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In the original post about antioxidants and their effects in helping to alleviate sepsis as well as multiple organ failure, the study tested 4 individual antioxidants, melatonin, vitamin E, NAC and vitamin C. Each supplement was tested individually, with melatonin showing the highest activity, but I suggested that since vitamin C and melatonin had different methods of action, there was the potential that if they were used as a combined treatment in sepsis, they might have synergy together and be more effective than either one alone.
Today, a study came out using melatonin and ascorbic acid together in animals with sepsis. Here is a link to that study :
https://onlinelibrary.wiley.com/doi/10.1111/1440-1681.13780
Here is a relevant quote from the study :
' Treatment with MEL, ASA and their combination significantly improved antioxidant capacity and reduced oxidative stress, with the combination treatment being more effective. The combination treatment also significantly reduced TNF-α and IL-1β levels and improved peroxisome proliferator-activated receptor (PPAR), arylesterase (ARE) and paraoxonase (PON) levels in the lung tissue. Histopathological examination showed reduced oedema and lymphocyte infiltration with a lung tissue appearance similar to the control group. Immunohistochemical staining for caspase 3 demonstrated reduced immune positivity in the treatment groups. In conclusion, this study supports the potential synergistic protective effects of MEL and ASA in treating sepsis-induced lung injury. The combination therapy could effectively reduce oxidative stress, inflammation and improve antioxidant capacity in septic rats, suggesting a promising strategy for treating sepsis-induced lung injury. '
So this animal study tends to confirm the idea that melatonin and ascorbic acid are more effective in sepsis than either one alone and although they only tested the lungs and not other major organs, these two proved to be synergistic in terms of lung protection.
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Melatonin
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Melatonin and Major Organ Protection in Sepsis and Multiple Organ Failure:
I have often written about melatonin on Earth Clinic and spoken of its multitude of health benefits for people. One thing that I have often mentioned is that melatonin is protective of the major organs of the body such as the heart, lungs ,kidneys, and liver to name a few.
A new study (May 6, 2023) was just published discussing the use of various antioxidants in people who have sepsis. Sepsis is an extreme uncontrolled response by the body to infection and is life threatening with death as a frequent outcome. Prior to death, multiple organ failure (MOF) can occur and adds significantly to the death rate. It is thought that antioxidants may help improve sepsis outcomes and that is what the following randomized clinical trial sets out to prove or disprove, whether antioxidants can reduce MOF associated with sepsis :
https://www.mdpi.com/2073-4409/12/9/1330
In this study, they used the following four very common antioxidants, NAC, vitamin C, vitamin E, melatonin or no antioxidant in the patient groups with sepsis and MOF to try and determine if these antioxidants would have any benefit in terms of reducing MOF. Of note is that this was a good sized study with 131 patients. Here is an important quote from the study that clearly suggests that antioxidants have potential to significantly reduce MOF :
' In this study, we found that patients with septic shock had a high SOFA ( Sequential Organ Failure Assessment) score on admission to the ICU. They had high PCT and CRP levels, elevated LPO and carbonylation, and decreased TAC. These variables were compensated by the treatment with antioxidants. '
In this study, it was shown that the melatonin group obtained the highest decrease in the SOFA score (75% of the patients). Here is a study quote that shows the response rate to each of the four antioxidants in terms of SOFA score reduction :
' All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NO3-/NO2- but increased Vit C levels. The SOFA score decreased with MT in 75%, Vit C 63% and NAC 50% vs. controls 33% (p = 0.0001, p = 0.03 and p = 0.001 respectively). MT diminished lipid peroxidation (LPO) (p = 0.01) and improved total antioxidant capacity (TAC) (p = 0.04). Vit E increased thiol levels (p = 0.02) and tended to decrease LPO (p = 0.06). Selenium levels were decreased in the control group (p = 0.04). '
The following study quote will give a little more perspective in relationship to the dosages used for each antioxidant :
' In addition to the standard therapy, each group of patients received an antioxidant orally or by nasoenteral tube for 5 days. In the NAC group, 600 mg effervescent tablets were administered every 12 h; in the MT group, extended-release capsules of 50 mg in a daily dose were administered; in the Vit C group, 1 g tablets every 6 h and in the Vit E group, capsules α-tocopherol of 400 IU were given every 8 h.'
So the NAC group received 1200 mg total per day in two divided doses given every 12 hours. The melatonin group received one 50 mg extended release capsule per day. The vitamin C group received 4000 mg per day in 4 divided doses of 1000 mg every 6 hours. The vitamin E group received 1200 IU in three divided doses of 400 IU every 8 hours.
So while melatonin reduced the SOFA score in the most patients (75% of patients in melatonin group) the highest percent of these four antioxidants, it did so at the lowest dose given in this study at just 50 mg per day. This illustrates the potency of melatonin when compared to the other three antioxidants and begs the question of what the SOFA score would have looked like had they used a dose of 100 mg or 200 mg of melatonin per day. Even at these higher doses, melatonin would still have the lowest dose compared to the other antioxidants. In the realm of high dose melatonin, 50 mg per day would not be very high. I take 132 mg per day of melatonin myself and have taken high dose melatonin for many years as a preventative and protective agent against many different diseases and health issues.
Another consideration is the fact that vitamin C and melatonin have different methods of action suggesting potential synergy between these two common and inexpensive antioxidants. What would it look like in this study if they had had a sixth leg to the study that combined vitamin C and melatonin? Or what if they used all four antioxidants combined in the patients?
So the point of all of this is to highlight just how good melatonin and antioxidants in general are at protecting the major organs under high oxidative stress conditions that are very damaging to the organs as seen in sepsis. Not just one organ, but multiple organs all at the same time! This study successfully helps to add further corroboration to what I have been saying about the organ protective effects of melatonin and also gives a basic idea of what dose of melatonin (50 mg) is needed in order to obtain these organ protective results. The question remains, what is the most optimal dose to obtain these protective effects of melatonin, but studies are slowly zeroing in on that currently unknown dose. Clearly 50 mg per day of melatonin has very significant benefit in sepsis induced multiple organ failure (MOF), but is it optimal?
Lastly, but also importantly, this study highlights a noninvasive way to effectively deal with MOF as it relates to sepsis, which has clearly shown it can be deadly as discussed in the following link :
As shown in the above link, worldwide, Sepsis affects 18 million people each year and kills 1400 people each day! This study clearly illustrates that sepsis affects 700,000 people in the US alone. Sepsis also has a mortality rate of 30%, but when you add in MOF to the sepsis, that rate jumps upward significantly to 50%!
This next study ( 2022 ) adds a bit more confirmation to the idea that melatonin may have benefit in sepsis associated MOF.
https://www.sciencedirect.com/science/article/pii/S0753332222009453
The above link says that melatonin is associated with a reduced risk of death in sepsis. It further states that evidence suggests that melatonin may help protect organs from sepsis related damage. The study further goes on to list many of the protective effects that melatonin has shown in many areas of the organs of the human body. The study goes on to reach the following conclusion and I make the same conclusion :
'Melatonin is a promising adjuvant for the treatment of sepsis, as it can protect organs by reducing inflammation, oxidation, endoplasmic reticulum stress, and apoptosis as well as protecting mitochondrial function and regulating various other pathways. The safety and minimal side effects of oral melatonin should encourage clinicians to consider melatonin therapy for patients with severe sepsis and septic shock.'
I think these studies and many more should encourage doctors to start using melatonin where it has already shown benefit such as these studies show for sepsis and multiple organ failure. The existing treatments are clearly insufficient for the task at hand as proven by the significant death rate and melatonin has shown significant benefit at dosing that is already known to be relatively safe.
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