Exposure to valproic acid is associated with less pulmonary infiltrates and improvements in diverse clinical outcomes and laboratory parameters in patients hospitalized with COVID-19

Abstract

Background Valproic acid (VPA) has shown beneficial effects in vitro against SARS-CoV-2 infection, but no study has analyzed its efficacy in the clinical setting. Methods This multicenter, retrospective study included 165 adult patients receiving VPA at the time of admission to hospital, and 330 controls matched for sex, age and date of admission. A number of clinical, outcome and laboratory parameters were recorded to evaluate differences between the two groups. Four major clinical endpoints were considered: development of lung infiltrates, in-hospital respiratory worsening, ICU admissions and death. Results VPA-treated patients had higher lymphocyte (P<0.0001) and monocyte (P = 0.0002) counts, and lower levels of diverse inflammatory parameters, including a composite biochemical severity score (P = 0.016). VPA patients had shorter duration of symptoms (P<0.0001), were more commonly asymptomatic (P = 0.016), and developed less commonly lung infiltrates (65.8%/88.2%, P<0.0001), respiratory worsening (20.6%/30.6%, P = 0.019) and ICU admissions (6.1%/13.0%, P = 0.018). There was no difference in survival (84.8%/88.8%, P = 0.2), although death was more commonly related to non-COVID-19 causes in the VPA group (36.0%/10.8%, P = 0.017). The cumulative hazard for developing adverse clinical endpoints was higher in controls than in the VPA group for infiltrates (P<0.0001), respiratory worsening (P<0.0001), and ICU admissions (P = 0.001), but not for death (0.6). Multivariate analysis revealed that VPA treatment was independently protective for the development of the first three clinical endpoints (P = 0.0002, P = 0.03, and P = 0.025, respectively), but not for death (P = 0.2). Conclusions VPA-treated patients seem to develop less serious COVID-19 than control patients, according to diverse clinical endpoints and laboratory markers.

A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase–meropenem complex

“…While VPA-G is hydrolyzed and released by the enzyme, carbapenems become permanently captured at the acyl-enzyme stage of the reaction -as it was seen in case of bacterial transpeptidases that these antibiotics also inhibit. Our results gain curious actuality by VPA being currently repurposed for the treatment of COVID-19, proving effective in blocking infection and viral spreading [55][56][57].…”

Targeting ATP2B1 impairs PI3K/Akt/Fox-O3 signaling and reduces SARS-COV-2 replication in vivo

“…The epigenetic changes regulating chromatin structure have been previously implicated in the pathophysiology of SARS-CoV-2 infection (Chlamydas et al, 2021), and, among the epigenetic drugs, the histone deacetylase inhibitor valproic acid (VPA) has been suggested to protect against the development of severe COVID19 (Collazos et al, 2022; Pitt et al, 2021). For the above reason, we have here verified which FOXO transcription factor (whose expression was found downregulated in COVID19 patients, see Figure 3C) was restored following VPA treatment.…”

“…The epigenetic changes regulating chromatin structure have been previously implicated in the pathophysiology of SARS-CoV-2 infection (Chlamydas et al, 2021), and, among the epigenetic drugs, the histone deacetylase inhibitor valproic acid (VPA) has been suggested to protect against the development of severe COVID19 (Collazos et al, 2022;Pitt et al, 2021).…”

A comprehensive update on CIDO: the community-based coronavirus infectious disease ontology

“…This example PPI has two participants: Note that 3C-like proteinase, another name for nsp5, can be inhibited by the chemical nirmatrelvir, a component of the Pfizer drug Paxlovid. Human histone deacetylase 2 (i.e., HDAC2), can be inhibited by a chemical 'Valproic Acid' , which has been found valuable against SARS-CoV-2 [53]. These relations are logically defined in CIDO as follows (Fig.…”