Effect of Montelukast Versus Co Enzyme in Sepsis

Overview

Sepsis is a leading cause of morbidity and mortality in intensive care units. Sepsis is a life-threatening organ dysfunction linked to a dysregulated host response to infection. It leads to overwhelming of systemic inflammation causing release of proinflammatory cytokines, which trigger overproduction of reactive oxygen species. Several animal studies with sepsis proved the effectiveness of montelukast and coenzyme Q10 as anti-inflammatory and antioxidants in preventing end organ damage, deterioration, and reducing mortality. Therefore, a clinical trial will be carried out to compare the efficacy and safety of montelukast versus co enzyme Q10 on the clinical outcome in patients with sepsis.

Sepsis is now defined as a life-threatening organ dysfunction linked to a dysregulated host response to infection. This organ dysfunction can be identified using the Sequential Organ Failure Assessment (SOFA). Sepsis is a leading cause of morbidity and mortality in the intensive care unit (ICU). It has been reported that the short-term mortality rate ranges from 30 to 50%, depending on illness severity. The global epidemiological burden of sepsis is, however, difficult to ascertain. It is estimated more than 30 million people are affected by sepsis every year worldwide, resulting in potentially 6 million deaths annually. The mortality rate estimated to be 30% in sepsis and 80% in septic shock in the USA, and 12.8% in sepsis and 45.7% in septic shock in Europe. Reduced rates of reporting may influence estimations in developing countries. Sepsis is characterized by overwhelming systemic inflammation causing a release of proinflammatory cytokines. The presence of infection leads to initial activation of the innate immune response. The resulting pro-inflammatory host response is both complex and redundant, involving many soluble inflammatory mediators, including cytokines \[e.g., tumor necrosis factor (TNF) α and interleukin (IL) 6\] and reactive oxygen/nitrogen species (e.g., nitric oxide (NO) and peroxynitrite), as well as multiple cell types, including neutrophils, macrophages, platelets, and endothelial cells. The up regulation of pro- and anti-inflammatory pathways leads to a system-wide release of cytokines, mediators, and pathogen-related molecules, resulting in activation of coagulation, and complement cascades, the resulting inflammation leads to progressive tissue damage, finally causing multi-organ dysfunction. Sepsis-induced mitochondrial damage or dysfunction can result in cellular metabolic disorders, insufficient energy production, and oxidative stress, which give rise to the apoptosis of organ cells and immune cells, thus ultimately generate immune disorders, multiple organ failure, and even death. As during sepsis limited amount of oxygen supply, the free radical production increases dramatically while the machinery of the antioxidant system becomes damaged. Activated leukocytes release inflammatory cytokines, which trigger overproduction of reactive nitrogen species (RNS) and nitrogen oxide. Nitrogen oxide can bind to reactive oxygen species (ROS) peroxides to form RNS, which unfortunately brings about further damage to mitochondria, including mitochondrial, and mitochondrial DNA damage. Hence, different treatment strategies have focused in minimizing this inflammatory syndrome without reaching a consensus. Numerous anti-inflammatory and antioxidants therapies have been proposed and studied, including corticosteroids, anti-cytokine approaches, selenium, vitamin C, as well as other various basic research-driven therapies. Montelukast is a cysteinyl leukotriene receptor antagonist with anti-inflammatory and antioxidant properties. Cysteinyl leukotrienes (CysLTs) are formed by inflammatory cells, such as mast cells, eosinophils, and basophils. CysLTs are potent pro-inflammatory mediators that increase microvascular permeability and are effective chemotactic agents. CysLT receptors are present in the airways, liver, and other organs. CysLT1 antagonists, such as Montelukast, have been reported to ameliorate experimental colitis, burn- and sepsis-induced multi-organ damage. Montelukast acts by inhibiting neutrophil infiltration, balancing oxidant-antioxidant status, and controlling inflammatory mediator generation. Montelukast possesses anti-inflammatory effect through the inhibition of TNF-alpha stimulated by IL-8 expression through changes in nuclear factor-Kb, and the antioxidant effect is due to decreasing the ROS, and reactive nitrogen species (e.g. NO) production, and hence it could help ameliorate inflammation associated with sepsis. Several studies reported montelukast as a safe and tolerable medication. It was reported in 1996 that the administration of 10 mg orally, montelukast to healthy adult patients, was well tolerated. Four years later, Storms and colleagues published safety data from 11 multicenters, randomized, controlled montelukast phase, which included numerous adult and pediatric patients. They reported that the administration of montelukast over 5 months as 200 mg/day, which is 20 times higher than the recommended clinical dose, was also tolerable and similar to placebo. Many experimental model studies showed how montelukast is effective against sepsis. Şener and his colleagues postulated that montelukast possesses an anti-inflammatory effect on sepsis-induced hepatic and intestinal damage and protects against oxidative injury by a neutrophil-dependent mechanism. Another study concluded that montelukast treatment after Cecal Ligation and Puncture-Induced Sepsis potentially reduced mortality in experimental sepsis that was attributed to the reduction of organs' oxidative stress and the decrease in plasma cytokine levels. It was found also that montelukast might have cardioprotective effects against the inflammatory process during endotoxemia. This effect was attributed to its antioxidant and/or anti-inflammatory properties. Coenzyme Q10 (Co enzyme Q10) is a fat-soluble molecule, naturally found in the diet and synthesized endogenously by all cells of our body in the mitochondrial inner membrane, that exists both in oxidized form (ubiquinone) and reduced form (ubiquinol). Co enzyme Q10 plays an essential role in the electron transport chain of mitochondria as the carrier of electrons from complex I and II to complex III. Disruption of this mechanism can compromise oxidative phosphorylation, thereby leading to decreased levels of cellular energy (adenosine triphosphate (ATP)) production. Previous studies have reported that Co enzyme Q10 (Co enzyme Q10) can prevent the start and diffusion of lipid peroxidation, scavenge free radicals, and decrease pro-inflammatory cytokine production. The deficiency of Co enzyme Q10 induced by mitochondrial failure in sepsis may play a role in hypoxia, oxidative organ damage, hypo-perfusion, and ultimately leading to death. There is considerable evidence from randomized controlled clinical studies that Co enzyme Q10 can ameliorate such inflammation, via effects on circulatory pro-inflammatory markers such as C-reactive protein (CRP), interleukins 1 and 8 (IL-1, IL-8), and tumor necrosis factor-alpha (TNF). CoenzymeQ10 showed its activity against sepsis in many previous studies. Coenzyme Q10 administered during the hypodynamic phase of sepsis decreased splenic, renal and cardiac damage and organ damage. It also assisted in the reduction of septic liver injury as indicated by the upregulation of beclin 1 as well as the suppression of AST, ALT, ALP, p62, IL-6, TNF-α, NLRP 3, and IL-1β as reported in another animal study. Moreover, it has been reported that critically ill patients had lower levels of CoenzymeQ10 levels on ICU admission compared to healthy controls and exhibited a further decrease in sepsis and septic shock. Donnino and colleagues provided original data suggesting a CoenzymeQ10 deficiency in patients with septic shock, and this is a new step toward a study testing CoenzymeQ10 as a potential therapeutic agent for patients with septic shock