Pentoxifylline decreases serum LDH levels and increases lymphocyte count in COVID-19 patients: Results from an external pilot study.

We have previously hypothesized that pentoxifylline could be beneficial for the treatment of COVID-19 given its potential to restore the immune response equilibrium, reduce the impact of the disease on the endothelium and alveolar epithelial cells, and improve the circulatory function.Serum lactate dehydrogenase (LDH) and lymphocyte count are accessible biomarkers that correlate with the severity of COVID-19, the need for hospitalization, and mortality, reflecting the host immune response's contribution to the seriousness of SARS-CoV-2 infection. We carried out this external pilot study on 38 patients with moderate and severe COVID-19 to test the effect pentoxifylline on parameters such as LDH, lymphocyte count, days of hospitalization, mortality, and proportion of patients requiring intubation. Twenty-six patients were randomized to receive 400 mg of pentoxifylline t.i.d. plus standard therapy (pentoxifylline group), while the rest received the standard treatment (control group). Linear regression models were built for statistically significant parameters. Pentoxifylline treatment was associated with a 64.25% increase (CI95% 11.83, 116.68) in lymphocyte count and a 29.61% decrease (CI95% 15.11, 44.10) in serum LDH. Although a trend towards reduced days of hospitalization, mortality, and proportion of patients requiring intubation was observed, no statistically significant difference was found for these parameters. Our findings open the possibility of pentoxifylline being repositioned as a drug for COVID-19 treatment with the advantages of a proven safety profile, availability, and no risk of immunosuppression; however, this evidence needs to be confirmed in a pragmatic randomized controlled trial.

Repositioning of pentoxifylline as an immunomodulator and regulator of the renin-angiotensin system in the treatment of COVID-19.

Pentoxifylline (PTX) is a phosphodiesterase inhibitor that increases cyclic adenosine monophosphate levels, which in turn activate protein kinase, leading to a reduction in the synthesis of proinflammatory cytokines to ultimately influence the renin-angiotensin system (RAS) in vitro by inhibiting angiotensin 1 receptor (AT1R) expression. The rheological, anti-inflammatory, and renin-angiotensin axis properties of PTX highlight this drug as a therapeutic treatment alternative for patients with COVID-19 by helping reduce the production of the inflammatory cytokines without deleterious effects on the immune system to delay viral clearance. Moreover, PTX can restore the balance of the immune response, reduce damage to the endothelium and alveolar epithelial cells, improve circulation, and prevent microvascular thrombosis. There is further evidence that PTX can improve ventilatory parameters. Therefore, we propose repositioning PTX in the treatment of COVID-19. The main advantage of repositioning PTX is that it is an affordable drug that is already available worldwide with an established safety profile, further offering the possibility of immediately analysing the result of its use and associated success rates. Another advantage is that PTX selectively reduces the concentration of TNF-α mRNA in cells, which, in the case of an acute infectious state such as COVID-19, would seem to offer a more strategic approach.

Enzyme activities involved in the glutamate-glutamine cycle are altered to reduce glutamate after spinal cord injury in rats.

Glutamate (Glu) neurotransmitter is involved in the excitotoxic damage after spinal cord injury (SCI). Glu is transformed into glutamine (Gln) by glutamine synthetase (GS) enzyme in glial cells. Once into the neurons, Gln is transformed back into Glu by phosphate-activated glutaminase (PAG). Glu is also a precursor for the synthesis of γ-aminobutyric acid through the action of the glutamic acid decarboxylase (GAD) enzyme. The contribution of all these Glu biotransformations after SCI has not been determined. The aim of this work is to characterize the role of GS, PAG, and GAD in the acute phase after SCI. Female Wistar rats were subjected to SCI by contusion and killed 2, 4, 8, and 12 h after surgery. Sham-injury animals, killed at the same time points served as controls. PAG and GAD activities were analyzed by high-performance liquid chromatography, whereas GS activity was determined by ultraviolet-visible spectroscopy. GS activity showed a significant decrease in animals with SCI at all time points evaluated versus the sham group. Similarly, the activity of the PAG was decreased at all time points compared with the control group. Finally, GAD activity was significantly increased in the SCI group when measured at 2, 4, and 8 h after lesion. The results of this study suggest that excitotoxicity is highly regulated through Glu/Gln and Glu/γ-aminobutyric acid cycles as an important mechanism to prevent further damage in the acute phase after lesion.

Differential time-course of the increase of antioxidant thiol-defenses in the acute phase after spinal cord injury in rats.

Spinal cord injury (SCI) is a world-wide health problem. After traumatic injury, spinal cord tissue starts a series of self-destructive mechanisms, known as the secondary lesion. The leading mechanisms of damage after SCI are excitotoxicity, free radicals' overproduction, inflammation and apoptosis. Metallothionein (MT) and reduced glutathione (GSH) are low-molecular-weight, cysteine-rich peptides able to scavenge free radicals. MT and GSH participation as neuroprotective molecules after SCI is unknown. The aim of the present study is to describe the changes of MT and GSH contents and GSH peroxidase (GPx) activity in the acute phase after SCI in rats. Female Wistar rats weighing 200-250g were submitted to spinal cord contusion model, by means of a computer-controlled device (NYU impactor). Rats receiving laminectomy were used as a control group. Animals were killed 2, 4, 12 and 24h after surgery. MT was quantified by the silver-saturation method, using atomic absorption spectrophotometry. GSH and GPx were assayed by spectrophotometry. Results indicate an increased MT content by effect of SCI, only at 4 and 24h, as compared to sham group values. Meanwhile, GSH was found decreased at 4, 12 and 24h after SCI. Interestingly, GPx activity was raised at all time points, indicating that this enzymatic defense is activated soon after SCI. Results suggest that thiol-based defenses, MT and GSH, are differentially expressed by spinal cord tissue to cope with the various processes of damage after lesion.

Acute alterations of glutamate, glutamine, GABA, and other amino acids after spinal cord contusion in rats.

Spinal cord injury (SCI) leads to an alteration of energetic metabolism. As a consequence, glutamate, glutamine, aspartate and other important amino acids are altered after damage, leading to important disregulation of the neurochemical pathways. In the present study, we characterized the acute-phase changes in tissue concentration of amino acids involved in neurotransmitter and non-neurotransmitter actions after SCI by contusion in rats. Animals were submitted to either laminectomy or SCI by contusion and sacrificed at 2, 4, 8, and 12 h after lesion, for the analysis of tissue amino acids by HPLC. Results showed that both aspartate and glutamate contents diminished after SCI, while glutamine concentrations raised, however, the sum of molar concentrations of glutamate plus glutamine remained unchanged at all time points. GABA concentrations increased versus control group, while glycine remained unchanged. Finally, citrulline levels increased by effect of SCI, while taurine-increased only 4 h after lesion. Results indicate complex acute-phase changes in amino acids concentrations after SCI, reflecting the different damaging processes unchained after lesion.