Posterior Reversible Encephalopathy Syndrome in a Patient With SARS-CoV-2 Infection Treated With Tocilizumab.

As the world has struggled to adapt to the coronavirus disease (COVID-19) pandemic, new evidence has emerged suggesting that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may manifest with a wide variety of neurologic symptoms. We present the case of a 70-year-old patient hospitalized for COVID-19 related pneumonia who was treated with off-label interleukin (IL)-6 inhibitor tocilizumab and eventually developed prolonged delirium. MRI findings were consistent with posterior reversible encephalopathy syndrome (PRES). PRES was felt to be from SARS-CoV-2 infection, tocilizumab, or a combination. The patient received symptomatic treatment without success. These findings are consistent with few other recent reports, which have chronicled PRES findings in patients with SARS-CoV-2 infections. However, this is only the second example of PRES in a COVID-19 patient treated with tocilizumab. While cases of PRES have been noted to occur with other infectious diseases, clinicians should be aware of the association with SARS-CoV-2 infection and tocilizumab therapy, particularly when considering tocilizumab treatment outside its approved indication. Future research efforts are needed to establish evidence-based guidelines for the management of these patients.

Kinetic and thermodynamic rationale for suberoylanilide hydroxamic acid being a preferential human histone deacetylase 8 inhibitor as compared to the structurally similar ligand, trichostatin a.

Of the different hydroxamate-based histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic acid (SAHA) has been approved by the Food and Drug Administration for the treatment of T-cell lymphoma. Interestingly, a structurally similar inhibitor, trichostatin A (TSA), which has a higher in vitro inhibitory potency against HDAC8, reportedly shows poor efficacy in clinical settings. To gain molecular insight into this discriminatory feature, we performed transient kinetic and isothermal titration calorimetric studies for the interaction of SAHA and TSA with the recombinant form of human HDAC8. The transient kinetic data revealed that the binding of both inhibitors to the enzyme showed biphasic profiles, which represented an initial encounter of the enzyme with the inhibitor followed by the isomerization of the transient enzyme-inhibitor complexes. The temperature-dependent transient kinetic studies with these inhibitors revealed that the bimolecular process is primarily dominated by favorable enthalpic changes, as opposed to the isomerization step, which is solely contributed by entropic changes. The standard binding enthalpy (ΔH°) of SAHA, deduced from the transient kinetic as well as the isothermal titration calorimetric experiments, was 2-3 kcal/mol higher than that of TSA. The experimental data presented herein suggest that SAHA serves as a preferential (target-specific and -selective) HDAC8 inhibitor as compared to TSA. Arguments that the detailed kinetic and thermodynamic studies may guide the rational design of HDAC inhibitors as therapeutic agents are presented.