japanese patent application describes its HPBCD complex for oral administration. The formulation has lower side effects, such as less sensing of numbness. 
On the other hand, Arima’s group observed that dimethylacetyl-β-cyclodextrin had inhibitory activity against the production of nitric oxide (NO) and various proinflammatory cytokines including tumor necrosis factor-α (TNF-α) in murine macrophages. The in vivo experiments by intraperitoneal administration showed 50% survival after 24 h compared to 0% for untreated and 10% for HPBCD-treated mice in lipopolysaccharide-induced septic shock. 
- A. Rosen, S.M. Seki, A. Fernandez-Castaneda, R.M. Beiter, J.D. Eccles, J.A. Woodfolk, A. Gaultier (2019) Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis, Science Translational Medicine DOI: http://dx.doi.org/10.1126/scitranslmed.aau5266
- S. Dastjerdi, M. Shamsipur (2016) 19F -nuclear magnetic resonance spectroscopy as a tool to investigate host-guest complexation of some antidepressant drugs with natural and modified cyclodextrins. Tropical Journal of Pharmaceutical Research 15(12), pp. 2675-2682. DOI: http://dx.doi.org/10.4314/tjpr.v15i12.20
- Yokoi, Y. (2011) Oral pharmaceutical compositions containing fluvoxamine maleate and cyclodextrins. Japanese Patent Application JP 2011088858
- Arima, K. Motoyama, A. Matsukawa, Y. Nishimoto, F. Hirayama, K. Uekama, (2005) Inhibitory effects of dimethylacetyl-β-cyclodextrin on lipopolysaccharide-induced macrophage activation and endotoxin shock in mice. Biochemical Pharmacology 70(10), pp. 1506-1517. https://doi.org/10.1016/j.bcp.2005.08.021